- Open Access
Bench-to-bedside review: Burn-induced cerebral inflammation – a neglected entity?
Critical Care volume 13, Article number: 215 (2009)
Severe burn injury remains a major burden on patients and healthcare systems. Following severe burns, the injured tissues mount a local inflammatory response aiming to restore homeostasis. With excessive burn load, the immune response becomes disproportionate and patients may develop an overshooting systemic inflammatory response, compromising multiple physiological barriers in the lung, kidney, liver, and brain. If the blood–brain barrier is breached, systemic inflammatory molecules and phagocytes readily enter the brain and activate sessile cells of the central nervous system. Copious amounts of reactive oxygen species, reactive nitrogen species, proteases, cytokines/chemokines, and complement proteins are being released by these inflammatory cells, resulting in additional neuronal damage and life-threatening cerebral edema. Despite the correlation between cerebral complications in severe burn victims with mortality, burn-induced neuroinflammation continues to fly under the radar as an underestimated entity in the critically ill burn patient. In this paper, we illustrate the molecular events leading to blood–brain barrier breakdown, with a focus on the subsequent neuroinflammatory changes leading to cerebral edema in patients with severe burns.
Severe burn injury remains a significant health issue for society and a life-threatening event for the victim. Each year, more than 1.2 million people in the United States alone suffer burn injuries ; some 100,000 of these patients are hospitalized, accounting for a total of 2 million hospital days . Thermal injuries mainly affect patients younger than 50 years of age  and remain one of the leading causes of childhood deaths, according to the Children's Burn Awareness Program. While the overall mortality has been reported to be 5%, it rapidly increases with advancing age and burn size up to 96% . Most fatalities (65%) seem to be linked to burn-induced multiple organ failure, and 93% of burn patients present with clinical signs of the systemic inflammatory response syndrome before succumbing to their injuries .
One of the critically impaired yet frequently overlooked organs in severe burn victims is the brain, despite the fact that cerebral complications in severe burn victims have been shown to highly correlate with mortality . Hypoxic brain injury has been found as a primary cause of death in up to 10% of severe burn patients in an age-dependent manner . The present review focuses on the neuroinflammatory changes occurring after severe burn injury and on the molecular mechanisms involved in their pathogenesis.
Breakdown of the blood–brain barrier and development of cerebral edema
Under physiological conditions, the blood–brain barrier (BBB) tightly regulates the molecules that enter the brain tissue. During the systemic inflammatory response syndrome, sepsis, or severe burn injury, however, this physical barrier between the systemic circulation and the cerebral parenchyma can be seriously compromised.
When peripheral tissues are exposed to severe burns, they release a plethora of proinflammatory mediators, cytotoxic proteases, reactive nitrogen species, and reactive oxygen species. These mediators then cause systemic reactions, such as fever [7, 8], hypogeusia , hyperalgesia [10, 11], severe burn-induced anorexia (wasting syndrome) [9, 12], hormonal alterations of the hypothalamic–pituitary–adrenal axis, and changes of endogenous catecholamine levels [13, 14]. All of these inflammatory changes attempt to restore equilibrium in the body. When the burn load is overwhelming, however, the systemic levels of released inflammatory mediators become excessive and disproportionate with deleterious outcome . The cerebral microvascular permeability is increased and enables previously blocked, large systemic molecules, such as albumin (Figure 1a), exudates, and numerous inflammatory cells to leak into the surrounding brain tissue.
These events cause subsequent neuronal damage  and cerebral edema [17, 18], and can result in critically increased intracranial pressure . The pathophysiological events leading to this severe inflammatory downward spiral are depicted in Figure 2. The extent of BBB leakage following severe burn seems to correlate with mortality in severe burn victims . In the following sections, we illustrate the molecular mechanisms involved in BBB failure.
Subcellular immunological changes
Activation of the complement system has been described following severe burns in experimental as well as patient settings [20, 21]. While beneficial in moderation, overshooting activation of complement can become harmful to the host. In fact, experimental burn trauma-induced secondary injury to the lungs  and burn-induced generation of the anaphylatoxin C5a could be linked to cardiac dysfunction, represented by significant reduction of left ventricular pressures and impaired sarcomere contractility . In addition, robust complement activation has been described as a key event in the neuropathophysiology of traumatic brain injury and meningitis .
Surprisingly, there is extremely limited literature on the role of the complement system in neuroinflammation following burns. It seems reasonable, however, to assume that the complement cascade plays an important role in the pathophysiology of burn-induced neuroinflammation, since components of the complement system are being expressed and released by multiple sessile cerebral cell types.
In our laboratory, we found evidence of burn-induced modulation of the two C5a receptors (C5aR and C5L2) following a standardized rat model of full-thickness scald injury, in which 30% of the total body surface area is burnt. We compared the expression of C5aR and C5L2 in the hippocampal areas of sham or burn animals (Flierl MA, Stahel PF, Touban BM, unpublished observations; Figure 1). While there seemed to be no change in the hippocampal expression of C5aR following burns, a significant upregulation of C5L2 was found 24 hours after burn trauma (Figure 1b,c). Contrary to earlier speculation, C5L2 has been recently identified as a functional receptor with a clearly proinflammatory role . C5L2 may therefore contribute to the complement-mediated neuro-inflammation after burns.
Cytokines and chemokines
Severe burn trauma induces rapid local production of pro-inflammatory cytokines by the affected tissues. Serum levels of TNFα, IL-1β and IL-6 have all been reported to be elevated following severe burn trauma in humans and animals [25–28]. While serum concentrations of IL-6, IL-8 and IL-1β correlate proportionally with the extent of the severe burn trauma, only serum IL-8 levels correlated positively with mortality [27, 29]. TNFα, IL-1β and IL-6 have all been demonstrated to directly induce a disruption of the BBB in vitro .
