Lactate shuttling drives the browning of white adipose tissue after burn.

High levels of plasma lactate are associated with increased mortality in critically injured patients, including those with severe burns. Although lactate has long been considered a waste product of glycolysis, it was recently revealed that it acts as a potent inducer of white adipose tissue (WAT) browning, a response implicated in mediating postburn cachexia, hepatic steatosis, and sustained hypermetabolism. Despite the clinical presentation of hyperlactatemia and browning in burns, whether these two pathological responses are linked is currently unknown. Here, we report that elevated lactate plays a causal signaling role in mediating adverse outcomes after burn trauma by directly promoting WAT browning. Using WAT obtained from human burn patients and mouse models of thermal injury, we show that the induction of postburn browning is positively correlated with a shift toward lactate import and metabolism. Furthermore, daily administration of l-lactate is sufficient to augment burn-induced mortality and weight loss in vivo. At the organ level, increased lactate transport amplified the thermogenic activation of WAT and its associated wasting, thereby driving postburn hepatic lipotoxicity and dysfunction. Mechanistically, the thermogenic effects of lactate appeared to result from increased import through MCT transporters, which in turn increased intracellular redox pressure, [NADH/NAD+], and expression of the batokine, FGF21. In fact, pharmacological inhibition of MCT-mediated lactate uptake attenuated browning and improved hepatic function in mice after injury. Collectively, our findings identify a signaling role for lactate that impacts multiple aspects of postburn hypermetabolism, necessitating further investigation of this multifaceted metabolite in trauma and critical illness.NEW & NOTEWORTHY To our knowledge, this study was the first to investigate the role of lactate signaling in mediating white adipose tissue browning after burn trauma. We show that the induction of browning in both human burn patients and mice is positively correlated with a shift toward lactate import and metabolism. Daily l-lactate administration augments burn-induced mortality, browning, and hepatic lipotoxicity in vivo, whereas pharmacologically targeting lactate transport alleviates burn-induced browning and improves liver dysfunction after injury.

Propranolol Normalizes Metabolomic Signatures Thereby Improving Outcomes After Burn.

OBJECTIVE AND BACKGROUND: Propranolol, a nonselective beta-receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta-blockade are well characterized, the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves outcomes after burn injury by profoundly modulating metabolic pathways. METHODS: In this phase II randomized controlled trial, patients with burns ≥20% of total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, inflammatory and lipidomic profiles, untargeted metabolomics, and molecular pathways. RESULTS: Fifty-two severely burned patients were enrolled in this trial (propranolol, n=23 and controls, n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism, as well as catecholamine degradation ( P <0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of proinflammatory palmitic acid ( P <0.05) and saturated fatty acids ( P <0.05) with an increased ratio of polyunsaturated fatty acids ( P <0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn ( P <0.05). These metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 ( P <0.05) and significantly reduced endoplasmic reticulum stress by decreasing phospho-JNK ( P <0.05). CONCLUSION: Propranolol's ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses.

Single-nuclei RNA Profiling Reveals Disruption of Adipokine and Inflammatory Signaling in Adipose Tissue of Burn Patients.

OBJECTIVE: We conducted a large-scale investigation of the systemic and adipose tissue-specific alterations in a clinical population of burn patients to identify factors that may influence hypermetabolism. BACKGROUND: Previous research has identified chronic disturbances in adipose tissue inflammation, lipolysis, and browning, which may drive the perpetuation of hypermetabolism following the severe adrenergic stress of a burn injury. Given that adipose tissue is thought to be a central node in the regulation of systemic metabolism, we believe that systematically delineating the pathologic role of adipose tissue postburn, will lead to the identification of novel interventions to mitigate morbidity and mortality from severe burns. METHODS: This was a single-institution cohort study, which obtained plasma and subcutaneous adipose tissue samples from severely burn adult patients over various time points during acute hospitalization. Whole-body clinical, metabolic, and inflammatory mediators were assessed in plasma, while genetic analyses through RT-qPCR and single-nuclei RNA sequencing were conducted in adipose tissue. RESULTS: Systemic inflammation and adrenergic stress increase IL-6 signaling, lipolysis, browning, and adipokine dysfunction in the adipose tissue of adult burn patients, which may further propagate the long-term hypermetabolic response. Moreover, using single-nuclei RNA sequencing, we provide the first comprehensive characterization of alterations in the adipose tissue microenvironment occurring at acute and chronic stages postburn. CONCLUSION: We provide novel insight toward the effect of burns on adipokine release, inflammatory signaling pathways, and adipose heterogeneity over the trajectory of acute and chronic stages.

