Myocardial dysfunction

Myocardial function can be compromised after burn injury due to overload of the right heart and direct depression of contractility shown in isolated heart studies [156, 157]. Increases in the afterload of both the left and right heart result from SVR and PVR elevations. The left ventricle compensates and CO can be maintained with increased afterload by augmented adrenergic stimulation and increased myocardial oxygen extraction. The right ventricle has a minimal capacity to compensate for increased afterload. In severe cases, desynchronization of the right and left ventricles is deleteriously superimposed on a depressed myocardium [158]. Burn injury greater than 45% TBSA can produce intrinsic contractile defects. Several investigators reported that aggressive early and sustained fluid resuscitation failed to correct left ventricular contractile and compliance defects [157– 159]. These data suggest that hypovolemia is not the only mechanism underlying the myocardial defects observed with burn shock. Serum from patients failing to sustain a normal CO after thermal injury have exhibited a markedly negative inotropic effect on in vitro heart preparations, which is likely due to the previously described shock factor [160]. In other patients with large burn injuries and normal cardiac indices, little or no depressant activity was detected.

Sugi and collegues studied intact, chronically instrumented sheep after a 40% TBSA flame burn injury and smoke-inhalation injury, and smoke inhalation injury alone. They found that maximal contractile effects were reduced after either burn injury or inhalation injury [161, 162]. Horton and others demonstrated decreased left ventricular contractility in isolated, coronary perfused, guinea pig hearts harvested 24 hours after burn injury [163]. This dysfunction was more pronounced in hearts from aged animals and was not reversed by resuscitation with isotonic fluid. It was largely reversed by treatment with 4 mL/kg of hypertonic saline dextran (HSD), but only if administered during the initial 4 to 6 hours of resuscitation [164, 165]. These authors also effectively ameliorated the cardiac dysfunction of thermal injury with infusions of antioxidants, arginine and calcium channel blockers [166–168]. Cioffi et al. in a similar model observed persistent myocardial depression after burn when the animals

received no resuscitation after burn injury [169]. As opposed to most studies, Cioffi reported that immediate and full resuscitation totally reversed abnormalities of contraction and relaxation after burn injury. Murphy et al. showed elevations of a serum marker for cardiac injury, Troponin I, for patients with a TBSA > 18%, despite good cardiac indices [170]. Resuscitation and cardiac function studies emphasize the importance of early and adequate fluid therapy and suggest that functional myocardial depression after burn-injury may not occur in patients receiving prompt and adequate volume therapy.

The primary mechanisms by which burn shock alters myocardial cell membrane integrity and impairs mechanical function remain unclear. Oxygenderived free radicals may play a key causative role in the cell membrane dysfunction that is characteristic of several low-flow states. Horton et al. showed that a combination therapy of free radical scavengers SOD and catalase significantly improved burn-mediated defects in left ventricular contractility and relaxation when administered along with adequate fluid resuscitation (4 mL/kg per percent of burn). Antioxidant therapy did not alter the volume of fluid resuscitation required after burn injury [166].

Effects on the renal system

Diminished blood volume and cardiac output result in decreased renal blood flow and glomerular filtration rate. Other stress-induced hormones and mediators such as angiotensin, aldosterone, and vasopressin further reduce renal blood flow immediately after the injury. These effects result in oliguria, which, if left untreated will cause acute tubular necrosis and renal failure. Twenty years ago, acute renal failure in burn injuries was almost always fatal. Today newer techniques in dialysis became widely used to support the kidneys during recovery [171]. The latest reports indicate an 88 % mortality rate for severely burned adults and a 56 % mortality rate for severely burned children in whom renal failure develops in the post-burn period [172, 173]. Early resuscitation decreases risks of renal failure and improves the associated morbidity and mortality [174].

Fig. 1. Metabolic changes underlying insulin resistance post-burn. Marked and sustained increases in catecholamine, glucocorticoid, glucagon and cytokine secretion are thought to initiate the cascade of events leading to the acute hypermetabolic response to severe burn injury and oppose the anabolic effects of insulin. By enhancing adipose tissue lipolysis and skeletal muscle proteolysis, they increase gluconeogenic substrates, including glycerol, alanine and lactate, thus augmenting hepatic glucose production in burned patients. Catecholamine-mediated augmentation of hepatic glycogenolysis, as well as direct sympathetic stimulation of glycogen breakdown, further aggravates the hyperglycemia in response to stress. Catecholamines and cytokines, such as IL-1, IL-6, MCP-1 and TNF, have also been shown to impair glucose disposal via alterations of the insulin signaling pathway and GLUT-4 translocation, resulting in peripheral insulin resistance

border undergoes atrophic changes associated with vesiculation of microvilli and disruption of the terminal web actin filaments. These findings were most pronounced 18 hours after injury, which suggests that changes in the cytoskeleton, such as those associated with cell death by apoptosis, are processes involved in the changed gut mucosa [177]. Burn also causes reduced uptake of glucose and amino acids, decreased absorption of fatty acids, and reduction in brush border lipase activity [178]. These changes peak in the first several hours after burn and return to normal at 48 to 72 hours after injury, a timing that parallels mucosal atrophy.

Intestinal permeability to macromolecules, which are normally repelled by an intact mucosal barrier, increases after burn [179]. Intestinal permeability to polyethylene glycol 3350, lactulose, and mannitol increases after injury, correlating to the extent of the burn [180]. Gut permeability increases even further when burn wounds become infected. A study using fluorescent dextrans showed that larger molecules appeared to cross the mucosa between the cells, whereas the smaller molecules traversed the mucosa through the epithelial cells, presumably by pinocytosis and vesiculation [181]. Mucosal permeability also paralleled increases in gut epithelial apoptosis.

