Total Body Surface Area Injury Research Articles

522 Testosterone Supplementation in Patients with Burn Hypermetabolism

Abstract Introduction After major burn injuries, patients experience a hypermetabolic response that leads to hyperdynamic circulatory, physiologic, catabolic, and immune system responses. Many transdisciplinary approaches have been tested to mitigate this postburn hypermetabolic syndrome such as comprehensive burn rehabilitation, nutritional support, monitoring, and pharmacological interventions. Oxandrolone, a synthetic analog of testosterone, has been shown to have higher anabolic properties and minimal androgenic effects and studied intensely in burn care. In 2023, the FDA asked all manufacturers of oxandrolone to cease production and subsequently removed the drug from market on June 28, 2023. Our study examines the cost and operationalization of an intramuscular (IM) testosterone protocol as an alternative in male burn patients with ≥20% total body surface area (TBSA). Methods A cost analysis was conducted using the National Drug Codes (NDC) and commercially available benchmarking data. The cost of oxandrolone and testosterone were included in our analysis. Following a thorough literature review, a protocol was developed for adult male patients with >20% TBSA burn injuries. Patients undergoing gender affirming hormone therapy, untreated obstructive sleep apnea, or hormonal blockers for cancer were excluded from the protocol. Results The protocol begins with total serum testosterone levels at the time of admission and weekly thereafter for male patients with ≥20% TBSA injury. Once a testosterone level < 150 ng/dL is detected, supplementation of testosterone with 200 mg IM once weekly for two weeks is started. Weekly evaluations include total body weight, metabolic panels, and nutritional panels. Cost comparison between oxandrolone and testosterone show an equivalent unit cost of $8.62 versus $8.38, respectively. Conclusions Drug shortages and supply chain challenges are becoming more common in burn care. We hypothesize testosterone to be both a clinically effective and cost-effective alternative to oxandrolone in the setting of burn hypermetabolism in male patients with major burns. Currently, burn experts are working with endocrinologists to assess pharmacologic alternatives for female patients and have obtained IRB-approval to evaluate both safety and efficacy of testosterone supplementation in the setting of burn hypermetabolism. Applicability of Research to Practice This study evaluates the safety and efficacy of testosterone supplementation as an alternative to oxandrolone in the setting of burn hypermetabolism. This study helps provide guidance to other burn centers in filling the gap in therapy that now exists in the pharmacologic management of hypermetabolic syndrome in patients with severe burns.

98 Plasma Extracellular Vesicles Released After Sever Burn Injury Modulate Macrophage Function

IntroductionExtracellular microvesicles (MVs) have emerged as key regulators of immune function across multiple diseases and potential biomarkers. Severe burn injury is a devastating trauma with significant immune dysfunction that results in an ~12% mortality rate due to sepsis-induced organ failure, pneumonia, and other infections. Severe burn causes a biphasic immune response: an early (0-72 hrs) hyper-inflammatory state, with release of pro-inflammatory damage-associated molecular pattern molecules (DAMPs), such as HMGB1, and cytokines (e.g.IL-1b), followed by an immunosuppressive state (1-2 weeks post injury), associated with increased susceptibility to life-threatening infections. We have reported that early after severe burn injury HMGB1 and IL-1b are enriched in plasma microvesicles (MVs), suggesting a role for MVs in post-burn immune activation. Here we tested the impact of MVs isolated after burn injury on phenotypic and functional consequences in vivo and in vitro using adoptive MV transfers.MethodsWe then assessed if the cargo of MVs following burn injury in humans could predict length of hospital stay. MVs isolated early from mice that underwent a 20% total body surface area (TBSA) burn injury (burn MVs) caused similar cytokine responses in naïve mice to those seen in burned mice early after injury. Burn MVs transferred to RAW264.7 macrophages caused similar functional (i.e. cytokine secretion) and genetic changes (measured by NanoStringTM) seen with their associated phase of post-burn immune dysfunction.ResultsBurn MVs isolated early (24h) induced MCP-1, IL-12p70 and IFNg, while MVs isolated later (1 and 2 weeks) blunted RAW proinflammatory responses to bacterial endotoxin (LPS). Unbiased LC-MS / MS proteomic analysis of early EVS (< 72 h post-injury) showed similarities in human and mice.ConclusionsIn our sample of large burn injury, EV SAA1 and CRP correlated with TBSA injury in both sexes and were correlated with length of hospital stay in women.