Recent studies in various animal models of neuroinflammation have confirmed breakdown of the BBB in a cytokine/chemokine-dependent manner [31–33]. Cytokines and chemokines are initially only produced at the burn site, but may become systemic and directly attack the BBB. In addition, severe burn injury significantly upregulates mRNA levels of TNFα, IL-1β and intercellular adhesion molecule 1 in brain tissue as early as 3 hours post injury . It is therefore important to recognize that severe burn trauma exposes the BBB to harmful proinflammatory mediators deriving from two different compartments: the brain and the systemic circulation. While, to date, there are no data available indicating what severity of burn injury is required to produce breakdown of the BBB in humans, most animal models cause severe burns on 60 to 70% of the body surface to induce BBB dysfunction [34, 35].
Nitric oxide (NO) has multifaceted biological and immunological functions [36, 37] and is biosynthesized by different isoforms of NO synthases localized in neurons, in endothelial cells, or in mitochondria . In contrast, inducible NO synthase is expressed in all nucleated cells that generate large bursts of NO in response to immunological stimuli . NO output by inducible NO synthase is generally associated with inflammatory conditions, such as hemorrhage, trauma, or severe burns [39, 40]. Inhibition of inducible NO synthase reduces microvascular leakage after experimental severe burn trauma , and beneficial effects of inducible NO synthase blockade following severe burns have been reported .
There is considerable debate about whether plasma of urinary levels of nitrate and nitrite bear any predictive value influencing clinical decision-making in burn patients. While some studies report elevated levels of NO, nitrite, and nitrate and correlate NO levels on day 5 post burn with mortality [43–45], other studies describe significantly depressed plasmatic nitrite levels and elevated nitrate levels . Reports about urinary nitrite and nitrate concentrations following burns also remain controversial [45–48]. The adverse effects of NO following severe burns may be mediated by interaction of NO with superoxide (O2-), resulting in formation of the highly toxic oxidant peroxynitrite . Peroxynitrite then causes extensive tissue damage and edema formation [50, 51]. Production of peroxynitrite has been described in organs remote to the site of severe burn injury, making it an important mediator of severe burn-induced multiple organ failure [52, 53].
Unexpectedly, mRNA expression of inducible NO synthase in the hypothalamus is significantly decreased following thermal injury , and NO levels rapidly declined in the cerebral cortex following severe burns . Hypotheses for this central/peripheral discrepancy include recruitment of NO from the brain towards the burn site, and/or a negative feedback loop blocking central NO because of its oxidative and free-radical deleterious effects .
Prostaglandin E2 and matrix metalloproteinases
Peripheral severe burn injury induces cyclooxygenase-2 as well as microsomal-type prostaglandin E synthase in endothelial cells of the central nervous system, resulting in elevated levels of prostaglandin E2 in the cerebrospinal fluid . Elevation of prostaglandin E2 levels in cerebrospinal fluids may therefore be involved in the pathogenesis of the central nervous system-mediated systemic reactions following severe burns. Ultimately, severe burn patients may benefit from administration of a cyclooxygenase-2-selective inhibitor in the treatment of central nervous system-mediated symptoms. Awareness of the increased risk of gastrointestinal bleeding following administration of cyclooxygenase-2-selective inhibitors, however, is important.
Matrix metalloproteinases have been recently identified as key players in the development of BBB dysfunction following severe burn injury [34, 35]. When upregulated following severe burns, these proteases may contribute to the degradation and destruction of the basal lamina of the BBB.
Disturbance of hormonal stress response
Following severe burn injury, the body reacts with a general stress response . After an initial ebb phase [12, 58], a universal hypercatabolism occurs . This hypermetabolism is, at least in part, mediated by catecholamines and correlates with the severity of injury . Following severe burn, plasma catecholamines increase as much as 10-fold [59, 60], resulting in hyperdynamic circulation . In addition, levels of norepinephrine and dopamine increase in certain areas of the brain [12, 58, 62] and increased levels of catecholamines mobilize substrates from the body's fat and protein stores, leading to loss of lean body mass and muscular wasting . Blockade of β-adrenergic receptors following severe burns therefore decreases thermogenesis, tachycardia, cardiac workload, and resting energy expenditure [63–65]. In severely burned children, treatment with the β-adrenoceptor blocker propranolol attenuated hypermetabolism and reversed muscle-protein catabolism [66, 67].
Alterations in hypothalamic function due to severe burns have also been described . More recent research confirmed disturbance of the hypothalamic–pituitary–adrenal axis in severely burned patients. Hypothalamic peptides and receptors of the corticotropin releasing factor family have been identified as putative mediators of severe burn-induced hypermetabolism [69, 70]. Serum prolactin has been found to correlate with burn severity  and, further downstream, temporary adrenal insufficiency has been reported in the early stages of severe burn trauma , which was associated with higher mortality rates . A study investigating the hypothalamic–pituitary–adrenal axis following thermal injury in children found a disrupted adrenocorticotropic hormone–adrenal feedback loop .
There are no reports to date directly investigating the activation of microglia and glial scarring following severe burns. In a recent study, the peripheral axon caliber and the conduction velocity were severely impaired after experimental severe burn injury . These morphological and functional deficits were observed at sides remote from the burn site. Axon caliber reduction and reduced neuronal conduction velocity following severe burns may therefore affect not only peripheral, but also central, neurons and may contribute to alterations of neuromuscular transmission and the development of limb and respiratory muscle weakness that often accompanies severe burns. Moreover, in burn-injured tissue, long-lasting activation of peripheral sensory neurons results in reorganization in the spinal cord . Histologically, the dorsal horn of the spinal cord shows decreased expression of μ-opioid receptors .