Changes in gut blood flow are related to changes in permeability. Intestinal blood flow was shown to decrease in animals, a change that was associated with increased gut permeability at 5 hours after burn [182]. This effect was abolished at 24 hours. Systolic hypotension has been shown to occur in the hours immediately after burn in animals with a 40% TBSA full-thickness injury. These animals showed an inverse correlation between blood flow and permeability to intact Candida [183].

The gastrointestinal response to burn is highlighted by mucosal atrophy, changes in digestive absorption, and increased intestinal permeability [175]. Atrophy of the small bowel mucosa occurs within 12 hours of injury in proportion to the burn size and is related to increased epithelial cell death by apoptosis [176]. The cytoskeleton of the mucosal brush

Burns cause a global depression in immune function, which is shown by prolonged allograft skin survival on burn wounds. Burned patients are then at great risk for a number of infectious complications, including bacterial wound infection, pneumonia, and fungal and viral infections. These susceptibilities and conditions are based on de-

pressed cellular function in all parts of the immune system, including activation and activity of neutrophils, macrophages, T lymphocytes, and B lymphocytes. With burns of more than 20 % TBSA, impairment of these immune functions is proportional to burn size.

Macrophage production after burn is diminished, which is related to the spontaneous elaboration of negative regulators of myeloid growth. This effect is enhanced by the presence of endotoxin and can be partially reversed with granulocyte col- ony-stimulating factor (G-CSF) treatment or inhibition of prostaglandin E2 [184]. Investigators have shown that G-CSF levels actually increase after severe burn. However, bone marrow G-CSF receptor expression is decreased, which may in part account for the immunodeficiency seen in burns [185]. Total neutrophil counts are initially increased after burn, a phenomenon that is related to a decrease in cell death by apoptosis [186]. However, neutrophils that are present are dysfunctional in terms of diapedesis, chemotaxis, and phagocytosis. These effects are explained, in part, by a deficiency in CD11 b/CD18 expression after inflammatory stimuli, decreased respiratory burst activity associated with a deficiency in p47-phox activity, and impaired actin mechanics related to neutrophil motile responses [187, 188]. After 48 to 72 hours, neutrophil counts decrease somewhat like macrophages with similar causes [185].

T-helper cell function is depressed after a severe burn that is associated with polarization from the interleukin-2 and interferon-(cytokine-based T-helper 1 (Th1) response toward the Th2 response [189]. The Th2 response is characterized by the production of interleukin-4 and interleukin-10. The Th1 response is important in cell-mediated immune defense, whereas the Th2 response is important in antibody responses to infection. As this polarization increases, so does the mortality rate [190]. Administration of interleukin-10 antibodies and growth hormone has partially reversed this response and improved mortality rate after burn in animals [191, 192]. Burn also impairs cytotoxic T- lymphocyte activity as a function of burn size, thus increasing the risk of infection, particularly from fungi and viruses. Early burn wound excision improves cytotoxic T-cell activity [193].

Summary and conclusion

Thermal injury results in massive fluid shifts from the circulating plasma into the interstitial fluid space causing hypovolemia and swelling of the burned skin. When burn injury exceeds 20–30% TBSA there is minimal edema generation in non-injured tissues and organs. The Starling-forces change to favor fluid extravasation from blood to tissue. Rapid edema formation is predominating from the development of strongly negative interstitial fluid pressure (imbibition pressure) and to a lesser degree by an increase in microvascular pressure and permeability.

Secondary to the thermal insult there is release of inflammatory mediators and stress hormones. Circulating mediators deleteriously increase microvascular permeability and alter cellular membrane function by which water and sodium enter cells. Circulating mediators also favor renal conservation of water and salt, impair cardiac contractility and cause vasoconstrictors, which further aggravates ischemia from combined hypovolemia and cardiac dysfunction. The end result of this complex chain of events is decreased intravascular volume, increased systemic vascular resistance, decreased cardiac output, endorgan ischemia, and metabolic acidosis. Early excision of the devitalized tissue appears to reduce the local and systemic effects of mediators released from burned tissue, thus reducing the progressive pathophysiologic derangements. Without early and full resuscitation therapy these derangements can result in acute renal failure, vascular ischemia, cardiovascular collapse, and death.

Edema in both the burn wound and particularly in the non-injured soft tissue is increased by resuscitation. Edema is a serious complication, which likely contributes to decreased tissue oxygen diffusion and further ischemic insult to already damaged cells with compromised blood flow increasing the risk of infection. Research should continue to focus on methods to ameliorate the severe edema and vasoconstriction that exacerbate tissue ischemia. The success of this research will require identification of key circulatory factors that alter capillary permeability, cause vasoconstriction, depolarize cellular membranes, and depress myocardial function. Hopefully, methods to prevent the release and to block the activity of specific mediators can be further developed in order to

reduce the morbidity and mortality rates of burn shock. The profound and overall metabolic alterations post-burn associated with persistent changes in glucose metabolism and impaired insulin sensitivity also significantly contribute to adverse outcome of this patient population and constitute another challenge for future therapeutic approaches of this unique patient population.