508 A Case Report of Trichosporon asahii Burn Infection: A Not-So-Fungi

Introduction Trichosporon asahii is a yeast-like basidiomycete that can cause infections in immunocompromised hosts including superficial infections, pneumonia, meningitis, fungemia, and disseminated trichosporonosis. These infections have become more common over the last 30 years in patients with burns or other immunosuppressive conditions. Disseminated T. asahii is intrinsically difficult to treat and carries a mortality rate as high as 70% despite the availability of effective medications.MethodsA 61-year-old male was admitted after falling into a vat of pig manure which was 160 degrees F, resulting in approximately 75% total body surface area injury to his anterior and posterior trunk, and bilateral upper and lower extremities. Throughout his hospital course, he underwent surgical debridement on multiple occasions with placement of homograft, autograft, and spray keratinocytes. The earliest cultures to demonstrate T. asahii growth were obtained on post-burn day (PBD) 23 and growth continued until PBD 32. Quantitative colony counts ranged from 600-365000000 CFU/g from left lower and upper extremities and chest. Cultures were obtained in preparation for cultured epithelial autograft placement which occurred on PBD 36. Susceptibility testing was sent and the minimum inhibitory concentration (MIC) results are reported in Table 1. Clinical and Laboratory Standards Institute (CLSI) guidelines for interpretation of susceptibility are not available for T. asahii, but suggested breakpoints are summarized in Table 1.ResultsOn PBD 23, topical amphotericin B irrigation and voriconazole oral suspension were initiated. A voriconazole level was obtained on PBD 31, which was subtherapeutic, and dosing was subsequently adjusted. In total, the patient received 13 days of topical amphotericin B and 21 days of voriconazole for treatment. Subsequent cultures demonstrated microbiologic cure of T. asahii.ConclusionsThis immunocompromised burn patient was successfully treated for Trichosporon asahii using a combination of topical and systemic antifungal agents.

Burn Injury Induces Proinflammatory Plasma Extracellular Vesicles That Associate with Length of Hospital Stay in Women: CRP and SAA1 as Potential Prognostic Indicators.

Severe burn injury is a devastating form of trauma that results in persistent immune dysfunction with associated morbidity and mortality. The underlying drivers of this immune dysfunction remain elusive, and there are no prognostic markers to identify at-risk patients. Extracellular vesicles (EVs) are emerging as drivers of immune dysfunction as well as biomarkers. We investigated if EVs after burn injury promote macrophage activation and assessed if EV contents can predict length of hospital stay. EVs isolated early from mice that received a 20% total body surface area (TBSA) burn promoted proinflammatory responses in cultured splenic macrophages. Unbiased LC-MS/MS proteomic analysis of early EVs (<72 h post-injury) from mice and humans showed some similarities including enrichment of acute phase response proteins such as CRP and SAA1. Semi-unbiased assessment of early human burn patient EVs found alterations consistent with increased proinflammatory signaling and loss of inhibition of CRP expression. In a sample of 50 patients with large burn injury, EV SAA1 and CRP were correlated with TBSA injury in both sexes and were correlated with length of hospital stay in women. These findings suggest that EVs are drivers of immune responses after burn injury and their content may predict hospital course.

A quantitative model of invasive Pseudomonas infection in burn injury.

To evaluate newer therapies for wound infections, it becomes necessary to quantify bacteria that invade from the infected wounds into the adjacent tissues. For example, antibody-targeted photolysis targets the invasive Pseudomonas with antibodies carrying photochemical dyes. A full-thickness burn wound was infected with Pseudomonas aeruginosa with a modification of previous methods. In mice, a skin fold was elevated, and two preheated brass blocks at 92 degrees to 95 degrees C were applied for 5 seconds, producing a 5% total body surface area injury with discrete margins. The eschars were immediately inoculated with Pseudomonas. Survival at 10 days was 100% with burn injury alone and 60% with infected burns. Pseudomonas (10(8)/gm) were recovered from the unburned muscle by 24 hours. The method produced uniform and reproducible quantitative bacteriology within the muscle immediately beneath the burn injury (SL < 0.05). Quantitative comparisons can be used to determine the effectiveness of newer modalities to control Pseudomonas burn wound infections.

