DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using ...the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
•Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design•KORD is selectively activated by salvinorin B, and not by endogenous opioids•KORD robustly silenced multiple neuronal subtypes•Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control
The κ-opioid receptor (KOR) was used as a template to generate a novel inhibitory DREADD (KORD), which is activated by salvinorin B and insensitive to endogenous opioid peptides. Sequential activation of the inhibitory KOR-DREADD and an excitatory M3-DREADD facilitated the bidirectional, multiplexed modulation of behavior.
•Quality of life is impacted by the total body surface area burned.•Length of stay is correlated with the total body surface area burned.•Length of stay is more strongly correlated with quality of ...life.•Returning to work improves the reported quality of life for burn patients.•Attention to body image should be given to help patients reintegrate post-injury.
Burn injuries create physiologic, physical, and emotional effects acutely and long-lasting. Recovery is extensive and requires long-term care. Impaired function related to pain, deconditioning, weakness, and contracture formation are common. We sought to determine factors that impact quality of life (QOL) post recovery. Specifically, to assess whether Health Related QOL (HRQOL) decreases with increasing percent total body surface area (TBSA) and length of stay (LOS). We also explored QOL as a function of burn mechanism.
Patients >18 years of age with >9.5% TBSA between 1 and 6 years post-burn injury were contacted by mail and asked if they were willing to participate. Those who agreed responded by returning their completed Burn Specific Health Scale-Brief (BSHS-B). Medical records were accessed to determine demographic and treatment information.
Statistical analysis revealed a strong correlation between total QOL (total score of BSHS-B) and LOS and TBSA. All domains were negatively correlated with increasing LOS and TBSA. LOS was most strongly correlated with decreasing work function and social function. There were no differences in QOL between burn mechanism.
QOL is greatly impacted by TBSA and LOS.More attention to body image and returning to work should be given, regardless of the type of burn mechanism.
•Adult burn patients in 2015 were prescribed nearly two times more narcotics (morphine equivalents) on discharge than in 2008.•Adult burn patients in 2015 were nearly twice as likely to receive a ...more complex opioid regimen than in 2008.•Patients with Medicare were prescribed less total narcotic than patients with private insurance.•Patients with Medicaid were prescribed a more complex regimen of narcotics than patients with private insurance.
Prescription opioid misuse is an epidemic international health crisis. Although burn providers are increasingly mindful of balancing pain relief with risk of opioid dependence, several burn centers have noticed their patients are still receiving an increased amount of opioids, termed “opioid creep.” We examined discharge narcotic prescriptions at a single burn center in the Midwest United States and found that patients discharged in 2015 received nearly twice the amount of narcotics (mean=600 morphine equivalents ME) than those discharged in 2008 (mean=350 ME), with a significantly increased likelihood of a more complex narcotic discharge regimen. The increase in ME remained significant even after controlling for age, burn size, intensive care unit stay, discharge day, substance abuse, comorbidity status, insurance, language, race, and ethnicity. The data do not clearly explain such a significant increase. Although such increase in opioid prescription is undesirable, so too is regression to historical under-treatment of burn pain. Protocoled pain-management order sets on admission and discharge, as well as incorporation of alternatives adjuncts to lessen pain, may allow for better pain control with less opioid misuse.
OBJECTIVE:To examine the development of acute kidney injury (AKI) after burn injury as an independent risk factor for increased morbidity and mortality over initial hospitalization and 1-year ...follow-up.
BACKGROUND:Variability in fluid resuscitation and difficulty recognizing early sepsis are major barriers to preventing AKI after burn injury. Expanding our understanding of the burden AKI has on the clinical course of burn patients would highlight the need for standardized protocols.
METHODS:We queried the Healthcare Cost and Utilization Project State Inpatient Databases in the states of Florida and New York during the years 2009 to 2013 for patients over age 18 hospitalized with a primary diagnosis of burn injury using ICD-9 codes. We identified and grouped 18,155 patients, including 1476 with burns >20% total body surface area, by presence of AKI. Outcomes were compared in these cohorts via univariate analysis and multivariate logistic regression models.
RESULTS:During initial hospitalization, AKI was associated with increased pulmonary failure, mechanical ventilation, pneumonia, myocardial infarction, length of stay, cost, and mortality, and also a lower likelihood of being discharged home. One year after injury, AKI was associated with development of chronic kidney disease, conversion to chronic dialysis, hospital readmission, and long-term mortality.
