Lung Protection After Severe Thermal Burns With Adenosine, Lidocaine, and Magnesium (ALM) Resuscitation and Importance of Shams in a Rat Model.

The management of severe burns remains a complex challenge. Adenosine, lidocaine, and magnesium (ALM) resuscitation therapy has been shown to protect against hemorrhagic shock and traumatic injury. The aim of the present study was to investigate the early protective effects of small-volume ALM fluid resuscitation in a rat model of 30% total body surface area (TBSA) thermal injury. Male Sprague-Dawley rats (320-340 g; n = 25) were randomly assigned to: 1) Sham (surgical instrumentation and saline infusion, without burn, n = 5), 2) Saline resuscitation group (n = 10), or 3) ALM resuscitation group (n = 10). Treatments were initiated 15-min after burn trauma, including 0.7 mL/kg 3% NaCl ± ALM bolus and 0.25-0.5 mL/kg/h 0.9% NaCl ± ALM drip, with animals monitored to 8.25-hr post-burn. Hemodynamics, cardiac function, blood chemistry, hematology, endothelial injury markers and histopathology were assessed. Survival was 100% for Shams and 90% for both ALM and Saline groups. Shams underwent significant physiological, immune and hematological changes over time as a result of surgical traums. ALM significantly reduced malondialdehyde levels in the lungs compared to Saline (P = .023), and showed minimal alveolar destruction and inflammatory cell infiltration (P < .001). ALM also improved cardiac function and oxygen delivery (21%, P = .418 vs Saline), reduced gut injury (P < .001 vs Saline), and increased plasma adiponectin (P < .001 vs baseline). Circulating levels of the acute phase protein alpha 1-acid glycoprotein (AGP) increased 1.6-times (P < .001), which may have impacted ALM's therapeutic efficacy. We conclude that small-volume ALM therapy significantly reduced lung oxidative stress and preserved alveolar integrity following severe burn trauma. Further studies are required to assess higher ALM doses with longer monitoring periods.

Major surgery leads to a proinflammatory phenotype: Differential gene expression following a laparotomy.

BACKGROUND: The trauma of surgery is a neglected area of research. Our aim was to examine the differential expression of genes of stress, metabolism and inflammation in the major organs of a rat following a laparotomy. MATERIALS AND METHODS: Anaesthetised Sprague-Dawley rats were randomised into baseline, 6-hr and 3-day groups (n = 6 each), catheterised and laparotomy performed. Animals were sacrificed at each timepoint and tissues collected for gene and protein analysis. Blood stress hormones, cytokines, endothelial injury markers and coagulation were measured. RESULTS: Stress hormone corticosterone significantly increased and was accompanied by significant increases in inflammatory cytokines, endothelial markers, increased neutrophils (6-hr), higher lactate (3-days), and coagulopathy. In brain, there were significant increases in M1 muscarinic (31-fold) and α-1A-adrenergic (39-fold) receptor expression. Cortical expression of metabolic genes increased ∼3-fold, and IL-1ß by 6-fold at 3-days. Cardiac ß-1-adrenergic receptor expression increased up to 8.4-fold, and M2 and M1 muscarinic receptors by 2 to 4-fold (6-hr). At 3-days, cardiac mitochondrial gene expression (Tfam, Mtco3) and inflammation (IL-1α, IL-4, IL-6, MIP-1α, MCP-1) were significantly elevated. Haemodynamics remained stable. In liver, there was a dramatic suppression of adrenergic and muscarinic receptor expression (up to 90%) and increased inflammation. Gut also underwent autonomic suppression with 140-fold increase in IL-1ß expression (3-days). CONCLUSIONS: A single laparotomy led to a surgical-induced proinflammatory phenotype involving neuroendocrine stress, cortical excitability, immune activation, metabolic changes and coagulopathy. The pervasive nature of systemic and tissue inflammation was noteworthy. There is an urgent need for new therapies to prevent hyper-inflammation and restore homeostasis following major surgery.

The role of matrix metalloproteinase-9 and its inhibitor TIMP-1 in burn injury: a systematic review.

Matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), are key mediators of acute inflammation and regulators of the wound healing process. The aim of this systematic review was to determine the local and systemic involvement of the MMP-9/TIMP-1 system following burn injury. Two databases (Scopus and MEDLINE) were searched for all studies reporting MMP-9 and/or TIMP-1 after burn injury. Based on our eligibility criteria, we reviewed 24 studies involving 508 burns patients in 11 clinical studies and 367 animals in 13 preclinical studies. Local, systemic, and peripheral gene expression, protein levels and activity of MMP-9 and TIMP-1 were assessed. Increased MMP-9 was reported at the site of injury early after burn trauma in all studies, and remained elevated in non-healing wounds. Increased TIMP-1 expression in burn wounds occurred later than MMP-9, and was persistent in hypertrophic burn scars. Similar to local expression, systemic MMP-9 and TIMP-1 concentrations were significantly elevated after burn injury in response to upregulation of proinflammatory cytokines. While no association was found between systemic MMP-9 concentration and extent of injury or outcome, serum or plasma TIMP-1 showed good correlation with survival and burn severity. This review also found evidence of the MMP-9/TIMP-1 system contributing to secondary tissue damage distant from the burn site, including burn-associated musculoskeletal damage and acute lung injury. In addition, increased MMP-9 synthesis and activity in the brain after peripheral burn may lead to blood-brain barrier dysfunction and cerebral edema, a significant contributor to mortality. This systematic review provides an overview of the available evidence of the role of MMP-9 and TIMP-1 in burn injury pathophysiology and finds that TIMP-1 may be a promising biomarker in outcome prognostication of burns patients. Large-scale studies of both pediatric and adult burns patients with increased female representation and repeated sampling are recommended to validate the reliability of TIMP-1 as a prognostic marker following burn injury.

The morbidity associated with paediatric burn wound escharotomies.

INTRODUCTION: An escharotomy is an effective surgical procedure for the rapid decompression of a constricting and unyielding eschar, to permit restoration of blood flow. However, an escharotomy is also a full-thickness incision, which adds additional scarring to the burn injury area. The cosmetic and functional morbidity of escharotomy scarring in children is poorly characterised. METHODS: Children who required a burn wound escharotomy at the Queensland Children's Hospital (QCH) between May 2011 and May 2020 were included. Demographics of these children were described. In addition, the number of operations for revision of escharotomy scars was recorded as an indicator of functional or cosmetic concern. RESULTS: A total of 19 patients required an escharotomy after a burn injury. Children with 1% to 96% TBSA burns required an escharotomy, with a median of 28% (IQR 10-39%) TBSA. Two patients (81% and 96% TBSA) died. Seventy-one percent (12/17) of survivors had operative revisions of their escharotomy scars. The median time from burn to first scar intervention was 35 weeks (IQR 19-70 weeks). CONCLUSION: There is substantial morbidity associated with escharotomies in children. Further investigation of the current methods of decompression after burn injury, and the long-term morbidity of escharotomy, is required.

Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis.

Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the "switch" hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered "an uncoordinated and sometimes contradictory therapeutic outcome." The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)-cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.

The role of invasive monitoring in the resuscitation of major burns: a systematic review and meta-analysis.

Increasingly, in major hospitals invasive monitoring endpoints are utilised to guide the acute resuscitation of burns. The aim of this review is to evaluate effects of invasive monitoring for major burns patients (>20% total body surface area) to prevent early organ dysfunction. Five databases were searched for randomised controlled trials and cohort studies that evaluated invasive monitoring within the acute phase (first 24 hours). Invasive monitoring included transesophageal echocardiogram, central venous pressure measurement, and pulmonary artery catheterisation. Primary outcomes included multiple organ failure scores, renal and cardiac dysfunction measurements, compartment syndrome and lactate at 24 hours. Secondary outcomes included mortality and intensive care unit stay. Ten studies involving 401 major burns patients were included. Data pooled from four studies demonstrated significantly improved cardiac index at 24 hours compared to non-invasive endpoints (MD: 0.65, 95% CI: 0.46-0.82, P=0.00001). Five studies pooled showed significantly increased urine output with invasive monitoring (MD: 0.18, 95% CI: 0.03-0.34, P=0.02), whereas there was no difference in blood lactate levels (MD: -0.11, 95% CI: -0.44-0.22, P=0.43). There was a trend for lower mortality in invasive monitoring groups compared with non-invasive controls; however, the difference was not significant. There remains insufficient evidence to determine whether invasive monitoring to guide fluid resuscitation improves patient outcomes after major burn trauma. Although meta-analysis determined significantly improved cardiac index and urine output, further studies are required.