Absence of change in hepatic lactate metabolism after burn injury

In response to severe injury, extraordinary quantities of lactate that are released from the peripheral tissues serve as substrate for hepatic gluconeogenesis. It is possible that as a result of burn injury, reaction kinetics involving lactate could be directly changed within the liver. The metabolic fate of [U- 14C]lactate was examined in vitro in fresh liver slices after a 20 per cent total body surface area injury. Glucose and CO 2 were produced in vitro by the liver tissues after the injury and no differences were seen in the metabolism of these substrates between the injured and control animals. These findings suggest that the intrinsic enzymatic processes within the liver are not directly altered by injury itself or by any of the associated inflammatory mediators which appear early after burns.

Effects of fluid resuscitation, burn eschar excision, and blockade of afferent pain responses on bacterial translocation and acid-base balance after murine burn injury.

We tested effects of fluid resuscitation, early burn excision/grafting, and blockade of afferent stimuli from the burn wound on bacterial translocation and acid-base balance after murine burn injury. Burn excisions were performed with patients either 15 minutes or 2 hours after burn injury under anesthesia, and excised wounds were immediately closed with murine allograft skin. Twenty-four hours after 25% total body surface area (TBSA) burn injury and 48 hours after 32% TBSA injury, mesenteric lymph nodes were cultured. Incidences of bacterial translocation in 25% and 32% TBSA burns were 31.6% and 68.4% of animals, respectively. Burned animals were in severe shock, and metabolic acidosis reached a nadir 12 hours after burn injury, with base deficit -27.8 +/- 0.6 mEq/L; 5% to 10% of animals died acutely after burn injury. After excision/grafting of burned mice at 2 hours after burn injury, the incidence of bacterial translocation was unchanged (35.7% with 25% TBSA burn, 73.3% with 32% TBSA burn), and mortality did not change. When 32% TBSA excisions were performed exactly 10 minutes after burn injury, four of the 13 mice died within several hours, and five (55.5%) of the nine survivors translocated. Rates of bacterial translocation in mice receiving anesthesia or excision/grafting without burn injury were 15.0% and 20%, respectively (p = NS compared with normal mice). Subcutaneous implantation of normal or burned skin into normal animals neither elicited shock nor increased the incidence of bacterial translocation. Increasing amounts of fluid resuscitation in the 25% TBSA burn model provided only delayed improvement of acid-base balance; increased amounts of fluid did not decrease bacterial translocation.(ABSTRACT TRUNCATED AT 250 WORDS)

Benefits of OKG supplementation

A group of 30 burn patients with 36–87% total body surface area (TBSA) burns was studied at 24–48 hr postburn. These included studies of (1) autologous and allogeneic mixed-lymphocyte reactions (MLR); (2) the immunoregulatory influence of mitomycin C-treated T cells, non-T cells, and unfractionated peripheral blood lymphocytes (PBL) on allogeneic MLR; and (3) correlation between the proportions of T-cell subsets defined with monoclonal antibodies (OKT4 and OKT8) and autologous MLR. Studies concerning adherent cell production of thromboxane, prostaglandin E2, and prostaglandin F2a and the immunomodulatory effects of Interleukin 1 (IL-1), Interleukin 2 (IL-2), and a prostaglandin inhibitor, WY-18251, on autologous MLR are presented. The autologous mixed-lymphocyte reaction was depressed in 60% of the burn patients tested. This depressed response correlated closely to the extent of third-degree injury (P < 0.025) and to TBSA injury >60% (P < 0.025). A linear correlation was observed between the depression in autologous MLR and a decrease in both the percentage of OKT4+ T cells and the OKT4+OKT8+ ratio. The response of T cells from burn patients in allogeneic MLR was normal. Age, sex, TBSA of the burn, and size of second-degree burn did not correlate with the abnormalities observed in MLR. Mitomycin C-treated mononuclear cells, purified T cells, or non-T cells from burned patients did not demonstrate any suppressive influence on MLR in normals. Monocyte number and arachidonic acid metabolism were investigated. In addition to increased numbers of monocytes following thermal injury, adherent cells produced increased quantities of thromboxane, prostaglandin E2, and prostaglandin F2a. The effects of Interleukin 1, Interleukin 2, and a prostaglandin inhibitor, WY-18251, were studied in autologous MLR (AMLR) of burned and normal patients. Interleukin 1 and WY-18251 did not induce any significant changes in proliferation in burned patients or normal controls. When compared to cultures without exogenous IL-2, an increase in AMLR was observed following the addition of IL-2 to burn patient cultures at Day 6 and Day 7 of culture. Although the addition of IL-2 did increase proliferation in AMLR of normal controls at Day 6 and Day 7, the enhancement observed for the burn patient cultures represented a restoration to the level of normal control cultures without IL-2. A dose-dependent increase in AMLR was observed in T cells isolated from normal and burned patients in the presence of purified Interleukin 2. These data suggest that burn-induced cell-mediated immunological alterations may be caused by an imbalance between regulatory T-cell subsets characterized by a decrease in helper inducer (OKT4+) cell number and a deficiency in the production of Interleukin 2. Burn patients appear to express the receptor for IL-2 and do not appear to be sensitive to modulation by prostaglandin inhibitors.