Nerve growth factor was detected recently in newly formed epithelial cells at wound edges . This growth factor may not only assist in wound reorganization and healing, but may also trigger hypersensitivity to heat and mechanical stimuli following severe burns [78, 79]. Nerve growth factor seems to increase the strength and distribution of afferent neuronal connections with the neurons of the dorsal horn , and thereby expands their receptive fields . These findings indicate that central plasticity occurs in the spinal cord after peripheral severe burns.
Neutrophils and macrophages
Severe burn injuries activate neutrophils and macrophages . Intracerebrally produced cytokines and chemokines chemoattract phagocytes via the BBB . In addition, once the BBB is severely compromised, systemic phagocytes can enter freely into the brain perivascular space . Activated phagocytes release their full inflammatory arsenal of proteases, reactive oxygen species, and reactive nitrogen species [84–86], exacerbating the neuroinflammatory response. The productive capacity of phagocytes for proinflammatory mediators is markedly enhanced following severe burns . Macrophages display increased oxidative metabolism after thermal injury , and patients with severe burns demonstrate evidence of increased oxygen free radical activity . Consequently, nonsurvivors of severe burn trauma display increased consumption of antioxidants when compared with survivors .
Neuropsychiatric effects and cognitive dysfunction
Severe burn trauma triggers significant electroencephalogram aberrations . During initial cardiovascular stabilization, resuscitation, and pain relief, less obvious neuropsychiatric consequences may be frequently masked by sedative treatments. Neuroses, cognitive impairment, and behavioral consequences have all been described in the literature after severe burns [89, 90]. During the initial phase after thermal injury, temporary amnesia may occur .
As mentioned above, NO levels are upregulated throughout the periphery following severe burn injury. In addition, NO has been shown to be an important biomolecule in the central nervous system, where neuronal NO synthases are widely present . The putative role of NO as a neuropsychiatric neurotransmitter concerns long-term potentiation in the hippocampus and long-term depression in the cerebellum [93, 94]. NO seems to be particularly involved in short-term memory and learning [92, 95]. Biobehavioral tests confirmed the important role of NO in the acquisition and consolidation of memories [96, 97]. Rapid and significant decreases of cerebral NO levels were recently found to account for the behavioral changes occurring in rats . It remains to be seen whether alterations of intracerebral NO metabolism may alleviate severe burn-induced cognitive impairment.
Approximately one-third of burn victims show evidence of physical, psychiatric, or alcohol-related problems, predisposing them to injury . During the critical resuscitative stage immediately following burn injury, patients frequently display cognitive changes such as extreme drowsiness, confusion, disorientation, delirium, and psychotic reactions . During the acute phase of recovery and restorative care, symptoms of depression, anxiety, sleep disturbance, and premorbid psychopathology are common . Following discharge, patients may develop symptoms of depression or post-traumatic stress disorder, which can develop anywhere from 1 month after burn trauma to 2 years after the initial burn [99, 101]. More than 50% of patients with burn injuries report moderate to severe depression symptoms early in their hospitalizations, and almost 50% retain these symptoms 2 years after injury [102, 103]. Interestingly, the extent of burn trauma does not predict the psychologic problems after burn trauma [102–104]. One year after burn trauma, approximately 20% of patients meet the diagnostic criteria for post-traumatic stress disorder .
Dysfunctional beliefs such as fear-avoidance or neuroticism have been described as long-term sequelae after burn trauma . Sleep disorders have also been described as long-term sequelae of burn trauma . A multidisciplinary team approach seems to be key to a successful management and long-term reintegration of the burn patient.
Impact of the immunopathophysiology on burn management
Advances in burn care have resulted in significant reduction of mortality rates over the past 50 years [108–110]. In particular, early and aggressive excision of the burn wound has had the greatest impact on burn patient morbidity and mortality by reducing the incidence of wound sepsis, hypercatabolism, numbers of operations, and hospital lengths of stay [111–114]. The current treatment guidelines therefore recommend routine and aggressive debridement of severe burn wounds at the first medical facility available . Even during infectious complications following severe burns, the cornerstone of treatment remains early, aggressive, and definitive surgical debridement – while antibiotics are only considered important adjuncts to management . Subsequent skin grafting is usually achieved with autologous or allogenic skin or biosynthetic dermal substitutes .
It is conceivable that the unquestionable benefit of early and aggressive excision of the burn wound is closely related to the pathophysiological changes described above. When the burn load is excessive, the local inflammatory response initiated by the injured peripheral tissues can spill over into the systemic circulation and result in the aforementioned inflammatory vicious cycle. The ensuing downward spiral may thus be disrupted early by aggressive initial debridement and may significantly reduce the systemic inflammatory burden with improved end-organ function and reduced morbidity and mortality. Early excision of full thickness burns is also associated with attenuation of burn-induced hypermetabolism [118–120].
Currently, bench-to-bedside transfer of several promising immunomodulatory treatment strategies – such as immunonutrition, administration of recombinant human activated protein C, or topical immunosupressants – are under investigation, as discussed in detail elsewhere . As a result, a recent report called for further translation of 'excellent animal work into the human arena' to advance care of the severely burnt patient .
Severe burn-induced neuroinflammation is a highly complex and intricate entity. Optimal management of the severely burned patient can only be achieved if the treating critical-care personnel are intimately familiar with the systemic and cerebral pathophysiology following severe burn trauma, and adjust their treatment modalities accordingly. While collapse of barriers in the lungs, kidneys, or liver is usually recognized by simple laboratory parameters and is treated as part of the severe burn management, burn-induced neuroinflammation evolves over time and thus cannot be detected on initial computerized tomography imaging evaluation. If the treating physician fails to appreciate the complex cerebral inflammatory events following burns, the patient may be cleared prematurely for surgical interventions, which can result in a potentially detrimental iatrogenic second hit. The treating physician therefore needs to maintain a high index of suspicion for this challenging entity. While some of the molecular events involved are well understood, many unanswered questions remain, which need to be addressed in experimental and clinical studies in order to advance care of the critically ill burn patient.
tumor necrosis factor.
