Injury Characteristics and von Willebrand Factor for the Prediction of Acute Respiratory Distress Syndrome in Patients With Burn Injury: Development and Internal Validation.

OBJECTIVE: To derive and validate a prediction model for the development of ARDS in burn-injured patients. SUMMARY BACKGROUND DATA: Burn injury carries the highest incidence of acute respiratory distress syndrome (ARDS) among all predisposing conditions, but few studies exist on risk factors in these patients. Studies employing biomarkers and clinical risk factors for predicting ARDS mortality have recently been examined but none exist for onset of ARDS nor in patients with burn injury. METHODS: This was a prospective multicenter study of 113 patients with isolated burn injury or inhalation injury. Clinical variables and plasma biomarkers representative of endothelial injury, epithelial injury, or inflammation were collected within 24 hours of admission. The most parsimonious model was chosen by considering discrimination, calibration, and model fit. RESULTS: Among the biomarkers measured in patients with burn injuries, a one-standard deviation increase in log-transformed levels of the A2 domain of von Willebrand factor in the first 24 hours was most strongly associated with the development of ARDS (OR 7.72; 95% CI: 1.64-36.28, P = 0.03). Of candidate models, a 3-variable model with %TBSA, inhalation injury, and von Willebrand factor-A2 had comparable discrimination to more complex models (area under the curve: 0.90; 95% CI 0.85-0.96). The 3-variable model had good model fit by Hosmer-Lemeshow test (P = 0.74) and maintained similar discrimination after accounting for performance optimism (Bootstrapped area under the curve: 0.90; 95% CI: 0.84-0.95). CONCLUSIONS: The 3-variable model with %TBSA, inhalation injury, and von Willebrand factor could be used to better identify at-risk patients for both the study and prevention of ARDS in patients with burn injury.

Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes.

This prospective study aimed to address changes in inflammatory response between different aged populations of patients who sustained burn and inhalation injury. Plasma and bronchoalveolar lavage (BAL) samples were collected from 104 patients within 15h of their estimated time of burn injury. Clinical variables, laboratory parameters, and immune mediator profiles were examined in association with clinical outcomes. Older patients were at higher odds for death after burn injury (odds ratio (OR)=7.37 per 10years, p=0.004). In plasma collected within 15h after burn injury, significant increases in the concentrations of interleukin 1 receptor antagonist (IL-1RA), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), granulocyte colony-stimulating factor (G-CSF), interferon-gamma-induced protein 10 (IP-10) and monocyte chemoattractant protein 1 (MCP-1) (p<0.05 for all) were observed in the ≥65 group. In the BAL fluid, MCP-1 was increased three-fold in the ≥65 group. This study suggests that changes in certain immune mediators were present in the older cohort, in association with in-hospital mortality.

Advanced Age Alters Monocyte and Macrophage Responses.

SIGNIFICANCE: With the growing population of baby boomers, there is a great need to determine the effects of advanced age on the function of the immune system. Recent Advances: It is universally accepted that advanced age is associated with a chronic low-grade inflammatory state that is referred to as inflamm-aging, which alters the function of both immune and nonimmune cells. Mononuclear phagocytes play a central role in both the initiation and resolution of inflammation in multiple organ systems and exhibit marked changes in phenotype and function in response to environmental cues, including the low levels of pro-inflammatory mediators seen in the aged. CRITICAL ISSUES: Although we know a great deal about the function of immune cells in young adults and there is a growing body of literature focusing on aging of the adaptive immune system, much less is known about the impact of age on innate immunity and the critical role of the mononuclear phagocytes in this process. FUTURE DIRECTIONS: In this article, there is a focus on the tissue-specific monocyte and macrophage subsets and how they are altered in the aged milieu, with the hope that this compilation of observations will spark an expansion of research in the field. Antioxid. Redox Signal. 25, 805-815.

Variable surgical outcomes after hospital consolidation: Implications for local health care delivery.