References

[1]Nguyen TT, Gilpin DA, Meyer NA et al (1996) Current treatment of severely burned patients. Ann Surg 223(1): 14–25

[2]Brigham PA, McLoughlin E (1996) Burn incidence and medical care use in the United States: estimates, trends, and data sources. J Burn Care Rehabil 17(2): 95–107

[3]Wolf S (2007) Critical care in the severely burned: organ support and management of complications. In: Herndon DN (ed) Total burn care, 3rd edn. Saunders Elsevier, London

[4]Vo LT, Papworth GD, Delaney PM et al (1998) A study of vascular response to thermal injury on hairless mice by fibre optic confocal imaging, laser doppler flowmetry and conventional histology. Burns 24(4): 319–324

[5]Heggers JP, Loy GL, Robson MC et al (1980) Histological demonstration of prostaglandins and thromboxanes in burned tissue. J Surg Res 28(2): 110–117

[6]Herndon DN, Abston S, Stein MD (1984) Increased thromboxane B2 levels in the plasma of burned and septic burned patients. Surg Gynecol Obstet 159(3): 210–213

[7]Morykwas MJ, David LR, Schneider AM et al (1999) Use of subatmospheric pressure to prevent progression of partial-thickness burns in a swine model. J Burn Care Rehabil 20(1 Pt 1): 15–21

[8]Nwariaku FE, Sikes PJ, Lightfoot E et al (1996) Effect of a bradykinin antagonist on the local inflammatory response following thermal injury. Burns 22(4): 324–327

[9]Chappell VL, LaGrone L, Mileski WJ (1999) Inhibition of leukocyte-mediated tissue destruction by synthetic fibronectin peptide (Trp-9-Tyr). J Burn Care Rehabil 20(6): 505–510

[10]Holland AJ, Martin HC, Cass DT (2002) Laser Doppler imaging prediction of burn wound outcome in children. Burns 28(1): 11–17

[11]Cockshott WP (1956) The history of the treatment of burns. Surg Cynecol Obstet 102: 116–124

[12]Haynes BW (1987) The history of burn care. In: Boswick JAJ (ed) The art and science of burn care. Aspen Publ, Rockville, MD, pp 3–9

[13]Underhill FP, Carrington GL, Kapsinov R et al (1923) Blood concentration changes in extensive superficial burns, and their significance for systemic treatment. Arch Intern Med 32: 31–39

[14]Cope O, Moore FD (1947) The redistribution of body water and fluid therapy of the burned patient. Ann Surg 126: 1010–1045

[15]Youn YK, LaLonde C, Demling R (1992) The role of mediators in the response to thermal injury. World J Surg 16(1): 30–36

[16]Aulick LH, Wilmore DW, Mason AD et al (1977) Influence of the burn wound on peripheral circulation in thermally injured patients. Am J Physiol 233:H520–526

[17]Settle JAD (1982) Fluid therapy in burns. J Roy Soc Med 1(75): 7–11

[18]Demling RH (1987) Fluid replacement in burned patients. Surg Clin North Am 67: 15–30

[19]Demling RH, Will JA, Belzer FO (1978) Effect of major thermal injury on the pulmonary microcirculation. Surgery 83(6): 746–751

[20]Baxter CR (1974) Fluid volume and electrolyte changes

of the early postburn period. Clin Plast Surg 1(4): 693–709

[21]Baxter CR, Cook WA, Shires GT (1966) Serum myocardial depressant factor of burn shock. Surg Forum

17:1–3

[22]Hilton JG, Marullo DS (1986) Effects of thermal trauma on cardiac force of contraction. Burns Incl Therm Inj

12:167–171

[23]Clark WR (1990) Death due to thermal trauma. In: Dolecek R, Brizio-Molteni L, Molteni A, Traber D (eds) Endocrinology of thermal trauma. Lea & Febiger, Philadelphia, PA, pp 6–27

[24]Lund T, Reed RK (1986) Acute hemodynamic effects of thermal skin injury in the rat. Circ Shock 20: 105–114

[25]Arturson G (1961) Pathophysiological aspects of the burn syndrome. Acta Chir Scand 274[Suppl 1]: $2–135

[26]Leape LL (1972) Kinetics of burn edema formation in primates. Ann Surg 176: 223–226

[27]Cioffi WG, Jr, Vaughan GM, Heironimus JD et al (1991) Dissociation of blood volume and flow in regulation of salt and water balance in burn patients. Ann Surg 214(3): 213–218; discussion 218–220

[28]Demling RH, Mazess RB, Witt RM et al (1978) The study of burn wound edema using dichromatic absorptiometry. J Trauma 18: 124–128

[29]Lund T, Wiig H, Reed RK (1988) Acute postburn edema: Role of strongly negative interstitial fluid pressure. Am J Physiol 255:H1069

[30]Onarheim H, Lund T, Reed R (1989) Thermal skin injury: II. Effects on edema formation and albumin extravasation of fluid resuscitation with lactated Ringer’s, plasma, and hypertonic saline (2,400 mosmol/l) in the rat. Circ Shock 27(1): 25–37

[31]Arturson G, Jakobsson OR (1985) Oedema measurements in a standard burn model. Burns 1: 1–7

[32]Leape LL (1968) Early burn wound changes. J Pediatr Surg 3: 292–299

[33]Leape LL (1970) Initial changes in burns: tissue changes in burned and unburned skin of rhesus monkeys. J Trauma 10: 488–492

[34]Shires GT, Cunningham Jr JN, Baker CRF et al (1972) Alterations in cellular membrane dysfunction during hemorrhagic shock in primates. Ann Surg 176(3): 288–295

[35]Nakayama S, Kramer GC, Carlsen RC et al (1984) Amiloride blocks membrane potential depolarization in rat skeletal muscle during hemorrhagic shock (abstract). Circ Shock 13: 106–107