Acute Phase Response in Critically Ill Elderly Burn Patients.

OBJECTIVES: Survival of elderly burn patients remains unacceptably poor. The acute phase, defined as the first 96 hours after burn, includes the resuscitation period and influences subsequent outcomes and survival. The aim of this study was to determine if the acute phase response post burn injury is significantly different in elderly patients compared with adult patients and to identify elements contributing to adverse outcomes. DESIGN: Cohort study. SETTING: Tertiary burn center. PATIENTS: Adult (< 65 yr old) and elderly (≥ 65 yr old) patients with an acute burn injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included all patients with an acute burn injury greater than or equal to 20% total body surface area to our burn center from 2011 to 2016. Clinical and laboratory measures during the acute phase were compared between adult and elderly patients. Outcomes included clinical hemodynamic measurements, organ biomarkers, volume of fluid resuscitation, cardiac agents, and the inflammatory cytokine response in plasma. Data were analyzed using the Student t test, Mann-Whitney U test, and Fisher exact test. A total of 149 patients were included, with 126 adults and 23 elderly. Injury severity was not significantly different among adult and elderly patients. Elderly had significantly lower heart rates (p < 0.05), cardiac index (p < 0.05), mean arterial pressure (p < 0.05), PaO2/FIO2 (p < 0.05), and pH (p < 0.05), along with higher lactate (p < 0.05). Organ biomarkers, particularly creatinine and blood urea nitrogen, showed distinct differences between adults and elderly (p < 0.05). Elderly had significantly lower levels of interleukin-6, monocyte chemotactic protein-1, monocyte chemotactic protein-3, and granulocyte-colony stimulating factor during the acute phase (p < 0.05). Overall mortality was significantly higher in elderly patients (5% vs 52%; p < 0.0001). CONCLUSIONS: Response to the burn injury during the acute phase response after burn is substantially different between elderly and adult burn patients and is characterized by cardiac depression and hypoinflammation.

The effect of diabetes on burn patients: a retrospective cohort study.

BACKGROUND: Hyperglycemia during the acute phase after burn is associated with increased morbidity and mortality. There is little knowledge regarding the effect of pre-existing hyperglycemia in the form of diabetes on the outcomes after severe burns. The objective is to determine the impact of diabetes on clinical outcomes after burns. METHODS: Single-center cohort study where adult diabetic (n = 76) and non-diabetic (n = 1186) burn patients admitted between 2006 and 2016 were included. Diabetic patients were stratified into those with well-controlled diabetes (n = 24) and poorly controlled diabetes (n = 33) using a HbA1c of 7% as a cutoff; additionally, diabetics were divided into well-controlled glycemia (n = 47) and poorly controlled glycemia (n = 22) based on daily blood glucose measurements during hospitalization. RESULTS: On univariate analysis, diabetics had a significantly increased median length of stay per percent total body surface area burn (2.1 vs. 1.6 days; p = 0.0026) and a greater number of overall morbidity (1.39 ± 1.63 vs. 0.8 ± 1.24; p = 0.001). After adjustment for patient characteristics, diabetics were associated with significantly increased total morbidity (RR 1.5; 95% CI 1.1-1.9). At discharge, almost two thirds of diabetics needed an escalation of anti-diabetic medication and a quarter had newly developed insulin dependency. There were no differences in morbidity or mortality in the diabetic subgroups. CONCLUSIONS: Diabetics had a longer hospitalization and increased morbidity, regardless of the quality of their anti-diabetic therapy prior to injury. Additionally, diabetes in burn patients is associated with an increased risk of total morbidity.

Pathophysiological Response to Burn Injury in Adults.