CONCLUSIONS:AKI is associated with a profound and severe increase in morbidity and mortality in burn patients during initial hospitalization and up to 1 year after injury. Consensus protocols for initial burn resuscitation and early sepsis recognition and treatment are crucial to avoid the consequences of AKI after burn injury.
The objective of this study was to quantify differences between estimated TBSA from referring hospitals vs calculated TBSA in the burn unit in regards to several variables. We conducted a ...retrospective review of 735 burn patients admitted over a 17-month period. Three hundred twenty-six patients fit the criteria of transfers with recorded %TBSA estimations from referring hospitals. Referring %TBSA was compared with actual %TBSA, and the difference was expressed as a percentage of actual %TBSA. This was then used to group referring estimations as underestimated (less than -25%), satisfactory (-25 to 25%), or overestimated (greater than 25%). A paired t-test was used to assess the paired differences for significance. Secondary variables were then assessed between groups. When assessing associations of these clinical measures, a one-way analysis of variance was used for continuous variables and Pearson's χ test or Fisher's exact test was used. Of the 326 patients analyzed, 13 were underestimated, 63 were satisfactory, and 250 were overestimated. The ratio of overestimation to underestimation exceeded 19:1 and the ratio of overestimation to satisfactory estimation was nearly 4:1, with a statistically significant difference in referred %TBSA and actual %TBSA (P < .0001). Within the over and underestimated groups, there were significant differences between referred %TBSA and actual %TBSA (P < .0001). Larger burns were more accurately estimated (P < .0001). There are significant inaccuracies between referring hospital estimated %TBSA and actual %TBSA, which consistently and grossly skew toward overestimation. Inaccuracy in burn size estimation is systemic and can affect patient care and burn unit efficiency.
Despite improvements in early treatment, survival following burn injury remains challenged by sepsis and multiple organ dysfunction syndrome (MODS). Additionally, susceptibility to infections and ...growing antibiotic resistance places burn patients at increased risk for infections with multiple-drug resistant organisms (MDROs). We therefore aimed to evaluate the impact of MDRO infections on survival and hospital length of stay, as well as examine the role of these organisms in the development of complications, such as acute kidney injury, sepsis, and MODS. To study this, we included all burn patients with infections, admitted between January 1, 2012, and December 31, 2013. Patients were divided into two groups: patients with infections caused by MDROs and patients with infections caused by susceptible organisms. Data were collected on all available cultures, as well as demographic, injury, and treatment-related variables from the medical record. The number of operative procedures (median: 2 vs 1, P < .0001), ventilator days (21 vs 0 days, P < .0001), total antibiotic days (21 vs 7days, P < .0001), and length of hospitalization (39 vs 14 days, P < .0001) were significantly different in the MDRO group vs the nonresistant group. While MDRO infection was not associated with patient mortality, univariable logistic regression analyses demonstrated >20% TBSA (odds ratio OR = 4.30, 95% confidence interval CI: 1.14-16.29, P = .03), acute kidney injury (OR = 10.93, 95% CI: 2.74-43.57, P = .001), sepsis (OR = 19.20, 95% CI: 3.79-97.27, P < .001), and MODS (OR = 85.49, 95% CI: 12.97-563.28, P < .0001) significantly increased the odds of patient mortality. These findings suggest that infections with MDROs are associated with a greater number of surgical procedures, longer duration of mechanical ventilation, more antibiotic days, and longer hospitalization.
Sepsis and septic shock occur commonly in severe burns. Acute kidney injury (AKI) is also common and often results as a consequence of sepsis. Mortality is unacceptably high in burn patients who ...develop AKI requiring renal replacement therapy and is presumed to be even higher when combined with septic shock. We hypothesized that high-volume hemofiltration (HVHF) as a blood purification technique would be beneficial in this population.
We conducted a multicenter, prospective, randomized, controlled clinical trial to evaluate the impact of HVHF on the hemodynamic profile of burn patients with septic shock and AKI involving seven burn centers in the United States. Subjects randomized to the HVHF were prescribed a dose of 70 ml/kg/hour for 48 hours while control subjects were managed in standard fashion in accordance with local practices.