[36]Arango A, Illner H, Shires GT (1976) Roles of ischemia in the induction of changes in cell membrane during hemorrhagic shock. J Surg Res 20(5): 473–476

[37]Holliday RL, Illner HP, Shires GT (1981) Liver cell membrane alterations during hemorrhagic shock in the rat. J Surg Res 31: 506–515

[38]Mazzoni MC, Borgstrom P, Intaglietta M et al (1989) Lumenal narrowing and endothelial cell swelling in skeletal muscle capillaries during hemorrhagic shock. Circ Shock 29(1): 27–39

[39]Garcia NM, Horton JW (1994) L-arginine improves resting cardiac transmembrane potential after burn injury. Shock 1(5): 354–358

[40]Button B, Baker RD, Vertrees RA et al (2001) Quantitative assessment of a circulating depolarizing factor in shock. Shock 15(3): 239–244

[41]Evans JA, Darlington DN, Gann DS (1991) A circulating factor(s) mediates cell depolarization in hemorrhagic shock. Ann Surg 213(6): 549–557

[42]Trunkey DD, Illner H, Arango A et al (1974) Changes in cell membrane function following shock and crossperfusion. Surg Forum 25: 1–3

[43]Brown JM, Grosso MA, Moore EE (1990) Hypertonic saline and dextran: Impact on cardiac function in the isolated rat heart. J Trauma 30: 646–651

[44]Evans JA, Massoglia G, Sutherland B et al (1993) Molecular properties of hemorrhagic shock factor (abstract). Biophys J 64:A384

[45]Anggard E, Jonsson CE (1971) Efflux of prostaglandins in lymph from scalded tissue. Acta Physiol Scand 81(4): 440–447

[46]Holliman CJ, Meuleman TR, Larsen KR et al (1983) The effect of ketanserin, a specific serotonin antagonist, on burn shock hemodynamic parameters in a porcine burn model. J Trauma 23(10): 867–871

[47]Majno G, Palade GE (1961) Studies on inflammation. 1. The effect of histamine and serotonin on vascular permeability: an electron microscopic study. J Biophys Biochem Cytol 11: 571–605

[48]Majno G, Shea SM, Leventhal M (1969) Endothelial contraction induced by histamine-type mediators: an electron microscopic study. J Cell Biol 42(3): 647–672

[49]Wilmore DW, Long JM, Mason AD, Jr et al (1974) Catecholamines: mediator of the hypermetabolic response to thermal injury. Ann Surg 180(4): 653–669

[50]Goodman-Gilman A, Rall TW, Nies AS et al (1990) The pharmacological basis of therapeutics. Pergamon Press, New York

[51]Friedl HS, Till GO, Tentz O et al (1989) Roles of histamine, complement and xanthine oxidase in thermal injury of skin. Am J Pathol 135(1): 203–217

[52]Boykin Jr JV, Manson NH (1987) Mechanisms of cimetidine protection following thermal injury. Am J Med 83(6A):76–81

[53]Till GO, Guilds LS, Mahrougui M et al (1989) Role of xanthine oxidase in thermal injury of skin. Am J Pathol 135(1): 195–202

[54]Tanaka H, Wada T, Simazaki S et al (1991) Effects of cimetidine on fluid requirement during resuscitation of third-degree burns. J Burn Care Rehabil 12(5): 425–429

[55]Harms B, Bodai B, Demling R (1981) Prostaglandin release and altered microvascular integrity after burn injury. J Surg Res 31: 27–28

[56]Anggard E, Jonsson CE (1971) Efflux of prostaglandins in lymph from scalded tissue. Acta Physiol Scand 81: 440–443

[57]Arturson G (1981) Anti-inflammatory drugs and burn edema formation. In: May R, Dogo G (eds) Care of the burn wound. Karger, Basel, pp 21–24

[58]Arturson G, Hamberg M, Jonsson CE (1973) Prostaglandins in human burn blister fluid. Acta Physiol Scand

87:27–36

[59]LaLonde C, Knox J, Daryani R (1991) Topical flurbiprofen decreases burn wound-induced hypermetabolism and systemic lipid peroxidation. Surgery 109: 645–651

[60]Huang YS, Li A, Yang ZC (1990) Roles of thromboxane and its inhibitor anisodamine in burn shock. Burns

4:249–253

[61]Heggers JP, Loy GL, Robson MC et al (1980) Histological demonstration of prostaglandins and thromboxanes in burned tissue. J Surg Res 28: 11–15

[62]Heggers JP, Robson MC, Zachary LS (1985) Thromboxane inhibitors for the prevention of progressive dermal ischemia due to thermal injury. J Burn Care Rehabil

6:46–48

[63]Demling RH, LaLonde C (1987) Topical ibuprofen decreases early postburn edema. Surgery 5: 857–861

[64]LaLonde C, Demling RH (1989) Inhibition of thromboxane synthetase accentuates hemodynamic instability and burn edema in the anesthetized sheep model. Surgery 5: 638–644

[65]Jacobsen S, Waaler BG (1966) The effect of scalding on the content of kininogen and kininase in limb lymph. Br J Pharmacol 27: 222–229

[66]Hafner JA, Fritz H (1990) Balance antiinflammation: the combined application of a PAF inhibitor and a cyclooxygenase inhibitor blocks the inflammatory takeoff after burns. Int J Tissue React 12: 203

[67]Carvajal H, Linares H, Brouhard B (1975) Effect of antihistamine, antiserotonin, and ganglionic blocking agents upon increased capillary permeability following burn edema. J Trauma 15: 969–975