BACKGROUND: With more hospital consolidations as an inevitable part of our future health care ecosystem, we investigated the relationship between hospital consolidations and operative outcomes. METHODS: Using the Health Care Cost and Utilization Project State Inpatient Database (Florida and California), the American Hospital Association Annual Survey Database, and Medicare's Case Mix Index data, we identified 19 hospitals that consolidated between 2007 and 2013 and propensity matched them with 19 independent hospitals, using patient and hospital characteristics. One year before consolidation and again 1 year after, we used difference-in-differences analysis to compare changes in the risk-adjusted complication rate of 7 elective operations performed in the consolidated hospitals and in the matched control group. RESULTS: Of the 7 procedures studied, 2 procedures saw a decrease in complication rate (lumbar and lumbosacral fusion of the posterior column posterior technique, difference-in-differences = -0.6%, P < .01; total hip replacement, difference-in-differences = -0.6%, P < .01); 3 procedures saw an increase in complication rate (transurethral prostatectomy, difference-in-differences = 4.1%, P < .01; cervical fusion of the anterior column anterior technique, difference-in-differences = 1.5%, P < .01; total knee replacement, difference-in-differences = 0.3%, P < .01); and 2 procedures saw no change in complication rate (laparoscopic cholecystectomy, lumbar and lumbosacral fusion of the anterior column posterior technique, both P > .05) after hospital consolidation. CONCLUSION: Arguments have been made that consolidated health care systems can share high-performing clinical services and infrastructure resources, such as electronic medical records, to improve quality. Our results indicate that hospital consolidation does not uniformly improve postoperative complication rates.

The acute pulmonary inflammatory response to the graded severity of smoke inhalation injury.

OBJECTIVES: To determine whether the graded severity of smoke inhalation is reflected by the acute pulmonary inflammatory response to injury. DESIGN: In a prospective observational study, we assessed the bronchoalveolar lavage fluid for both leukocyte differential and concentration of 28 cytokines, chemokines, and growth factors. Results were then compared to the graded severity of inhalation injury as determined by Abbreviated Injury Score criteria (0, none; 1, mild; 2, moderate; 3, severe; 4, massive). SETTING: All patients were enrolled at a single tertiary burn center. PATIENTS: The bronchoalveolar lavage fluid was obtained from 60 patients within 14 hrs of burn injury who underwent bronchoscopy for suspected smoke inhalation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Those who presented with worse grades of inhalation injury had higher plasma levels of carboxyhemoglobin and enhanced airway neutrophilia. Patients with the most severe inhalation injuries also had a greater requirement for tracheostomy, longer time on the ventilator, and a prolonged stay in the intensive care unit. Of the 28 inflammatory mediators assessed in the bronchoalveolar lavage fluid, 21 were at their highest in those with the worst inhalation injury scores (grades 3 and 4), the greatest of which was interleukin-8 (92,940 pg/mL, grade 4). When compared in terms of low inhalation injury (grades 1-2) vs. high inhalation injury (grades 3-4), we found significant differences between groups for interleukin-4, interleukin-6, interleukin-9, interleukin-15, interferon-γ, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1 (p < .05 for all). CONCLUSIONS: These data reveal that the degree of inhalation injury has basic and profound effects on burn patient morbidity, evokes complex changes of multiple alveolar inflammatory proteins, and is a determinant of the pulmonary inflammatory response to smoke inhalation. Accordingly, future investigations should consider inhalation injury to be a graded phenomenon.

Early pulmonary immune hyporesponsiveness is associated with mortality after burn and smoke inhalation injury.