Herndon DN, Spies M: Modern burn care. Semin Pediatr Surg 2001, 10: 28-31. 10.1053/spsu.2001.19389
Burn incidence and treatment in the US: 2000 Fact Sheet[http://www.ameriburn.org]
Latenser BA, Miller SF, Bessey PQ, Browning SM, Caruso DM, Gomez M, Jeng JC, Krichbaum JA, Lentz CW, Saffle JR, Schurr MJ, Greenhalgh DG, Kagan RJ: National Burn Repository 2006: a ten-year review. J Burn Care Res 2007, 28: 635-658.
Bloemsma GC, Dokter J, Boxma H, Oen IM: Mortality and causes of death in a burn centre. Burns 2008, 34: 1103-1107. 10.1016/j.burns.2008.02.010
Sevitt S: A review of the complications of burns, their origin and importance for illness and death. J Trauma 1979, 19: 358-369. 10.1097/00005373-197905000-00010
Pereira CT, Barrow RE, Sterns AM, Hawkins HK, Kimbrough CW, Jeschke MG, Lee JO, Sanford AP, Herndon DN: Age-dependent differences in survival after severe burns: a unicentric review of 1,674 patients and 179 autopsies over 15 years. J Am Coll Surg 2006, 202: 536-548. 10.1016/j.jamcollsurg.2005.11.002
Childs C: Fever in burned children. Burns Incl Therm Inj 1988, 14: 1-6.
Caldwell FT Jr, Graves DB, Wallace BH: The effect of indomethacin on the cytokine cascade and body temperature following burn injury in rats. Burns 1999, 25: 283-294. 10.1016/S0305-4179(99)00002-9
Cohen IK, Schechter PJ, Henkin RI: Hypogeusia, anorexia, and altered zinc metabolism following thermal burn. JAMA 1973, 223: 914-916. 10.1001/jama.223.8.914
Coderre TJ, Melzack R: Increased pain sensitivity following heat injury involves a central mechanism. Behav Brain Res 1985, 15: 259-262. 10.1016/0166-4328(85)90181-0
Latarjet J, Choinere M: Pain in burn patients. Burns 1995, 21: 344-348. 10.1016/0305-4179(95)00003-8
Chance WT, Nelson JL, Kim M, Foley-Nelson T, Chen MH, Fischer JE: Burn-induced alterations in feeding, energy expenditure, and brain amine neurotransmitters in rats. J Trauma 1987, 27: 503-509. 10.1097/00005373-198705000-00008
Murton SA, Tan ST, Prickett TC, Frampton C, Donald RA: Hormone responses to stress in patients with major burns. Br J Plast Surg 1998, 51: 388-392.
Wilmore DW, Long JM, Mason AD Jr, Skreen RW, Pruitt BA Jr: Catecholamines: mediator of the hypermetabolic response to thermal injury. Ann Surg 1974, 180: 653-669. 10.1097/00000658-197410000-00031
Moati F, Miskulin M, Godeau G, Robert AM: Blood–brain barrier permeabilizing activity in sera of severe-burn patients: relation to collagenolytic activity. Neurochem Res 1979, 4: 377-383. 10.1007/BF00963807
Sepulchre C, Moati F, Miskulin M, Huisman O, Moczar E, Robert AM, Monteil R, Guilbaud J: Biochemical and pharmacological properties of a neurotoxic protein isolated from the blood serum of heavily burned patients. J Pathol 1979, 127: 137-145. 10.1002/path.1711270306
Barone CM, Jimenez DF, Huxley VH, Yang XF: In vivo visualization of cerebral microcirculation in systemic thermal injury. J Burn Care Rehabil 2000,21(1 Pt 1):20-25. 10.1097/00004630-200021010-00005
Barone M, Jimenez F, Huxley VH, Yang XF: Morphologic analysis of the cerebral microcirculation after thermal injury and the response to fluid resuscitation. Acta Neurochir Suppl 1997, 70: 267-268.
Hamann GF, Okada Y, Fitridge R, del Zoppo GJ: Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 1995, 26: 2120-2126.
Till GO, Beauchamp C, Menapace D, Tourtellotte W Jr, Kunkel R, Johnson KJ, Ward PA: Oxygen radical dependent lung damage following thermal injury of rat skin. J Trauma 1983, 23: 269-277. 10.1097/00005373-198304000-00001
Bjornson AB, Bjornson HS, Altemeier WA: Reduction in alternative complement pathway mediated C3 conversion following burn injury. Ann Surg 1981, 194: 224-231.
Hoesel LM, Niederbichler AD, Schaefer J, Ipaktchi KR, Gao H, Rittirsch D, Pianko MJ, Vogt PM, Sarma JV, Su GL, Arbabi S, Westfall MV, Wang SC, Hemmila MR, Ward PA: C5a-blockade improves burn-induced cardiac dysfunction. J Immunol 2007, 178: 7902-7910.