Autologous and allogeneic mixed-lymphocyte responses following thermal injury in man: The immunomodulatory effects of interleukin 1, interleukin 2, and a prostaglandin inhibitor, WY-18251

A group of 30 burn patients with 36–87% total body surface area (TBSA) burns was studied at 24–48 hr postburn. These included studies of (1) autologous and allogeneic mixed-lymphocyte reactions (MLR); (2) the immunoregulatory influence of mitomycin C-treated T cells, non-T cells, and unfractionated peripheral blood lymphocytes (PBL) on allogeneic MLR; and (3) correlation between the proportions of T-cell subsets defined with monoclonal antibodies (OKT4 and OKT8) and autologous MLR. Studies concerning adherent cell production of thromboxane, prostaglandin E 2, and prostaglandin F 2a and the immunomodulatory effects of Interleukin 1 (IL-1), Interleukin 2 (IL-2), and a prostaglandin inhibitor, WY-18251, on autologous MLR are presented. The autologous mixed-lymphocyte reaction was depressed in 60% of the burn patients tested. This depressed response correlated closely to the extent of third-degree injury ( P < 0.025) and to TBSA injury >60% ( P < 0.025). A linear correlation was observed between the depression in autologous MLR and a decrease in both the percentage of OKT4+ T cells and the OKT4+ OKT8+ ratio. The response of T cells from burn patients in allogeneic MLR was normal. Age, sex, TBSA of the burn, and size of second-degree burn did not correlate with the abnormalities observed in MLR. Mitomycin C-treated mononuclear cells, purified T cells, or non-T cells from burned patients did not demonstrate any suppressive influence on MLR in normals. Monocyte number and arachidonic acid metabolism were investigated. In addition to increased numbers of monocytes following thermal injury, adherent cells produced increased quantities of thromboxane, prostaglandin E 2, and prostaglandin F 2a. The effects of Interleukin 1, Interleukin 2, and a prostaglandin inhibitor, WY-18251, were studied in autologous MLR (AMLR) of burned and normal patients. Interleukin 1 and WY-18251 did not induce any significant changes in proliferation in burned patients or normal controls. When compared to cultures without exogenous IL-2, an increase in AMLR was observed following the addition of IL-2 to burn patient cultures at Day 6 and Day 7 of culture. Although the addition of IL-2 did increase proliferation in AMLR of normal controls at Day 6 and Day 7, the enhancement observed for the burn patient cultures represented a restoration to the level of normal control cultures without IL-2. A dose-dependent increase in AMLR was observed in T cells isolated from normal and burned patients in the presence of purified Interleukin 2. These data suggest that burn-induced cell-mediated immunological alterations may be caused by an imbalance between regulatory T-cell subsets characterized by a decrease in helper inducer (OKT4+) cell number and a deficiency in the production of Interleukin 2. Burn patients appear to express the receptor for IL-2 and do not appear to be sensitive to modulation by prostaglandin inhibitors.

Intramuscular pressure in the burned arm: measurement and response to escharotomy

Using a wick catheter technique, sequential measurements of intramuscular pressure were obtained in 31 burned arms in 18 patients. Abnormally high pressures were recorded in 90 percent of extremities and exceeded the potentially harmful level of 30 mm Hg in 42 percent. Correlation of intramuscular pressure with signs and symptoms of extremity compression, including Doppler pulses, was poor. Intramuscular pressure elevation appeared to parallel edema formation beneath the burn wound. A high incidence of pressure measurements in excess of 30 mm Hg was found in patients who had 30 percent or greater total body surface area injury (67 percent), 10 percent or greater full-thickness burns (75 percent), and extremities with circumferential involvement (57 percent). In every case escharotomy produced a dramatic decrease in intramuscular pressure, while a randomized group of extremities that were not decompressed developed sustained pressures as high as 64 mm Hg despite the presence of intact Doppler pulses. Extremities treated in this manner appeared slower in resolving edema and regaining motion and strength. Measurement of intramuscular pressure beneath the burn eschar is recommended in evaluating all patients at risk from extremity burns.