This prospective study aims to address mortality in the context of the early pulmonary immune response to burn and inhalation injury. The authors collected bronchoalveolar lavage fluid from 60 burn patients within 14 hours of their injury when smoke inhalation was suspected. Clinical and laboratory parameters and immune mediator profiles were compared with patient outcomes. Patients who succumbed to their injuries were older (P = .005), had a larger % TBSA burn (P < .001), and required greater 24-hour resuscitative fluids (P = .002). Nonsurvivors had lower bronchoalveolar lavage fluid concentrations of numerous immunomodulators, including C5a, interleukin (IL)-1ß, IL-1RA, IL-8, IL-10, and IL-13 (P < .05 for all). Comparing only those with the highest Baux scores to account for the effects of age and % TBSA burn on mortality, nonsurvivors also had reduced levels of IL-2, IL-4, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1ß, and tumor necrosis factor-α (P < .05 for all). The apparent pulmonary immune hyporesponsiveness in those who died was confirmed by in vitro culture, which revealed that pulmonary leukocytes from nonsurvivors had a blunted production of numerous immune mediators. This study demonstrates that the early pulmonary immune response to burn and smoke inhalation may be attenuated in patients who succumb to their injuries.

Circulating proteasomes after burn injury.

The objective of the study is to test whether circulating proteasomes are increased in burn patients and to assess whether possible alterations are associated with severity of injury, organ failure, and/or clinically relevant outcomes. In this study, plasma was obtained from burn patients on days 0 (admission, n = 50), 1 (n = 36), 3 (n = 35), 5 (n = 28), 7 (n=34), and 30 (n = 10) (controls: 40 volunteers). The 20S/26S proteasome levels were measured by enzyme-linked immunosorbent assay. Proteasome peptidase activity was assessed using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). Percentage of TBSA burned, presence of inhalation injury, development of sepsis/multiple organ failure, and sequential organ failure assessment scores were documented. On admission, plasma proteasome activity was higher in patients than in controls (P = .011). 26S proteasomes were not detectable. The 20S proteasome concentrations (median [25th/75th percentile]) peaked on day 0 (673 [399/1566] ng/mL; control: 195 [149/249] ng/mL, P < .001), gradually declined within 7 days, and fully returned to baseline at day 30 (116.5 [78/196] ng/mL). Elevated 20S proteasomes were associated with the presence of inhalation injury and correlated linearly with %TBSA in patients without inhalation injury. Initial 20S proteasome concentrations discriminated the presence of inhalation injury in patients with (sensitivity 0.88 and specificity 0.71) and without (sensitivity 0.83 and specificity 0.97) cutaneous burns but did not discriminate sepsis/multiple organ failure development or survival. Circulating 20S proteasome is a biomarker of tissue damage. The 20S proteasome plasma concentrations in patients with burns and/or inhalation injury are unlikely to predict outcomes but may be useful for the diagnosis of inhalation injury.

Proteasomes in human bronchoalveolar lavage fluid after burn and inhalation injury.

The purpose of this study was to determine whether 26S proteasome is detectable in human bronchoalveolar lavage fluid (BALF) and whether burn and inhalation injury is accompanied by changes in BALF proteasome content or activity. BALF was obtained on hospital admission from 28 patients with burn and inhalation injury (controls: 10 healthy volunteers). Proteasome concentrations were quantified by enzyme-linked immunosorbent assay, and their native molecular mass was assessed by gel filtration. Proteasome peptidase activity was measured using a chymotryptic-like peptide substrate in combination with epoxomicin (specific proteasome inhibitor). BALF protein was increased in patients (P<.001) and correlated positively with the degree of inhalation injury. The 20S/26S proteasomes were detectable in all BALF by enzyme-linked immunosorbent assay. Gel filtration confirmed the presence of intact 20S and 26S proteasome that was stable without soluble ATP/Mg. In all BALF chymotryptic-like activity was detectable and could be inhibited with epoxomicin by 60 to 70% (P<.01). Absolute amounts of 20S/26S proteasomes and proteasome activity were increased in patients (P<.001 for all). The relative BALF composition after injury was characterized by increased concentrations of 20S proteasome/mg protein (P=.0034 vs volunteers), decreased concentrations of 26S proteasome/mg protein (P=.041 vs volunteers), and reduced specific proteasome activity (P=.044 vs volunteers). The 26S proteasome per milligram and specific proteasome activity were even further reduced in patients who developed ventilator-associated pneumonia (P=.045 and P=.03 vs patients without ventilator-associated pneumonia). This study supports the novel concept that extracellular proteasomes could play a pathophysiological role in the injured lung and suggests that insufficient proteasome function may increase susceptibility for pulmonary complications.