During a 4-year period, a total of nine subjects were enrolled for the intervention during the ramp-in phase and 28 subjects were randomized, 14 each into the control and HVHF arms respectively. The study was terminated due to slow enrollment. Ramp-in subjects were included along with those randomized in the final analysis. Our primary endpoint, the vasopressor dependency index, decreased significantly at 48 hours compared to baseline in the HVHF group (p = 0.007) while it remained no different in the control arm. At 14 days, the multiple organ dysfunction syndrome score decreased significantly in the HVHF group when compared to the day of treatment initiation (p = 0.02). No changes in inflammatory markers were detected during the 48-hour intervention period. No significant difference in survival was detected. No differences in adverse events were noted between the groups.
HVHF was effective in reversing shock and improving organ function in burn patients with septic shock and AKI, and appears safe. Whether reversal of shock in these patients can improve survival is yet to be determined.
Clinicaltrials.gov NCT01213914 . Registered 30 September 2010.
Anemia of critical illness is resistant to exogenous erythropoietin. Packed red blood cells transfusions is the only treatment option, and despite related cost and morbidity, there is a need for ...alternate strategies. Erythrocyte development can be divided into erythropoietin-dependent and erythropoietin-independent stages. We have shown previously that erythropoietin-dependent development is intact in burn patients and the erythropoietin-independent early commitment stage, which is regulated by β1/β2-adrenergic mechanisms, is compromised. Utilizing the scald burn injury model, we studied erythropoietin-independent late maturation stages and the effect of β1/β2, β-2, or β-3 blockade in burn mediated erythropoietin-resistant anemia.
Burn mice were randomized to receive daily injections of propranolol (nonselective β1/β2 antagonist), nadolol (long-acting β1/β2 antagonist), butoxamine (selective β2 antagonist), or SR59230A (selective β3 antagonist) for 6 days after burn. Total bone marrow cells were characterized as nonerythroid cells, early and late erythroblasts, nucleated orthochromatic erythroblasts and enucleated reticulocyte subsets using CD71, Ter119, and Syto-16 by flow cytometry. Multipotential progenitors were probed for MafB expressing cells.
Although propranolol improved early and late erythroblasts, only butoxamine and selective β3-antagonist administrations were positively reflected in the peripheral blood hemoglobin and red blood cells count. While burn impeded early commitment and late maturation stages, β1/β2 antagonism increased the early erythroblasts through commitment stages via β2 specific MafB regulation. β3 antagonism was more effective in improving overall red blood cells through late maturation stages.
The study unfolds novel β2 and β3 adrenergic mechanisms orchestrating erythropoietin resistant anemia after burn, which impedes both the early commitment stage and the late maturation stages, respectively.
Pearls From the National Burn Repository Kahn, Steven A; Bernal, Nicole; Mosier, Michael J
Journal of burn care & research,
06/2018, Letnik:
39, Številka:
4
Journal Article
This study examines health outcomes in burn patients with sepsis. We hypothesized that burn patients with sepsis would have an increased odds risk for in-hospital death and longer intensive care unit ...(ICU) stays. This was a retrospective cohort of consecutive patients admitted to the burn ICU with total BSA (TBSA) ≥10% and/or inhalation injury between January 2008 and March 2015. Overall 407 burn patients were included; the case-rate for sepsis was 39.1% (n = 159); 20.1% (n = 82) patients were septic and 18.9% (n = 77) patients experienced septic shock. Patients with septic shock had the highest mortality rate (13.31% no sepsis vs 3.7% sepsis vs 49.4% septic shock, P < .01). Median 28-day ICU-free days was higher in patients without sepsis (23 days Interquartile range (IQR) 14-27 no sepsis vs 0 days IQR 0-10 sepsis vs 0 days IQR 0-0 septic shock, P < .01). Sepsis (with or without shock) increased odds of in-hospital death (odds ratio 7.04, 95% confidence interval 1.93-25.7) in reference to the no sepsis group. With each incremental Sequential Organ Failure Assessment (SOFA) score or 10% TBSA increase, the odds risk for in-hospital death increased by 56 and 75%, respectively. Our study characterized outcomes in patients with sepsis after severe burn injury. The odds risk for in-hospital death was greater in patients with sepsis, increasing burn severity according to TBSA and SOFA score.
PDF