OBJECTIVE: The aim of this study was to compare the hypermetabolic, and inflammatory trajectories in burned adults to gain insight into the pathophysiological alterations and outcomes after injury. SUMMARY OF BACKGROUND DATA: Burn injury leads to a complex response that is associated with hypermetabolism, morbidity, and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated in adult burn patients. METHODS: Burned adult patients (n = 1288) admitted to our center from 2006 to 2016 were enrolled in this prospective study. Demographics, clinical data, metabolic and inflammatory markers, hypermetabolism, organ function, and clinical outcomes were obtained throughout acute hospitalization. We then stratified patients according to burn size (<20%, 20% to 40%, and >40% total body surface area [TBSA]) and compared biomedical profiles and clinical outcomes for these patients. RESULTS: Burn patients were hypermetabolic with elevated resting energy expenditure (REE) associated with increased browning of white adipose tissue from weeks 2 to 4. Hyperglycemia and hyperinsulinemia peaked 7 to 14 days after injury. Oral glucose tolerance and insulin resistance (QUICKI, HOMA2) tests further confirmed these findings with similar areas under the curve for moderate (20% to 40% TBSA) and severe burn (>40% TBSA). Lipid metabolism in sera revealed elevated pro-inflammatory stearic and linoleic acid, with complementary increases in anti-inflammatory free fatty acids. Similar increases were observed for inflammatory cytokines, chemokines, and metabolic hormones. White adipose tissue from the site of injury had increased ER stress, mitochondrial damage, and inflammasome activity, which was exacerbated with increasing burn severity. CONCLUSIONS: In this large prospective trial, we delineated the complexity of the pathophysiologic responses postburn in adults and concluded that these profound responses are time and burn size dependent. Patients with medium-size (20% to 40% TBSA) burn demonstrated a very robust response that is similar to large burns.

Glucose Control in Severely Burned Patients Using Metformin: An Interim Safety and Efficacy Analysis of a Phase II Randomized Controlled Trial.

OBJECTIVE: To determine whether metformin can achieve glucose control no worse than insulin (noninferiority) without the danger of hypoglycemia (superiority). In addition, to assess whether metformin has any additional effects on lipolysis and inflammation that will enhance burn recovery (superiority). SUMMARY BACKGROUND DATA: Hyperglycemia and insulin resistance after burn injury are associated with increased morbidity and mortality. Insulin administration improves postburn infections, severity of sepsis, and morbidity, but also causes a 4-5-fold increase in hypoglycemia, which is associated with a 9-fold increase in mortality. METHODS: Severely burned adult patients with burns over 20% total body surface area (TBSA) burn were prospectively randomized in this Phase II clinical trial to either metformin or insulin (standard of care) treatment. Primary outcomes were glucose levels and incidence of hypoglycemia. Secondary outcomes included glucose and fat metabolism, and clinical outcomes. RESULTS: Forty-four patients were enrolled in this Phase II clinical trial, 18 metformin and 26 insulin patients. Demographics, burn size, concomitant injuries, and mortality were comparable between both groups. Metformin controlled blood glucose as equally as insulin with no difference between the 2 treatment groups, P > 0.05. While there was a 15% incidence of hypoglycemia in the insulin group, there was only 1 mild hypoglycemic episode (6%) in the metformin group, P < 0.05. Oral glucose tolerance tests at discharge revealed that metformin significantly improved insulin sensitivity, P < 0.05. Furthermore, metformin had a strong antilipolytic effect after burn injury when compared with insulin and was associated with significantly reduced inflammation, P < 0.05. CONCLUSIONS: Metformin decreases glucose equally as effective as insulin without causing hypoglycemia, with additional benefits including improved insulin resistance and decreased endogenous insulin synthesis when compared with insulin controls. These results indicate that metformin is safe in burn patients and further supports the use of metformin in severely burned patients for postburn control of hyperglycemia and insulin resistance.

Burned Adults Develop Profound Glucose Intolerance.

