Pathophysiology of Severe Burn Injuries: New Therapeutic Opportunities From a Systems Perspective

Abstract

Severe burn injury elicits a profound stress response with the potential for high morbidity and mortality. If polytrauma is present, patient outcomes appear to be worse. Sex-based comparisons indicate females have worse outcomes than males. There are few effective drug therapies to treat burn shock and secondary injury progression. The lack of effective drugs appears to arise from the current treat-as-you-go approach rather than a more integrated systems approach. In this review, we present a brief history of burns research and discuss its pathophysiology from a systems' perspective. The severe burn injury phenotype appears to develop from a rapid and relentless barrage of damage-associated molecular patterns, pathogen-associated molecular patterns, and neural afferent signals, which leads to a state of hyperinflammation, immune dysfunction, coagulopathy, hypermetabolism, and intense pain. We propose that if the central nervous system control of cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored early, these secondary injury processes may be minimized. The therapeutic goal is to switch the injury phenotype to a healing phenotype by reducing fluid leak and maintaining tissue O2 perfusion. Currently, no systems-based therapies exist to treat severe burns. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine, and magnesium (ALM) to treat hemorrhagic shock, traumatic brain injury, and sepsis. Our early studies indicate that the ALM therapy holds some promise in supporting cardiovascular and pulmonary functions following severe burns. Future research will investigate the ability of ALM therapy to treat severe burns with polytrauma and sex disparities, and potential translation to humans.

Keywords: ALM; adenosine, lidocaine, magnesium; fluids; military; pathophysiology; shock; trauma.

Figure 1.

Brief History of the Main Events of Burn Trauma From the 1500s to the Present. Most Major Advances in Emergency Care and Clinical Management Have Been Driven by Wars and Great Fires (See Text)

Figure 2.

Schematic of the Systems’ Effect of Severe Burn Trauma on the CNS and Organs of the Body. New Drug Therapies Are Required to Break These CNS-Driven Injury Cycles That Lead to Poor Outcomes and Treat the System, Not Single Nodal Targets That Treat One Symptom After Another as They Occur in the Burn Patient (See Text). CNS, Central Nervous System; DAMP, Damage-Associated Molecular Pattern; PAMP, Pathogen-Associated Molecular Pattern; TBSA, Total Body Surface Area

Figure 3.

Selecting the Optimal Intravenous (IV) Fluid Composition, Volume, and Timing to Treat Severe Burn Patients Remains Challenging. Decisions Should Be Based on Clinical Assessment of the Patient’s Individual Needs and Cardiac Responsiveness to Fluids. Delivering a Fluid Too Little, Too Much, or Too Early in Hypovolemic Burn Patients Can Do More Harm Than Good. There Is a Clear Need for Consensus Guidance on the Selection and Administration of IV Fluid Therapy to Accurately Improve Tissue Perfusion and Restore Sufficient O₂ Supply to Tissue Mitochondria After Severe Burn Injury to Prevent End-Organ Dysfunction and Poor Outcomes. CNS, Central Nervous System; ADP, Adenosine Diphosphate; ATP, Adenosine Triphosphate