Stahel PF, Barnum SR: The role of the complement system in CNS inflammatory diseases. Expert Rev Clin Immunol 2006, 2: 445-456. 10.1586/1744666X.2.3.445
Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Köhl J, Gerard C, Sarma JV, Ward PA: Functional roles for C5a receptors in sepsis. Nat Med 2008, 14: 551-557. 10.1038/nm1753
Cannon JG, Friedberg JS, Gelfand JA, Tompkins RG, Burke JF, Dinarello CA: Circulating interleukin-1 beta and tumor necrosis factor-alpha concentrations after burn injury in humans. Crit Care Med 1992, 20: 1414-1419. 10.1097/00003246-199210000-00009
Reyes R Jr, Wu Y, Lai Q, Mrizek M, Berger J, Jimenez DF, Barone CM, Ding Y: Early inflammatory response in rat brain after peripheral thermal injury. Neurosci Lett 2006, 407: 11-15. 10.1016/j.neulet.2006.07.071
de Bandt JP, Chollet-Martin S, Hernvann A, Lioret N, du Roure LD, Lim SK, Vaubourdolle M, Guechot J, Saizy R, Giboudeau J: Cytokine response to burn injury: relationship with protein metabolism. J Trauma 1994, 36: 624-628. 10.1097/00005373-199405000-00004
Gauglitz GG, Song J, Herndon DN, Finnerty CC, Boehning D, Barral JM, Jeschke MG: Characterization of the inflammatory response during acute and post-acute phases after severe burn. Shock 2008, 30: 503-507. 10.1097/SHK.0b013e31816e3373
Dugan AL, Malarkey WB, Schwemberger S, Jauch EC, Ogle CK, Horseman ND: Serum levels of prolactin, growth hormone, and cortisol in burn patients: correlations with severity of burn, serum cytokine levels, and fatality. J Burn Care Rehabil 2004, 25: 306-313. 10.1097/01.BCR.0000124785.32516.CB
de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J: The influence of cytokines on the integrity of the blood–brain barrier in vitro. J Neuroimmunol 1996, 64: 37-43. 10.1016/0165-5728(95)00148-4
Terao S, Yilmaz G, Stokes KY, Russell J, Ishikawa M, Kawase T, Granger DN: Blood cell-derived RANTES mediates cerebral microvascular dysfunction, inflammation, and tissue injury after focal ischemia–reperfusion. Stroke 2008, 39: 2560-2570. 10.1161/STROKEAHA.107.513150
McColl BW, Rothwell NJ, Allan SM: Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 2008, 28: 9451-9462. 10.1523/JNEUROSCI.2674-08.2008
Pan W, Hsuchou H, Yu C, Kastin AJ: Permeation of blood-borne IL15 across the blood–brain barrier and the effect of LPS. J Neurochem 2008, 106: 313-319. 10.1111/j.1471-4159.2008.05390.x
Berger J, Sprague SM, Wu Y, Davis WW, Jimenez DF, Barone CM, Ding Y: Peripheral thermal injury causes early blood–brain barrier dysfunction and matrix metalloproteinase expression in rat. Neurol Res 2007, 29: 610-614.
Swann K, Berger J, Sprague SM, Wu Y, Lai Q, Jimenez DF, Barone CM, Ding Y: Peripheral thermal injury causes blood–brain barrier dysfunction and matrix metalloproteinase (MMP) expression in rat. Brain Res 2007, 1129: 26-33. 10.1016/j.brainres.2006.10.061
Lowenstein CJ, Dinerman JL, Snyder SH: Nitric oxide: a physiologic messenger. Ann Intern Med 1994, 120: 227-237.
Napolitano LM, Campbell C: Nitric oxide inhibition normalizes splenocyte interleukin-10 synthesis in murine thermal injury. Arch Surg 1994, 129: 1276-1282. discussion 1282–1283.
Schulz R, Triggle CR: Role of NO in vascular smooth muscle and cardiac muscle function. Trends Pharmacol Sci 1994, 15: 255-259. 10.1016/0165-6147(94)90321-2
Nathan C: Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997, 100: 2417-2423. 10.1172/JCI119782
Szabo C, Thiemermann C: Invited opinion: role of nitric oxide in hemorrhagic, traumatic, and anaphylactic shock and thermal injury. Shock 1994, 2: 145-155. 10.1097/00024382-199408000-00011
Sozumi T: The role of nitric oxide in vascular permeability after a thermal injury. Ann Plast Surg 1997, 39: 272-277. 10.1097/00000637-199709000-00009
Rawlingson A, Shendi K, Greenacre SA, England TG, Jenner AM, Poston RN, Halliwell B, Brain SD: Functional significance of inducible nitric oxide synthase induction and protein nitration in the thermally injured cutaneous microvasculature. Am J Pathol 2003, 162: 1373-1380.
Onuoha G, Alpar K, Jones I: Vasoactive intestinal peptide and nitric oxide in the acute phase following burns and trauma. Burns 2001, 27: 17-21. 10.1016/S0305-4179(00)00073-5
Preiser JC, Reper P, Vlasselaer D, Vray B, Zhang H, Metz G, Vanderkelen A, Vincent JL: Nitric oxide production is increased in patients after burn injury. J Trauma 1996, 40: 368-371. 10.1097/00005373-199603000-00007
do Rosario Caneira da Silva M, Mota Filipe H, Pinto RM, Salaverria Timoteo de C, Godinho de Matos MM, Cordeiro Ferreira A, Toscano Rico JM: Nitric oxide and human thermal injury short term outcome. Burns 1998, 24: 207-212. 10.1016/S0305-4179(98)00014-X
Gamelli RL, George M, Sharp-Pucci M, Dries DJ, Radisavljevic Z: Burn-induced nitric oxide release in humans. J Trauma 1995, 39: 869-877. discussion 877–878. 10.1097/00005373-199511000-00010
Abrahams M, Sjoberg F, Oscarsson A, Sundqvist T: The effects of human burn injury on urinary nitrate excretion. Burns 1999, 25: 29-33. 10.1016/S0305-4179(98)00141-7
Becker WK, Shippee RL, McManus AT, Mason AD Jr, Pruitt BA Jr: Kinetics of nitrogen oxide production following experimental thermal injury in rats. J Trauma 1993, 34: 855-862. 10.1097/00005373-199306000-00015
Carreras MC, Pargament GA, Catz SD, Poderoso JJ, Boveris A: Kinetics of nitric oxide and hydrogen peroxide production and formation of peroxynitrite during the respiratory burst of human neutrophils. FEBS Lett 1994, 341: 65-68. 10.1016/0014-5793(94)80241-6
Rachmilewitz D, Stamler JS, Karmeli F, Mullins ME, Singel DJ, Loscalzo J, Xavier RJ, Podolsky DK: Peroxynitrite-induced rat colitis – a new model of colonic inflammation. Gastroenterology 1993, 105: 1681-1688.