[68]Ferrara JJ, Westervelt CL, Kukuy EL et al (1996) Burn edema reduction by methysergide is not due to control of regional vasodilation. J Surg Res 61(1): 11–16

[69]Zhang XJ, Irtun O, Zheng Y et al (2000) Methysergide reduces nonnutritive blood flow in normal and scalded skin. Am J Physiol 278(3):E452–461

[70]Wilmore DW, Long JM, Mason AD et al (1974) Catecholamines: mediator of the hypermetabolic response to thermal injury. Ann Surg 80: 653–659

[71]Hilton JG (1984) Effects of sodium nitroprusside on thermal trauma depressed cardiac output in the anesthesized dog. Burns Incl Therm Inj 10: 318–322

[72]McCord J, Fridovieh I (1978) The biology and pathology of oxygen radicals. Ann lntern Med 89: 122–127

[73]Demling RH, LaLonde C (1990) Early postburn lipid peroxidation: effect of ibuprofen and allopurinol. Surgery 107: 85–93

[74]Demling R, Lalonde C, Knox J et al (1991) Fluid resuscitation with deferoxamine prevents systemic burn-in- duced oxidant injury. J Trauma 31(4): 538–543

[75]Rawlingson A, Greenacre SA, Brain SD (2000) Generation of peroxynitrite in localised, moderate temperature burns. Burns 26(3): 223–227

[76]Lindblom L, Cassuto J, Yregard L et al (2000) Importance of nitric oxide in the regulation of burn oedema, proteinuria and urine output. Burns 26(1): 13–17

[77]Lindblom L, Cassuto J, Yregard L et al (2000) Role of nitric oxide in the control of burn perfusion. Burns 26(1): 19–23

[78]Slater TF, Benedetto C (1979) Free radical reactions in relation to lipid peroxidation, inflamnation and prostaglandin metabolism. In: Berti F, Veto G (eds) The prostaglandin system. Plenum Press, New York, pp 109–126

[79]McCord JM (1979) Oxygen-derived free radicals in post ischemic tissue injury. N Engl J Med 312: 159–163

[80]Tanaka H, Matsuda H, Shimazaki S et al (1997) Reduced resuscitation fluid volume for second-degree burns with delayed initiation of ascorbic acid therapy. Arch Surg 132(2): 158–161

[81]Tanaka H, Lund T, Wiig H et al (1999) High dose vitamin C counteracts the negative interstitial fluid hydrostatic pressure and early edema generation in thermally injured rats. Burns 25(7): 569–574

[82]Dubick MA, Williams CA, Elgjo GI et al (2005) High dose vitamin C infusion reduces fluid requirements in the resuscitation of burn injured in sheep. Shock 24(2): 139–144

[83]Tanaka H, Matsuda T, Yukioka T et al (1996) High dose vitamin C reduces resuscitation fluid volume in severely burned patients. Proceedings of the American Burn Association 28: 77

[84]Fischer SF, Bone HG, Powell WC et al (1997) Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis. Crit Care 25(9): 1151–1159

[85]Ono I, Gunji H, Hasegawa T et al (1993) Effects of a platelet activating factor antagonist on edema formation following burns. Burns 3: 202–207

[86]Fink MP (1991) Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis. Crit Care Med 19(5): 627–641

[87]Cui X, Sheng Z, Guo Z (1998) Mechanisms of early gas- tro-intestinal ischemia after burn: hemodynamic and hemorrheologic features [Chinese]. Chin J Plast Surg Burns 14(4): 262–265

[88]Crum RL, Dominie W, Hansbrough JF (1990) Cardiovaseular and neuroburnoral responses following burn injury. Arch Surg 125: 1065–1070

[89]Sun K, Gong A, Wang CH et al (1990) Effect of peripheral injection of arginine vasopressin and its receptor antagonist on burn shock in the rat. Neuropeptides

1:17–20

[90]Kiang JG, Wei-E T (1987) Corticotropin-releasing factor inhibits thermal injury. J Pharmacol Exp Ther 2: 517–520

[91]Michie DD, RS G, Mason Jr AD (1963) Effects of hydralazine and high molecular weight dextran upon the circulatory responses to severe thermal burns. Circ Res

13:46–48

[92]Hart DW, Wolf SE, Mlcak R et al (2000) Persistence of muscle catabolism after severe burn. Surgery 128(2): 312–319

[93]Mlcak RP, Jeschke MG, Barrow RE et al (2006) The influence of age and gender on resting energy expenditure in severely burned children. Ann Surg 244(1): 121–130

[94]Przkora R, Barrow RE, Jeschke MG et al (2006) Body composition changes with time in pediatric burn patients. J Trauma 60(5): 968–971

[95]Dolecek R (1989) Endocrine changes after burn trau- ma–a review. Keio J Med 38(3): 262–276

[96]Jeffries MK, Vance ML (1992) Growth hormone and cortisol secretion in patients with burn injury. J Burn Care Rehabil 13(4): 391–395

[97]Klein GL, Bi LX, Sherrard DJ et al (2004) Evidence supporting a role of glucocorticoids in short-term bone loss in burned children. Osteoporos Int 15(6): 468–474

[98]Goodall M, Stone C, Haynes BW, Jr (1957) Urinary output of adrenaline and noradrenaline in severe thermal burns. Ann Surg 145(4): 479–487

[99]Coombes EJ, Batstone GF (1982) Urine cortisol levels after burn injury. Burns Incl Therm Inj 8(5): 333–337

