Burn injury is a common type of traumatic injury, causing considerable morbidity and mortality. Worldwide, an estimated 6 million patients seek medical help for burns annually. In the United States, burns due to fire and flames and hot objects or substances represent 2.4% of all trauma cases and are responsible for 1.6% of the traumatic deaths^[1].In China, the annual incidence of severe burns was 0.2 to 3.6/10000 inhabitant, mortality was usually between 1.6% and 12% and is decreasing in time^[2].Although mortality in burn patients has decreased in the last decades, severe burns, however, continue to cause devastating morbidity and significant mortality.

Severe burn patients required aggressive resuscitation, operation and metabolic support to reduce mortality.Burns greater than 20 to 25% TBSA are associated with increased capillary permeability and intravascular volume deficits that are most severe in the first 24 hours following injury.Excessive depletion of fluid from the circulation in massive burn injury result in hypovolemic shock.This hypovolemic state not only induces early death, but also a predisposing cause of many life-threatening complications.Infusion of electrolyte solutions is the primary treatment of severe hypovolemia due to severe burns.A delay in the initiation of fluid therapy would increase the mortality rate^[3].Studies have shown that severely burn-injured children have increased mortality rates and higher rates of organ failure when initiation of fluid therapy is delayed by even a few hours^{[3, 4]}.However, mass burn casualties often result from accidents, forest fire, war, and acts of terrorism.Literature indicates that most deaths occur early (< 48 hours) in severe burns who receive only palliative care or no curative ('active') care^[5].We postulated these austere environments presents challenges not commonly encountered among civilian burn injuries.These challenges may include delayed initial resuscitation and definitive coverage for the lack of medical supplies, prolonged transport to the burn center for the lack of transportation and medical facilities.These gaps all highlight the need for the prompt treatment of burn shock patients to win more time until regular treatment was available.This brief review aims on some both effective and practical resuscitation of burn shock to cut down the mortality in an austere environment.

We first reviewed oral and enteral resuscitation which can be for applied in scenarios of delayed IV fluid therapy due to logistical constraints.Oral resuscitation does not need sterile conditions as the intravenous fluid resuscitation.Dry powder consists of electrolyte and glucose can be compounded with drinking water which differs from that of administration of intravenous fluids requires sterile conditions.Also oral rehydration does not demand intravenous injection skills.Soldiers or forest rangers were susceptible to injury in the line of their duty can carry dry powder as an alternative methods for self-help and mutual rescue^[6].

Oral rehydration solutions (ORS) have been developed and recommended by the WHO since 1970s, which is one of the glucose-electrolytes solutions and has various modified formulas, mainly bicarbonate-based, citrate-based and reduced osmolarity ORSs to improve the management of diarrhea patients^[7].It was proven as a robust treatment in a mass casualty setting of cholera in refugees fleeing a war in East Pakistan (now Bangladesh) in 1971.In this setting with limited or no intravenous (IV) fluid therapy available, ORS alone decreased deaths from about 40% to 3% and was administered by friends and families of the cholera victims without any prior training^[8].Later experiences in mass outbreaks of cholera in Peru and Rwanda confirmed its efficacy^[9].

Enteral fluids have the potential of both resuscitating from shock and providing nutrition.Michell et al.evaluated the effects of WHO ORS after a 40% TBSA burn in anesthetized swine compared with the IV infusion of lactated Ringer's infused by Parkland formula^[10].Changes in hematocrit, hemodynamics, and measured PV showed equivalent resuscitative effects of enteral and IV resuscitation.Also, Hu et al.have conducted an extensive series of animal experiments dealing with experimental treatment of burn shock.Enteral resuscitation has been evaluated in either rats or dog shock model of which was designed to have a high mortality rate in untreated controls (typically >50% in less than 6-hrs).A consistent finding of these studies was the great survival benefit of large volumes of isotonic NaCl when administered via the oral or intraperitoneal routes.Several clinical reports have credited that the ORS is valuable and efficient in burn resuscitation.

However, the ideal fluid replacement "drink" for burn shock is yet unknown but should be investigated.Burn-induced ischemic/reperfusive injury significantly inhibits the gastrointestinal (GI) function barricade the efficiency of ORS resuscitation^[11~15].Sallam et al.has found that burn delayed ORS intestinal transit in a rat model subjected to full-thickness burn involving 60% of the total body surface area (TBSA)^[12].Hu et al.has found that a novel ORS, pyruvate-enriched ORS (Pyr-ORS), was superior to the standard bicarbonate-based ORS for intestinal absorption of sodium and water by approximately 30% in rats with burn injury^[16].They postulated that Pyr-ORS induced the activation of the intestinal HIF-1-EPO signaling pathway^[17].Besides, Hu and his colleagues also found that carbachol promoted intestinal absorption rate and PV by increasing the intestinal blood flow and Na^+-K^+-ATPase activity^[18].These results suggest that pyruvate, carbachol may have potential clinical benefits in burn shock patients requiring oral fluid therapy.