Greenacre S, Ridger V, Wilsoncroft P, Brain SD: Peroxynitrite: a mediator of increased microvascular permeability? Clin Exp Pharmacol Physiol 1997, 24: 880-882. 10.1111/j.1440-1681.1997.tb02709.x
Chen LW, Hsu CM, Wang JS, Chen JS, Chen SC: Specific inhibition of iNOS decreases the intestinal mucosal peroxynitrite level and improves the barrier function after thermal injury. Burns 1998, 24: 699-705. 10.1016/S0305-4179(98)00114-4
Soejima K, Traber LD, Schmalstieg FC, Hawkins H, Jodoin JM, Szabo C, Szabo E, Virag L, Salzman A, Traber DL: Role of nitric oxide in vascular permeability after combined burns and smoke inhalation injury. Am J Respir Crit Care Med 2001,163(3 Pt 1):745-752.
Lestaevel P, Agay D, Peinnequin A, Cruz C, Cespuglio R, Clarencon D, Multon E, Chancerelle Y: Effects of a thermal injury on brain and blood nitric oxide (NO) content in the rat. Burns 2003, 29: 557-562. 10.1016/S0305-4179(03)00152-9
Halm MP, Poquin D, Lestaevel P, Chancerelle Y, Graff C: Brain and cognitive impairments from burn injury in rats. Burns 2006, 32: 570-576. 10.1016/j.burns.2005.12.005
Ozaki-Okayama Y, Matsumura K, Ibuki T, Ueda M, Yamazaki Y, Tanaka Y, Kobayashi S: Burn injury enhances brain prostaglandin E2 production through induction of cyclooxygenase-2 and microsomal prostaglandin E synthase in cerebral vascular endothelial cells in rats. Crit Care Med 2004, 32: 795-800. 10.1097/01.CCM.0000114576.60077.FC
Jeschke MG, Chinkes DL, Finnerty CC, Kulp G, Suman OE, Norbury WB, Branski LK, Gauglitz GG, Mlcak RP, Herndon DN: Pathophysiologic response to severe burn injury. Ann Surg 2008, 248: 387-401. 10.1097/SLA.0b013e318176c4b3
Chance WT, Nelson JL, Foley-Nelson T, Kim MW, Fischer JE: The relationship of burn-induced hypermetabolism to central and peripheral catecholamines. J Trauma 1989, 29: 306-312. 10.1097/00005373-198903000-00005
Goodall M, Stone C, Haynes BW Jr: Urinary output of adrenaline and noradrenaline in severe thermal burns. Ann Surg 1957, 145: 479-487. 10.1097/00000658-195704000-00004
Wilmore DW, Aulick LH: Metabolic changes in burned patients. Surg Clin North Am 1978,58(6):1173-1187.
Asch MJ, Feldman RJ, Walker HL, Foley FD, Popp RL, Mason AD Jr, Pruitt BA Jr: Systemic and pulmonary hemodynamic changes accompanying thermal injury. Ann Surg 1973, 178: 218-221. 10.1097/00000658-197308000-00020
Chance WT, Berlatzky Y, Minnema K, Trocki O, Alexander JW, Fischer JE: Burn trauma induces anorexia and aberrations in CNS amine neurotransmitters. J Trauma 1985, 25: 501-507. 10.1097/00005373-198506000-00005
Baron PW, Barrow RE, Pierre EJ, Herndon DN: Prolonged use of propranolol safely decreases cardiac work in burned children. J Burn Care Rehabil 1997, 18: 223-227. 10.1097/00004630-199705000-00008
Herndon DN, Barrow RE, Rutan TC, Minifee P, Jahoor F, Wolfe RR: Effect of propranolol administration on hemodynamic and metabolic responses of burned pediatric patients. Ann Surg 1988, 208: 484-492. 10.1097/00000658-198810000-00010
Breitenstein E, Chiolero RL, Jequier E, Dayer P, Krupp S, Schutz Y: Effects of beta-blockade on energy metabolism following burns. Burns 1990, 16: 259-264. 10.1016/0305-4179(90)90136-K
Hart DW, Wolf SE, Chinkes DL, Lal SO, Ramzy PI, Herndon DN: Beta-blockade and growth hormone after burn. Ann Surg 2002, 236: 450-456. discussion 456–457. 10.1097/00000658-200210000-00007
Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR: Reversal of catabolism by beta-blockade after severe burns. N Engl J Med 2001, 345: 1223-1229. 10.1056/NEJMoa010342
Wilmore DW, Orcutt TW, Mason AD Jr, Pruitt BA: Alterations in hypothalamic function following thermal injury. J Trauma 1975, 15: 697-703. 10.1097/00005373-197508000-00012
Chance WT, Dayal R, Friend LA, Sheriff S: Possible role of CRF peptides in burn-induced hypermetabolism. Life Sci 2006, 78: 694-703. 10.1016/j.lfs.2005.05.083
Chance WT, Dayal R, Friend LA, Thomas I, Sheriff S: Mediation of burn-induced hypermetabolism by CRF receptor-2 activity. Life Sci 2007, 80: 1064-1072. 10.1016/j.lfs.2006.11.047
Sheridan RL, Ryan CM, Tompkins RG: Acute adrenal insufficiency in the burn intensive care unit. Burns 1993, 19: 63-66. 10.1016/0305-4179(93)90103-F
Fuchs P, Groger A, Bozkurt A, Johnen D, Wolter T, Pallua N: Cortisol in severely burned patients: investigations on disturbance of the hypothalamic–pituitary–adrenal axis. Shock 2007, 28: 662-667.