[100]Norbury WB, Herndon DN (2007) Modulation of the hypermetabolic response after burn injury. In: Herndon DN (ed) Total burn care, 3rd edn. Saunders & Elsevier, New York, pp 420–433

[101]Sheridan RL (2001) A great constitutional disturbance. N Engl J Med 345(17): 1271–1272

[102]Pereira C, Murphy K, Jeschke M et al (2005) Post burn muscle wasting and the effects of treatments. Int J Biochem Cell Biol 37(10): 1948–1961

[103]Wolfe RR (1981) Review: acute versus chronic response to burn injury. Circ Shock 8(1): 105–115

[104]Cuthbertson DP, Angeles Valero Zanuy MA, Leon Sanz ML (2001) Post-shock metabolic response. 1942. Nutr Hosp 16(5): 175–182

[105]Galster AD, Bier DM, Cryer PE et al (1984) Plasma palmitate turnover in subjects with thermal injury. J Trauma 24(11): 938–945

[106]Cree MG, Aarsland A, Herndon DN et al (2007)Role of fat metabolism in burn trauma-induced skeletal muscle insulin resistance. Crit Care Med35[9 Suppl]: S476–483

[107]Childs C, Heath DF, Little RA et al (1990) Glucose metabolism in children during the first day after burn injury. Arch Emerg Med7(3): 135–147

[108]Jeschke MG, Mlcak RP, Finnerty CC et al (2007) Burn size determines the inflammatory and hypermetabolic response. Crit Care 11(4):R90

[109]Gauglitz GG, Herndon DN, Kulp GA et al (2009) Abnormal insulin sensitivity persists up to three years in pediatric patients post-burn. J Clin Endocrinol Metab 94(5): 1656–1664

[110]Herndon DN, Tompkins RG (2004) Support of the metabolic response to burn injury. Lancet 363(9424): 1895–1902

[111]Jeschke MG, Chinkes DL, Finnerty CC et al (2008) Pathophysiologic response to severe burn injury. Ann Surg 248(3): 387–401

[112]Wilmore DW, Aulick LH, Pruitt BA, Jr (1978) Metabolism during the hypermetabolic phase of thermal injury. Adv Surg 12: 193–225

[113]Cuthbertson DP, Angeles Valero Zanuy MA, Leon Sanz ML (2001) Post-shock metabolic response. 1942. Nutr Hosp 16(5): 176–182; discussion 175–176

[114]Herndon DN, Hart DW, Wolf SE et al (2001) Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 345(17): 1223–1229

[115]Baron PW, Barrow RE, Pierre EJ et al (1997) Prolonged use of propranolol safely decreases cardiac work in burned children. J Burn Care Rehabil 18(3): 223–227

[116]Minifee PK, Barrow RE, Abston S et al (1989) Improved myocardial oxygen utilization following propranolol infusion in adolescents with postburn hypermetabolism. J Pediatr Surg 24(8): 806–810; discussion 810–801

[117]Bessey PQ, Jiang ZM, Johnson DJ et al (1989) Posttraumatic skeletal muscle proteolysis: the role of the hormonal environment. World J Surg 13(4): 465–470; discussion 471

[118]Hart DW, Wolf SE, Chinkes DL et al (2000) Determinants of skeletal muscle catabolism after severe burn. Ann Surg 232(4): 455–465

[119]Chang DW, DeSanti L, Demling RH (1998) Anticatabolic and anabolic strategies in critical illness: a review of current treatment modalities. Shock 10(3): 155–160

[120]Newsome TW, Mason AD, Jr, Pruitt BA, Jr (1973) Weight loss following thermal injury. Ann Surg 178(2): 215–217

[121]Jahoor F, Desai M, Herndon DN et al (1988) Dynamics of the protein metabolic response to burn injury. Metabolism 37(4): 330–337

[122]Kinney JM, Long CL, Gump FE et al (1968) Tissue composition of weight loss in surgical patients. I. Elective operation. Ann Surg 168(3): 459–474

[123]Rutan RL, Herndon DN (1990) Growth delay in postburn pediatric patients. Arch Surg 125(3): 392–395

[124]Wolfe RR, Goodenough RD, Burke JF et al (1983) Response of protein and urea kinetics in burn patients to different levels of protein intake. Ann Surg 197(2): 163–171

[125]Wolfe RR, Herndon DN, Jahoor F et al (1987) Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 317(7): 403–408

[126]Yu YM, Tompkins RG, Ryan CM et al (1999) The metabolic basis of the increase of the increase in energy expenditure in severely burned patients. JPEN J Parenter Enteral Nutr 23(3): 160–168

[127]Gauglitz GG, Halder S, Boehning DF et al (2010) Postburn hepatic insulin resistance is associated with Er stress. Shock 33(3): 299–305

[128]Gauglitz GG, Finnerty CC, Herndon DN et al (2008) Are serum cytokines early predictors for the outcome of burn patients with inhalation injuries who do not survive? Crit Care 12(3):R81

[129]Gauglitz GG, Toliver-Kinsky TE, Williams FN et al (2010) Insulin increases resistance to burn wound in- fection-associated sepsis. Crit Care Med 38(1): 202–208

[130]Wilmore DW, Mason AD, Jr, Pruitt BA, Jr (1976) Insulin response to glucose in hypermetabolic burn patients. Ann Surg 183(3): 314–320

[131]Gearhart MM, Parbhoo SK (2006) Hyperglycemia in the critically ill patient. AACN Clin Issues 17(1): 50–55