OBJECTIVES: Metabolic alterations after burn injury have been well described in children; however, in adult patients, glucose metabolism and insulin sensitivity are essentially unknown. We sought to characterize metabolic alterations and insulin resistance after burn injury and determine their magnitude and persistence at discharge. DESIGN: Prospective, cohort study. SETTING: Tertiary burn centre. PATIENTS: Nondiabetic adults with an acute burn involving greater than or equal to 20% total body surface area. INTERVENTIONS: An oral glucose tolerance test was administered at discharge. MEASUREMENTS AND MAIN RESULTS: Glucose, insulin, and C-peptide levels were measured to derive surrogate measures of insulin resistance and ß-cell function, including quantitative insulin sensitivity check index, homeostasis model assessment of ß-cell function, homeostasis model assessment of insulin sensitivity, homeostasis model assessment of insulin resistance, and the composite whole-body insulin sensitivity index. Patients were grouped according to the degree of glucose tolerance: normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or diabetes. Forty-five adults, 44 ± 15 years old and with 38% ± 14% total body surface area burned, underwent an oral glucose tolerance test at discharge. Median quantitative insulin sensitivity check index (0.348 [0.332-0.375]) and median homeostasis model assessment of insulin resistance (1.13 [0.69-1.45]) were abnormal, indicating insulin resistance and impaired insulin production at discharge. Two-thirds of patients (n = 28) met criteria for impaired fasting glucose/impaired glucose tolerance or diabetes. CONCLUSIONS: We have demonstrated that burn-injured adults remain hyperglycemic, are insulin resistant, and express defects in insulin secretion at discharge. Patients with lower burn severity (total body surface area, 20-30%) express similar metabolic alterations as patients with larger burns (total body surface area, ≥ 30%). Glucose tolerance testing at discharge offers an opportunity for early identification of burn patients who may be at high risk of prediabetes and diabetes. Our findings demonstrated that two-thirds of burn patients had some degree of glucose intolerance. With this in mind, surveillance of glucose intolerance post discharge should be considered. As hyperglycemia and insulin resistance are associated with poor outcomes, studies should focus on how long these profound alterations persist.

The efficacy of 2 doses of epidural morphine for postcesarean delivery analgesia: a randomized noninferiority trial.

BACKGROUND: A single dose of epidural morphine is effective in reducing pain after cesarean delivery but is associated with adverse effects. In this study, we sought to establish whether half the traditional dose of epidural morphine, when administered as part of a multimodal analgesia regimen after cesarean delivery, was associated with noninferior analgesia and fewer adverse effects. METHODS: Ninety term parturients undergoing cesarean delivery under epidural anesthesia were enrolled in this randomized, double-blinded, noninferiority study. Patients were randomly allocated to receive either 3 mg epidural morphine or, half this dose, 1.5 mg epidural morphine. In addition, subjects received regular systemic ketorolac and acetaminophen. Rescue analgesia (oral oxycodone) was administered for breakthrough pain. The primary outcome was the difference between groups in total opioid consumption (measured in median IV morphine equivalents) within the first 24 hours. A prespecified noninferiority margin of 3.33 mg was used. Secondary outcomes included total opioid consumption from 24 to 48 hours, numerical rating scale pain scores, time to first request for analgesics, overall pain relief, maternal satisfaction, quality of recovery, and adverse effects. RESULTS: Data were analyzed for 87 participants. Noninferiority was demonstrated as the difference in median 24-hour opioid consumption between the 1.5 mg epidural morphine (EM) and 3 mg EM groups was 0 mg (1-sided 95% confidence interval [CI], 2.5 mg), which was less than the prespecified noninferiority margin of 3.33 mg. No significant differences were found between groups in the median 24- to 48-hour opioid consumption or the median total opioid consumption within 48 hours. Pain scores, overall pain relief, and satisfaction at 24 and 48 hours were not significantly different between groups. The 1.5 mg EM group had a lower incidence of moderate and severe pruritus at 6 and 12 hours (relative risk [RR] 0.44, 95% CI, 0.2-0.9 and RR 0.41, 95% CI, 0.2-0.8, respectively) and had less nausea and vomiting at 6 hours (RR 0.22, 95% CI, 0.05-0.9). There was no difference in average pain scores at 12 weeks between the 2 groups. CONCLUSION: When used as part of a multimodal analgesia regimen, 1.5 mg epidural morphine provided noninferior postcesarean analgesia and caused fewer adverse effects compared with 3 mg epidural morphine.

CLASSIC IL-6 SIGNALING IS ASSOCIATED WITH POOR OUTCOMES IN BURN PATIENTS.