Palmieri TL, Levine S, Schonfeld-Warden N, O'Mara MS, Greenhalgh DG: Hypothalamic–pituitary–adrenal axis response to sustained stress after major burn injury in children. J Burn Care Res 2006, 27: 742-748.
Higashimori H, Whetzel TP, Mahmood T, Carlsen RC: Peripheral axon caliber and conduction velocity are decreased after burn injury in mice. Muscle Nerve 2005, 31: 610-620. 10.1002/mus.20306
Woolf CJ: Evidence for a central component of post-injury pain hypersensitivity. Nature 1983, 306: 686-688. 10.1038/306686a0
Ueda M, Hirose M, Takei N, Ibuki T, Naruse Y, Amaya F, Ibata Y, Tanaka M: Nerve growth factor induces systemic hyperalgesia after thoracic burn injury in the rat. Neurosci Lett 2002, 328: 97-100. 10.1016/S0304-3940(02)00456-1
Matsuda H, Koyama H, Sato H, Sawada J, Itakura A, Tanaka A, Matsumoto M, Konno K, Ushio H, Matsuda K: Role of nerve growth factor in cutaneous wound healing: accelerating effects in normal and healing-impaired diabetic mice. J Exp Med 1998, 187: 297-306. 10.1084/jem.187.3.297
Lewin GR, Rueff A, Mendell LM: Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur J Neurosci 1994, 6: 1903-1912. 10.1111/j.1460-9568.1994.tb00581.x
Lewin GR, Ritter AM, Mendell LM: Nerve growth factor-induced hyperalgesia in the neonatal and adult rat. J Neurosci 1993, 13: 2136-2148.
Lewin GR, Winter J, McMahon SB: Regulation of afferent connectivity in the adult spinal cord by nerve growth factor. Eur J Neurosci 1992, 4: 700-707. 10.1111/j.1460-9568.1992.tb00179.x
McMahon SB, Wall PD: Receptive fields of rat lamina 1 projection cells move to incorporate a nearby region of injury. Pain 1984, 19: 235-247. 10.1016/0304-3959(84)90002-2
Schwacha MG: Macrophages and post-burn immune dysfunction. Burns 2003, 29: 1-14. 10.1016/S0305-4179(02)00187-0
Charo IF, Ransohoff RM: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 2006, 354: 610-621. 10.1056/NEJMra052723
Schwacha MG, Somers SD: Thermal injury-induced immunosuppression in mice: the role of macrophage-derived reactive nitrogen intermediates. J Leukocyte Biol 1998, 63: 51-58.
Schwacha MG, Somers SD: Thermal injury-induced enhancement of oxidative metabolism by mononuclear phagocytes. J Burn Care Rehabil 1999,20(1 Pt 1):37-41.
Ogle CK, Guo X, Wu JZ, Ogle JD: Production of cytokines and PGE 2 and cytotoxicity of stimulated bone marrow macrophages after thermal injury and cytotoxicity of stimulated U-937 macrophages. Inflammation 1993, 17: 583-594. 10.1007/BF00914196
Nguyen TT, Cox CS, Traber DL, Gasser H, Redl H, Schlag G, Herndon DN: Free radical activity and loss of plasma antioxidants, vitamin E, and sulfhydryl groups in patients with burns: the 1993 Moyer Award. J Burn Care Rehabil 1993, 14: 602-609. 10.1097/00004630-199311000-00004
Hughes JR, Cayaffa JJ, Boswick JA Jr: Seizures following burns of the skin. III. Electroencephalographic recordings. Dis Nerv Syst 1975, 36: 443-447.
Van Loey NE, Maas CJ, Faber AW, Taal LA: Predictors of chronic posttraumatic stress symptoms following burn injury: results of a longitudinal study. J Trauma Stress 2003, 16: 361-369. 10.1023/A:1024465902416
Yu BH, Dimsdale JE: Posttraumatic stress disorder in patients with burn injuries. J Burn Care Rehabil 1999, 20: 426-433. discussion 422–425. 10.1097/00004630-199909000-00017
Andreasen NJ, Noyes R Jr, Hartford CE, Brodland G, Proctor S: Management of emotional reactions in seriously burned adults. N Engl J Med 1972, 286: 65-69.