[132]Robinson LE, van Soeren MH (2004) Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control. AACN Clin Issues 15(1): 45–62

[133]Khani S, Tayek JA (2001) Cortisol increases gluconeogenesis in humans: its role in the metabolic syndrome. Clin Sci (Lond) 101(6): 739–747

[134]Gore DC, Jahoor F, Wolfe RR et al (1993) Acute response of human muscle protein to catabolic hormones. Ann Surg 218(5): 679–684

[135]Carlson GL (2001) Insulin resistance and glucose-in- duced thermogenesis in critical illness. Proc Nutr Soc 60(3): 381–388

[136]Wolfe RR, Durkot MJ, Allsop JR et al (1979) Glucose metabolism in severely burned patients. Metabolism 28(10): 1031–1039

[137]Cree MG, Zwetsloot JJ, Herndon DN et al (2007) Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. Ann Surg 245(2): 214–221

[138]Hunt DG, Ivy JL (2002) Epinephrine inhibits insulinstimulated muscle glucose transport. J Appl Physiol 93(5): 1638–1643

[139]Gustavson SM, Chu CA, Nishizawa M et al (2003) Interaction of glucagon and epinephrine in the control of hepatic glucose production in the conscious dog. Am J Physiol Endocrinol Metab 284(4):E695–707

[140]Mastorakos G, Chrousos GP, Weber JS (1993) Recombinant interleukin-6 activates the hypothalamic-pitui- tary-adrenal axis in humans. J Clin Endocrinol Metab 77(6): 1690–1694

[141]Lang CH, Dobrescu C, Bagby GJ (1992) Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130(1): 43–52

[142]Akita S, Akino K, Ren SG et al (2006) Elevated circulating leukemia inhibitory factor in patients with extensive burns. J Burn Care Res 27(2): 221–225

[143]Fan J, Li YH, Wojnar MM et al (1996) Endotoxin-in- duced alterations in insulin-stimulated phosphorylation of insulin receptor, IRS-1, and MAP kinase in skeletal muscle. Shock 6(3): 164–170

[144]del Aguila LF, Claffey KP, Kirwan JP (1999) TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol 276(5 Pt 1): E849–855

[145]Sell H, Dietze-Schroeder D, Kaiser U et al (2006) Monocyte chemotactic protein-1 is a potential player in the negative cross-talk between adipose tissue and skeletal muscle. Endocrinology 147(5): 2458–2467

[146]Baracos V, Rodemann HP, Dinarello CA et al (1983) Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (inter- leukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med 308(10): 553–558

[147]Saffle JR, Graves C (2007) Nutritional support of the burned patient. In: Herndon DN (ed) Total burn care, 3rd edn. Saunders Elsevier, London, pp 398–419

[148]DeFronzo RA, Jacot E, Jequier E et al (1981) The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30(12): 1000–1007

[149]Flakoll PJ, Hill JO, Abumrad NN (1993) Acute hyperglycemia enhances proteolysis in normal man. Am J Physiol 265(5 Pt 1): E715–721

[150]McClave SA, Snider HL (1992) Use of indirect calorimetry in clinical nutrition. Nutr Clin Pract 7(5): 207–221

[151]Arora NS, Rochester DF (1982) Respiratory muscle strength and maximal voluntary ventilation in undernourished patients. Am Rev Respir Dis 126(1): 5–8

[152]Greenhalgh DG, Saffle JR, Holmes JHt et al (2007) American Burn Association consensus conference to define sepsis and infection in burns. J Burn Care Res 28(6): 776–790

[153]Williams FN, Herndon DN, Hawkins HK et al (2009) The leading causes of death after burn injury in a single pediatric burn center. Crit Care 13(6): R183

[154]Murray CK, Loo FL, Hospenthal DR et al (2008) Incidence of systemic fungal infection and related mortality following severe burns. Burns 34(8): 1108–1112

[155]Pruitt BA, Jr, McManus AT, Kim SH et al (1998) Burn wound infections: current status. World J Surg 22(2): 135–145

[156]Martyn JAJ, Wilson RS, Burke JF (1986) Right ventricular function and pulmonary hemodynamics during dopamine infusion in burned patients. Chest 89: 357–360

[157]Adams HR, Baxter CR, Izenberg SD (1984) Decreased contractility and compliance of the left ventricle as complications of thermal trauma. Am Heart J 108(6): 1477–1487

[158]Merriman Jr TW, Jackson R (1962) Myocardial function following thermal injury. Circ Res 11: 66–69

[159]Horton JW, White J, Baxter CR (1987) Aging alters myocardial response during resuscitation in burn shock. Surg Forum 38: 249–251

[160]Baxter CR, Shires GT (1968) Physiological response to crystalloid resuscitation of severe burns. Ann NY Acad Sci 150: 874–894

[161]Sugi K, Newald J, Traber LD (1988) Smoke inhalation injury causes myocardial depression in sheep. Anesthesiology 69: A 111

[162]Sugi K, Theissen JL, Traber LD et al (1990) Impact of carbon monoxide on cardiopulmonary dysfunction after smoke inhalation injury. Circ Res 66: 69–75

[163]Horton JW, Baxter CR, White J (1989) Differences in cardiac responses to resuscitation from burn shock. Surgery, Gynecology & Obstetrics 168(3): 201–213

[164]Horton JW, White DJ, Baxter CR (1990) Hypertonic saline dextran resuscitation of thermal injury. Ann Surg 211(3): 301–311

[165]Horton JW, Shite J, Hunt JL (1995) Delayed hypertonic saline dextran administration after burn injury. J Trauma 38(2): 281–286