ABSTRACT: Background: Interleukin (IL)-6 is a multifunctional cytokine with both a proinflammatory and anti-inflammatory role. In many studies, IL-6 increases rapidly after burn injury and is associated with poor outcomes. However, there are two aspects to IL-6; it can signal via its soluble IL-6 receptor (sIL-6R), which is referred to as trans-signaling and is regarded as the proinflammatory pathway. The role of sIL-6R postburn injury has yet to be explored in its entirety. We hypothesized that patients with a lower ratio of IL-6 to sIL-6R would have worse outcomes. Methods: Patients admitted to our burn center within 7 days of injury were included in this study. Patients were divided into two groups based on IL-6 and sIL-6R levels measured within the first 7 days postburn injury. Patients were in the high ratio group if their IL-6/sIL-6R ratio was ≥0.185. Clinical outcomes included organ biomarkers, morbidities, and hospital length of stay. Groups were compared using Student's t test, Mann-Whitney U , and Fisher's exact test as appropriate; a P value of <0.05 was considered statistically significant. Results: We studied 86 patients with a median age of 50 years (36-66 years) and a median total body surface area burn of 18% (10-31). There were 40 patients categorized with a low IL-6/sIL-6R ratio and 46 patients with a high IL-6/sIL-6R ratio. Patients in the high IL-6/sIL-6R ratio group had a significantly greater total body surface area burn ( P < 0.001) and a significantly greater proportion of patients with inhalation injury ( P = 0.001). Levels of IL-6 were significantly higher in patients with a high IL-6/sIL-6R ratio ( P < 0.0001). However, levels of sIL-6R were not significantly different among the low and high groups ( P = 0.965). Mortality was significantly greater in the high IL-6/sIL-6R ratio group (3% vs. 26%; P = 0.002). Conclusions: Interestingly, patients with a higher ratio of IL-6/sIL-6R had significantly greater mortality. Using sIL-6R as a marker for the proinflammatory immune response, we expected patients with a lower IL-6/sIL-6R ratio to have poor outcomes, typically associated with a hyperinflammatory or exaggerated immune response. However, the absolute value of sIL-6R did not differ. This suggests that classical signaling of IL-6 via its membrane-bound receptor, with an anti-inflammatory function, is important.

Admission creatinine is associated with poor outcomes in burn patients.

INTRODUCTION: Renal failure is the most common organ failure in severely burned patients. However, defining acute kidney injury and renal failure is very challenging. This study was designed to determine the relationship between a biomarker commonly measured on admission, serum creatinine, and outcomes in burn patients. METHODS: We conducted a retrospective cohort study of adult patients (≥ 18 years) with a burn ≥ 5% total body surface area (TBSA) and a serum creatinine level measured within the first 72 h after injury. Patients were admitted over an 11-year period and divided into two groups based on creatinine levels measured within the first 72 h after injury. Patients were categorized in the high creatinine group if they had a measured creatinine ≥107 µmol/L (≥1.21 mg/dL); this value was chosen as the threshold for creatinine based on our institution's reference range. Clinical outcomes included morbidities, hospital length of stay, and mortality. Multivariable logistic regression was used to model the association between high admission creatinine and each outcome, adjusting for patient and injury characteristics. RESULTS: We studied 923 patients, mean age 47 ± 18 years and median 13% (IQR 8-24) TBSA burned. There were 718 patients categorized with low admission creatinine and 205 patients with high admission creatinine. After adjustment for patient and injury characteristics, high admission creatinine was associated with a significantly higher rate of sepsis (OR 3.44; 95% CI 2.11-5.59), pneumonia (OR 4.56; 95% CI 1.8-11.53), and mortality (OR 3.59; 95% CI 1.91-6.75). CONCLUSIONS: Elevated creatinine on admission is associated with an increased risk of morbidity and mortality. We suggest that admission creatinine can be used as a "red flag" to identify patients at a higher risk for poor outcomes.

Identifying Risk Factors That Increase Analgesic Requirements at Discharge Among Patients With Burn Injuries.

Patients with burn injuries require large doses of opioids and gabapentinoids to achieve pain control and are often discharged from hospital with similar amounts. This study aimed to identify patient risk factors that increase analgesic requirements among patients with burn injuries and to determine the relationship between opioid and gabapentinoid use. Patient charts from July 1, 2015 to 2018 were reviewed retrospectively to determine analgesic requirements 24 hours before discharge. Linear mixed regression models were performed to determine patient risk factors (age, gender, history of substance misuse, TBSA of burn, length of stay in hospital, history of psychiatric illness, or surgical treatment) that may increase analgesic requirements. This study found that patients with a history of substance misuse (P = .01) or who were managed surgically (P = .01) required higher doses of opioids at discharge. Similarly, patients who had undergone surgical debridement required more gabapentinoids (P < .001). For every percent increase in TBSA, patients also required 14 mg more gabapentinoids (P = .01). In contrast, older patients (P = .006) and those with a longer hospital stay (P = .009) required fewer amounts of gabapentinoids before discharge. By characterizing factors that increase analgesic requirements at discharge, burn care providers may have a stronger understanding of which patients are at greater risk of developing chronic opioid or gabapentinoid misuse. The quantity and duration of analgesics prescribed at discharge may then be tailored according to these patient specific risk factors.