Oral resuscitation might be also impeded by the lack of proper drinking fluid in an austere environment.Besides, enteral solutions may never be recommended with abdominal or thoracic trauma^[19].So we second reviewed some drugs mandatory to protect body cells as well as organ functions from ravage of burn shock so that it might help the victims to win time until regular therapy was available.

DNA transcription is regulated, in part, by acetylation of nuclear histones that are controlled by 2 groups of enzymes:histone deacetylases(HDAC) and histone acetyl transferases(HAT).Acetylation is rapidly emerging as a key mechanism that regulates the expression of numerous genes (epigenetic modulation through activation of nuclear histone proteins), as well as functions of multiple cytoplasmic proteins involved in key cellular functions such as cell survival, repair/healing, signaling, and proliferation.It has been reported that burn injury lead to an imbalance of intracellular histone acetylase and deacetylase, resulting in increase in death^[20].Curtis et al.has found that the levels of HDAC1 and phosphorylated-HDAC1 significant increased in a mice model subjected to 15% TBSA scald injury^[21].

Cellular acetylation can be increased immediately through the administration of histone deacetylase inhibitors (HDACI).To date, more than 15 HDACIs have been tested in preclinical and early clinical studies for cancer therapy^[22].Many of them are broad-spectrum-or pan-HDACIs which inhibit many of the Class Ⅰ, Ⅱ and Ⅳ isoforms, including suberoylanilide hydroxamic acid (SAHA), trichostatin A (TSA), and valproic acid (VPA).Tubacin is one of a few HDACIs that have been reported as HDAC6-specific inhibitor^[23].

Experimental evidence has shown that treatment with pharmacological HDACIs, such as VPA increases endurance of animals subjected to lethal blood loss.The survival benefit is seen even when the drugs are administered postinsult, and is reproducible in different species including large animal models of polytrauma.

The use of valproic acid has repeatedly been proved effective in improving survival rate in animal model of hemorrhagic or traumatic shock, and even septic shock^[24~28].In the Gonzales experiment with rats and a blood loss of 60% of total blood volume, the survival rate was 70% 12 h after the blood loss when valproic acid was given before exsanguinations, while the survival rate was 0% in the control group^[29].The surviving time was prolonged 5 fold in the treatment group as compared with that of control group.Alam HB.conducted a hemorrhagic shock experiment in pigs, and they found the administration of valproic acid (400mg/kg) could raise the survival rate from 25% in shock animals without the treatment to 86% in the treatment group^[30].Repeated successes of HDACIs in well-designed animal models of hemorrhagic shock (small and large animals) and septic shock (pre- and postshock treatments) suggest that modulation of protein acetylation is potentially a very useful strategy for the treatment of these critical diseases.

In our study, it was shown in a canine model of 50% TBSA full-thickness burn, valproic acid treatment alone resulted in a survival rate of 70% and 60% 24h and 72h after the injury, respectively, while the survival rate of untreated animals at the same time points was 40% and 10%, respectively.The difference in survival rates was obviously significant^[31].

Valproic acid is a pan-inhibitor that blocks most of the known HDAC isoforms.Targeting individual HDAC isoforms may increase survival and reduce complications.Sillesen et al.experiment aims on HDAC gene expression following trauma^[32].They have found that the expression trajectories of HDAC1, HDAC3, HDAC6, HDAC11, and SIRT3 correlate with outcomes following trauma and may potentially serve as biomarkers.Chang et al.has found that tubastatin A (HDAC-6 inhibitor) significantly reduced the mortality of hemorrhagic shock model in a rat model of 55% blood loss (mortality in 24 hours, 75% vs 37.5%)^[33].

Fluid resuscitation must be started promptly in order to achieve the best outcomes. The high survival rates of modern burn care are attributed to application of prompt and aggressive resuscitation using intravenous infusion of lactated Ringer's^[3].Half or more of the fluid requirements in the first 24 hrs must be administered in the first 8 hrs for optimal outcomes.Studies have shown that severely burn-injured children have increased mortality rates and higher rates of organ failure when initiation of fluid therapy is delayed by even a few hours.However, mass burn casualties can result from accidents, war, and acts of terrorism, which demanding a reconsideration of enteral resuscitation for situations where the number of patients exceeds the resources to provide standard of care. There is a need to have a better means for the initial resuscitation of burn shock. We are suggesting the use of new solutions and oral therapy for the management of burn injury in an environment where long delays in evacuation may occur, but these concepts require further research regarding their efficacy and safety before they can be fully implemented. At present, we still must rely on intravenous therapeutics to maintain thermally injured patients.

HDACIs have been described above for their prosurvival and anti-inflammatory properties. The combined prosurvival and anti-inflammatory effectiveness makes them a highly attractive choice for the treatment of lethal hemorrhagic shock and its septic complications. It should also be emphasized that, although early use of VPA may improve survival after a serious burn, adequate replacement of fluid is still necessary to finally tide over burn shock in a patient with a deep burn involving a large area of the body. The treatment is only meaningful when intravascular fluid replacement is temporarily lacking.