[166]Horton JW, White J, Baxter CR (1988) The role of oxygen derived free radicles in burn-induced myocardial contractile depression. J Burn Care Rehab 9(6): 589–598

[167]Horton JW, Garcia NM, White J et al (1995) Postburn cardiac contractile function and biochemical markers of postburn cardiac injury. J Am Coll Surgeons 181: 289–298

[168]Horton JW, White J, Maass D et al (1998) Arginine in burn injury improves cardiac performance and prevents bacterial translocation. J Appl Physiol 84(2): 695–702

[169]Cioffi WG, DeMeules JE, Gameili RL (1986) The effects of burn injury and fluid resuscitation on cardiac function in vitro. J Trauma 26: 638–643

[170]Murphy JT, Horton JW, Purdue GF et al (1997) Evaluation of troponin-I as an indicator of cardiac dysfunction following thermal injury. Burn Care Rehabil 45(4): 700–704

[171]Leblanc M, Thibeault Y, Querin S (1997) Continuous haemofiltration and haemodiafiltration for acute renal failure in severely burned patients. Burns 23(2): 160–165

[172]Chrysopoulo MT, Jeschke MG, Dziewulski P et al (1999) Acute renal dysfunction in severely burned adults. J Trauma 46(1): 141–144

[173]Jeschke MG, Barrow RE, Wolf SE et al (1998) Mortality in burned children with acute renal failure. Arch Surg 133(7): 752–756

[174]Wolf SE, Rose JK, Desai MH et al (1997) Mortality determinants in massive pediatric burns. An analysis of 103 children with > or = 80% TBSA burns ( > or = 70% fullthickness). Ann Surg 225(5): 554–565; discussion 565–559

[175]LeVoyer T, Cioffi WG, Jr, Pratt L et al (1992) Alterations in intestinal permeability after thermal injury. Arch Surg 127(1): 26–29; discussion 29–30

[176]Wolf SE, Ikeda H, Matin S et al (1999) Cutaneous burn increases apoptosis in the gut epithelium of mice. J Am Coll Surg 188(1): 10–16

[177]Ezzell RM, Carter EA, Yarmush ML et al (1993) Thermal injury-induced changes in the rat intestine brush border cytoskeleton. Surgery 114(3): 591–597

[178]Carter EA, Udall JN, Kirkham SE et al (1986) Thermal injury and gastrointestinal function. I. Small intestinal nutrient absorption and DNA synthesis. J Burn Care Rehabil 7(6): 469–474

[179]Deitch EA, Rutan R, Waymack JP (1996) Trauma, shock, and gut translocation. New Horiz 4(2): 289–299

[180]Deitch EA (1990) Intestinal permeability is increased in burn patients shortly after injury. Surgery 107(4): 411–416

[181]Berthiaume F, Ezzell RM, Toner M et al (1994) Transport of fluorescent dextrans across the rat ileum after cutaneous thermal injury. Crit Care Med 22(3): 455–464

[182]Horton JW (1994) Bacterial translocation after burn injury: the contribution of ischemia and permeability changes. Shock 1(4): 286–290

[183]Gianotti L, Alexander JW, Fukushima R et al (1993) Translocation of Candida albicans is related to the

blood flow of individual intestinal villi. Circ Shock 40(4): 250–257

[184]Gamelli RL, He LK, Liu H et al (1998) Burn wound in- fection-induced myeloid suppression: the role of prostaglandin E2, elevated adenylate cyclase, and cyclic adenosine monophosphate. J Trauma 44(3): 469–474

[185]Shoup M, Weisenberger JM, Wang JL et al (1998) Mechanisms of neutropenia involving myeloid maturation arrest in burn sepsis. Ann Surg 228(1): 112–122

[186]Chitnis D, Dickerson C, Munster AM et al (1996) Inhibition of apoptosis in polymorphonuclear neutrophils from burn patients. J Leukoc Biol 59(6): 835–839

[187]Rosenthal J, Thurman GW, Cusack N et al (1996) Neutrophils from patients after burn injury express a deficiency of the oxidase components p47-phox and p67-phox. Blood 88(11): 4321–4329

[188]Vindenes HA, Bjerknes R (1997) Impaired actin polymerization and depolymerization in neutrophils from patients with thermal injury. Burns 23(2): 131–136

[189]Hunt JP, Hunter CT, Brownstein MR et al (1998) The effector component of the cytotoxic T-lymphocyte response has a biphasic pattern after burn injury. J Surg Res 80(2): 243–251

[190]Zedler S, Bone RC, Baue AE et al (1999) T-cell reactivity and its predictive role in immunosuppression after burns. Crit Care Med 27(1): 66–72

[191]Kelly JL, Lyons A, Soberg CC et al (1997) Anti-interleu- kin-10 antibody restores burn-induced defects in T-cell function. Surgery 122(2): 146–152

[192]Takagi K, Suzuki F, Barrow RE et al (1998) Recombinant human growth hormone modulates Th1 and Th2 cytokine response in burned mice. Ann Surg 228(1): 106–111

[193]Hultman CS, Yamamoto H, deSerres S et al (1997) Early but not late burn wound excision partially restores vir- al-specific T lymphocyte cytotoxicity. J Trauma 43(3): 441–447

Correspondence: Gerd G. Gauglitz, M.D., MMS, Department of Dermatology and Allergology, Ludwig Maximilians University, Frauenlobstraße 9 –11, 80337 Munich, Germany, E-mail: gerd.gauglitz@med.uni-muenchen.de