Comparison of Clinical Outcomes of Lower Extremity Burns in Diabetic and Nondiabetic Patients: A Retrospective Analysis.

Diabetes mellitus is an increasingly prevalent chronic disease that leads to long-term health consequences. Some long-term clinical sequelae of diabetes include coronary artery disease, peripheral vascular disease, peripheral neuropathy, and impaired wound healing. These can increase hospital stay and complications such as wound infections and amputations among patients with lower extremity burns. A retrospective analysis was performed of all isolated lower extremity burns from a single tertiary burn care center from 2006 to 2017. Patients were stratified by diabetic status and the incidence of lower extremity amputations was the primary outcome. Multivariable regression was used to model the association between diabetes and amputations, adjusting for patient and injury characteristics. A total of 198 patients were identified as meeting inclusion criteria, 160 were nondiabetic and 38 were diabetic. Age was significantly different between nondiabetic and diabetic patients; mean age was 46 ± 18 vs 62 ± 17 years (P < .0001). Length of stay was also significantly different, median length of stay was 11 (interquartile range 7-15) vs 18 (interquartile range 12-24; P < .001), with diabetic patients staying longer. There was a significantly greater proportion of diabetic patients that had an amputation (control 4% vs diabetic 29%; P < .0001). After adjustment for patient and injury characteristics, there was a significant association between diabetes and amputation (P = .002). Among patients with isolated lower extremity burns, those with a preexisting condition of diabetes had a longer hospitalization and increased amputations, despite similar size of burn. Diabetes is an important risk factor to acknowledge in patients with these injuries to optimize care.

EVALUATING SEPSIS CRITERIA IN DETECTING ALTERATIONS IN CLINICAL, METABOLIC, AND INFLAMMATORY PARAMETERS IN BURN PATIENTS.

ABSTRACT: Sepsis has become the leading cause of death in burn patients. Furthermore, sepsis and septic complications result in significant morbidities and longer hospitalization, which has profound impacts on the healthcare system. Despite this, sepsis in burn patients is surprisingly poorly understood and characterized. This retrospective, single-institution cohort study aimed to increase our understanding of the septic response after burns. We hypothesized that different sepsis definitions will results in distinctive septic trajectories and biochemical patterns after injury. Sepsis was defined by our burn center-specific prospective definition, the American Burn Association criteria, Sepsis-3 criteria, and the Mann-Salinas criteria. Applying these definitions, we compared clinical, metabolic, and inflammatory markers in septic and nonseptic burn patients. We found that the Sepsis-3 criteria are the most reliable screening tool used before clinical diagnoses for detecting sepsis trajectories and biochemical patterns. Moreover, we characterized distinct temporal alterations in biomarkers during the pre- and post-septic periods in burn patients, which may be incorporated into future sepsis definitions to improve the accuracy of a sepsis diagnosis in burn patients.

Time to surgical closure of complex infectious wounds: a single-center retrospective cohort study.

INTRODUCTION: Surgical management of NSTIs can result in complex wounds, and closure of these wounds is often difficult or complicated. Although surgical factors influencing mortality and LOS have been well described, little is known about patient, wound, and surgical factors associated with time to closure. OBJECTIVE: The purpose of this study is to identify patient, wound, and surgical factors that may influence time to closure of NSTIs. MATERIALS AND METHODS: The records of patients who presented to a tertiary care center over an 11-year period (2007-2017) with an NSTI requiring surgical closure were retrospectively reviewed. RESULTS: Forty-seven patients met the inclusion criteria. The average time to closure was 31.1 days, with an average of 4.8 procedures. Most patients were middle aged (mean, 50.3 years; range, 20-81 years), immunocompetent, and nondiabetic upon admission. Closure was achieved mainly with autograft. The percent TBSA was described in 19 cases (40%). There was no association between substance use (alcohol, smoking, or other), anticoagulant medication use, or medical comorbidities and time to closure. On multivariable analysis, flap closure (P =.02) and increased number of surgical procedures (P =.003)-the latter reflecting the need for an increased number of debridements-were associated with increased time to closure. CONCLUSIONS: The data in this study suggest that use of local flaps for wound closure and increased number of surgical procedures (particularly debridements) may be predictors of time to closure in patients with an NSTI.