Bredt DS, Snyder SH: Nitric oxide, a novel neuronal messenger. Neuron 1992, 8: 3-11. 10.1016/0896-6273(92)90104-L
O'Dell TJ, Hawkins RD, Kandel ER, Arancio O: Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA 1991, 88: 11285-11289. 10.1073/pnas.88.24.11285
Shibuki K, Okada D: Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 1991, 349: 326-328. 10.1038/349326a0
Majlessi N, Choopani S, Bozorgmehr T, Azizi Z: Involvement of hippocampal nitric oxide in spatial learning in the rat. Neurobiol Learn Mem 2008, 90: 413-419. 10.1016/j.nlm.2008.04.010
Chapman PF, Atkins CM, Allen MT, Haley JE, Steinmetz JE: Inhibition of nitric oxide synthesis impairs two different forms of learning. Neuroreport 1992, 3: 567-570. 10.1097/00001756-199207000-00005
Bohme GA, Bon C, Lemaire M, Reibaud M, Piot O, Stutzmann JM, Doble A, Blanchard JC: Altered synaptic plasticity and memory formation in nitric oxide synthase inhibitor-treated rats. Proc Natl Acad Sci USA 1993, 90: 9191-9194. 10.1073/pnas.90.19.9191
Williams EE, Griffiths TA: Psychological consequences of burn injury. Burns 1991, 17: 478-480. 10.1016/0305-4179(91)90075-R
Wiechman SA, Patterson DR: ABC of burns. Psychosocial aspects of burn injuries. BMJ 2004, 329: 391-393. 10.1136/bmj.329.7462.391
Sullivan SR, Friedrich JB, Engrav LH, Round KA, Heimbach DM, Heckbert SR, Carrougher GJ, Lezotte DC, Wiechman SA, Honari S, Klein MB, Gibran NS: 'Opioid creep' is real and may be the cause of 'fluid creep'. Burns 2004, 30: 583-590. 10.1016/j.burns.2004.03.002
Wiechman Askay S, Patterson DR: What are the psychiatric sequelae of burn pain? Curr Pain Headache Rep 2008, 12: 94-97. 10.1007/s11916-008-0018-1
Ptacek JT, Patterson DR, Heimbach DM: Inpatient depression in persons with burns. J Burn Care Rehabil 2002, 23: 1-9. 10.1097/00004630-200201000-00003
Wiechman SA, Ptacek JT, Patterson DR, Gibran NS, Engrav LE, Heimbach DM: Rates, trends, and severity of depression after burn injuries. J Burn Care Rehabil 2001, 22: 417-424. 10.1097/00004630-200111000-00012
Ehde DM, Patterson DR, Wiechman SA, Wilson LG: Post-traumatic stress symptoms and distress 1 year after burn injury. J Burn Care Rehabil 2000, 21: 105-111. 10.1097/00004630-200021020-00005
Esselman PC: Burn rehabilitation: an overview. Arch Phys Med Rehabil 2007,88(12 Suppl 2):S3-S6. 10.1016/j.apmr.2007.09.020
Willebrand M, Andersson G, Kildal M, Gerdin B, Ekselius L: Injury-related fear-avoidance, neuroticism and burn-specific health. Burns 2006, 32: 408-415. 10.1016/j.burns.2005.11.005
Esselman PC, Thombs BD, Magyar-Russell G, Fauerbach JA: Burn rehabilitation: state of the science. Am J Phys Med Rehabil 2006, 85: 383-413. 10.1097/01.phm.0000202095.51037.a3
McGwin G Jr, Cross JM, Ford JW, Rue LW 3rd: Long-term trends in mortality according to age among adult burn patients. J Burn Care Rehabil 2003, 24: 21-25. 10.1097/00004630-200301000-00006
Saffle JR, Davis B, Williams P: Recent outcomes in the treatment of burn injury in the United States: a report from the American Burn Association Patient Registry. J Burn Care Rehabil 1995,16(3 Pt 1):219-232. discussion 288–289. 10.1097/00004630-199505000-00002
Merrell SW, Saffle JR, Sullivan JJ, Larsen CM, Warden GD: Increased survival after major thermal injury. A nine year review. Am J Surg 1987, 154: 623-627. 10.1016/0002-9610(87)90229-7
Janzekovic Z: A new concept in the early excision and immediate grafting of burns. J Trauma 1970, 10: 1103-1108.
Sheehy E: Primary excision: innovation in pediatric burn care. RN 1974, 37: 21-25.
Burke JF, Bondoc CC, Quinby WC: Primary burn excision and immediate grafting: a method shortening illness. J Trauma 1974, 14: 389-395. 10.1097/00005373-197405000-00005
Still JM Jr, Law EJ: Primary excision of the burn wound. Clin Plast Surg 2000, 27: 23-47.
White CE, Renz EM: Advances in surgical care: management of severe burn injury. Crit Care Med 2008,36(7 Suppl):S318-S324. 10.1097/CCM.0b013e31817e2d64
West MA, Moore EE, Shapiro MB, Nathens AB, Cuschieri J, Johnson JL, Harbrecht BG, Minei JP, Bankey PE, Maier RV: Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core – standard operating procedures for clinical care VII – guidelines for antibiotic administration in severely injured patients. J Trauma 2008, 65: 1511-1519. 10.1097/TA.0b013e318184ee35
Heimbach DM, Warden GD, Luterman A, Jordan MH, Ozobia N, Ryan CM, Voigt DW, Hickerson WL, Saffle JR, DeClement FA, Sheridan RL, Dimick AR: Multicenter postapproval clinical trial of Integra dermal regeneration template for burn treatment. J Burn Care Rehabil 2003, 24: 42-48. 10.1097/00004630-200301000-00009
Hart DW, Wolf SE, Chinkes DL, Gore DC, Mlcak RP, Beauford RB, Obeng MK, Lal S, Gold WF, Wolfe RR, Herndon DN: Determinants of skeletal muscle catabolism after severe burn. Ann Surg 2000, 232: 455-465. 10.1097/00000658-200010000-00001
Hart DW, Wolf SE, Chinkes DL, Beauford RB, Mlcak RP, Heggers JP, Wolfe RR, Herndon DN: Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after severe burn. J Trauma 2003, 54: 755-761. discussion 761–764. 10.1097/01.TA.0000060260.61478.A7
Herndon DN, Tompkins RG: Support of the metabolic response to burn injury. Lancet 2004, 363: 1895-1902. 10.1016/S0140-6736(04)16360-5
Ipaktchi K, Arbabi S: Advances in burn critical care. Crit Care Med 2006,34(9 Suppl):S239-S244. 10.1097/01.CCM.0000232625.63460.D4
Namias N: Advances in burn care. Curr Opin Crit Care 2007, 13: 405-410. 10.1097/MCC.0b013e328263888f
The authors declare that they have no competing interests.
About this article
Cite this article
Flierl, M.A., Stahel, P.F., Touban, B.M. et al. Bench-to-bedside review: Burn-induced cerebral inflammation – a neglected entity?. Crit Care 13, 215 (2009). https://doi.org/10.1186/cc7794
- Nitric Oxide
- Systemic Inflammatory Response Syndrome
- Thermal Injury
- Reactive Nitrogen Species
- Severe Burn