Implications of formal alcohol screening in burn patients.

The purpose of this study was to screen burn patients for alcohol use disorders to identify those at increased risk for repeat injury and adverse effects of alcohol use. We examined associations of at-risk drinking and dependence symptoms as measured by a formal screening tool and blood alcohol concentration (BAC) to guide further screening, treatment, and research. We hypothesized that the majority of drinkers would not have symptoms of alcohol dependence, that BAC would be inadequate to screen for alcohol disorders, and that at-risk drinkers would be more likely to be unemployed and uninsured than healthy drinkers. Formal screening of English speakers, age 16 to 75, admitted to the burn service for over 24 hours was conducted for a 6-month period, using the Alcohol Use Disorders Identification Test. Of the 123 patients eligible for the study, 110 (89.4%) were approached for formal screening, four refused (3.6%), and 13 were missed (10.6%). BAC was obtained in 68 of 110 (61.8%); no patient who reported abstinence had a positive BAC. Of the 106 screened, 34.9% were nondrinkers, 11.3% drank daily or almost daily, and 28.3% binge drank at least monthly (>4 drinks per occasion for men, >3 for women). Of the patients who drank, only eight patients reported one or more sign of dependence in the last year (11.6%). For the group as a whole, 20.9% met Alcohol Use Disorders Identification Test criteria for at-risk drinking, with an average BAC of 39.8 mg/dl, (range 0-242 mg/dl). Using BAC of >or=80 mg/dl, only 5.6% of patients would have been identified as at-risk drinkers. Twenty-three percent of patients had no health insurance, 36% of whom were at-risk drinkers compared with 17.3% of insured patients (P < .05). For the group as a whole, 41.8% of patients were unemployed. At-risk drinking did not differ between employed and unemployed patients (24.6% vs 17.8%, P > .05). Among burn patients, formal alcohol screening identified that one in five patients is at risk for further problems from their drinking and that most at-risk drinkers are binge drinkers and do not show signs of dependency. Formal screening identified more at-risk drinkers than BAC. Implications of the screening findings are 1) because most burn patients who drink are binge but not dependent drinkers, alcohol withdrawal should be infrequent, and 2) animal models of alcohol use and burn injury should study acute intoxication and binge exposure. In addition, 3) we would expect burn patients to respond to brief interventions for alcohol use disorders similar to trauma and primary care patients.

Adverse clinical outcomes associated with elevated blood alcohol levels at the time of burn injury.

Elevated blood alcohol content (BAC) on admission is associated with poorer outcomes, larger burns and more inhalation injury. This study's purpose was to examine the effects of alcohol through a matched case-controlled study, measuring early and extended markers of clinical outcomes. The hypothesis was that patients with an elevated admission BAC would require more resuscitation and have a longer hospital stay. Admissions 16 to 75 years of age with 15 to 75% TBSA and admission BACs were identified. Patients with BAC >30 mg/dl (BAC+, cases) were matched with patients with undetectable BAC (BAC-, controls), according to age, sex, TBSA, inhalation injury and mechanism. Screening identified 258 patients, 146 with admission BACs. Twenty-seven had a BAC > or = 30 mg/dl. There were 24 matched pairs. At 24 hours, BAC+ group had larger acute physiology and chronic health evaluation II scores (23.33 vs 18.75, P < .05), fluid requirements (5.25 vs 3.82 L (cc/kg/TBSA), P < .05), and base deficit (11.15 vs 7.15, P < .05). The duration of mechanical ventilation (14.85 vs 4.23 days, P < .05), intensive care unit length of stay (22.85 vs 9.38, P < .05), hospital length of stay (28.95 vs 15.68, P < .05), and mean hospital charges ($239,507 vs $144,598, P < .05) were increased in the BAC+ patients. Despite matched baseline injury characteristics, elevated BAC was associated with poorer short term and extended clinical outcomes, illustrating the impact of alcohol intoxication on physiologic derangement after burn injury.