Outbreak of Carbapenemase-Producing Enterobacteriaceae in a Regional Burn Center.

Antimicrobial resistance is an increasing problem in hospitals worldwide; however, the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) in our region is low. Burn patients are vulnerable to infection because of the loss of the protective skin barrier, thus burn centers prioritize infection prevention and control (IP&C). This report describes a CPE outbreak in a regional burn center. In a period of 2.5 months, four nosocomial cases of CPE were identified, three containing the Klebsiella pneumoniae carbapenemase (KPC) gene and one Verona integrin-encoded metallo-ß-lactamase (VIM) gene. The first two cases were identified while there was no CPE patient source on the unit. CPE KPC gene was then isolated in sink drains of three rooms. In addition to rigorous IP&C practices already in place, we implemented additional outbreak measures including restricting admissions to patients with complex burns or burns ≥10% TBSA, admitting patients to other in-patient units, and not permitting elective admissions. We began cohorting patients using nursing team separation for CPE-positive and -negative patients and geographical separation on the unit. Despite aggressive IP&C measures already in place, hospital-acquired CPE colonization/infection occurred. Given that CPE contaminated sinks of the same enzyme were identified, we believe hospital sink drains may the source. This highlights the importance of sink design and engineering solutions to prevent the formation of biofilm and reduce splashing. CPE infections are associated with poor outcomes in patients and significant health system costs due to a longer length of stay and additional institutional resources.

Prescribing patterns of opioids and adjunctive analgesics for patients with burn injuries.

PURPOSE: Large quantities of analgesics are prescribed to control pain among patients with burn injuries and may lead to chronic use and dependency. This study aimed to determine whether patients are overprescribed analgesics at discharge and to identify factors that influence prescribing patterns. MATERIAL AND METHODS: A retrospective review of patient charts (n = 199) between July 1, 2015-2018 were reviewed from a registry at a single burn center. Opioid, neuropathic pain agent, acetaminophen, and ibuprofen quantities given before and at discharge were compared. Linear mixed regression models were used to identify factors that increased the amount of analgesics prescribed. RESULTS: On average, patients were prescribed significantly more analgesics at discharge compared to what was consumed pre-discharge (p < 0.0001). Specifically, on average, providers did not overprescribe the daily dose, but overprescribed the duration of pain medications required. For every increase in percent TBSA, 14 MEQ more opioids, 203 mg more neuropathic pain agents, 843 mg more acetaminophen, and 126 mg more ibuprofen were prescribed (p < 0.05). Surgery was a predictor for higher opioid and neuropathic pain agent prescriptions (p = 0.03), while length of stay was associated with fewer neuropathic pain agents prescribed (p = 0.04). Fewer ibuprofen were given to patients with a history of substance misuse (p = 0.01). CONCLUSIONS: The quantity of analgesics prescribed at discharge varied widely and often prescribed for long durations of time. Standardized prescribing guidelines should be developed to optimize how analgesics are prescribed at discharge.

Sepsis Definitions in Burns.

Background: Sepsis is the leading cause of death in burns. Despite its importance, sepsis lacks a proper definition. An established definition will lead to early and accurate diagnosis, prompt treatment, and a reduced mortality rate. The aim of this work is to discuss current definitions and to look ahead at novel definitions with clinical implications. Method: A review of the current understanding of sepsis definitions in burns. Results: Adaptation of sepsis definitions in the general population and specific burn definitions have gotten better but still need improvements and, potentially, incorporation of molecular, laboratory, patient-specific, and clinical factors. This work includes the history, evolution, and predictive value of current definitions of sepsis in burns. A review of current and future markers of sepsis and potentially useful definitions are presented. Conclusions: Sepsis definitions have evolved over the last decades and will continue to do so. We believe the best definition in burn patients is the Sepsis-3 that was developed originally for critically ill patients. However, there are several studies investigating more specific definitions with better sensitivity and specificity.