Using a Normothermia Bundle With Perioperative Prewarming to Reduce Patient Hypothermia.

PURPOSE: To determine if implementing a normothermia bundle, which includes preoperative forced-air warming blankets, reduces incidence of inadvertent perioperative hypothermia (IPH). DESIGN: Intervention study using retrospective chart review. METHODS: Patients received a preoperative forced-air warming blanket and temperature management with the normothermia bundle. Temperature status data was collected from patient charts to evaluate the incidences of IPH and findings from this data analysis was used to measure improvement in perioperative temperature management. FINDINGS: Of 200 patients, 63 (31.5%) remained normothermic, 37 (18.5%) had at least one documented hypothermic temperature, and 100 (50%) had no documented temperature during the intraoperative phase of care. Although compliance with intraoperative temperature monitoring decreased by 13% postintervention, the incidence of documented IPH in reviewed records was decreased by 3.6-fold. CONCLUSION: Implementing a normothermia bundle that includes a preoperative forced-air warming blanket may lower the incidences of IPH, especially in surgical cases lasting over 120 minutes.

Abdominal Surgical Patients Randomized to Aromatherapy for Pain Management.

PURPOSE: Evaluate aromatherapy for postoperative abdominal pain in hospitalized patients. DESIGN: A randomized controlled trial design. METHODS: Study participants (n = 172) were randomized to receive either standard care or standard care and aromatherapy (AT) for postsurgical pain up to 24 hours after admission to a nonintensive care surgical unit. A convenience sample was recruited before surgery and given instructions on self-rating pain intensity. The AT group was topically administered a drop of lavender essential oil after medication and at random for pain. Pain scores and medications data were collected. FINDINGS: Of the evaluable patients (n = 147), demographic data were similar (standard care and AT groups). The use of aromatherapy showed no substantial benefit at improving pain scores or reducing medication use (the primary objectives of the study). A subgroup analysis of patients who received a regional nerve block for pain management, however, showed more than fivefold improvement in pain scores after the use of aromatherapy. The AT group used more medications at baseline (P = .032), whereas 70% less medications were used (P = .031) by 24 hours. CONCLUSIONS: Aromatherapy aided in control of pain intensity for abdominal surgical patients. In patients who received a regional nerve block, significant improvement in pain level occurred as effects of the block diminished.

Alterations in tissue microRNA after heat stress in the conscious rat: potential biomarkers of organ-specific injury.

BACKGROUND: Heat illness remains a significant cause of morbidity in susceptible populations. Recent research elucidating the cellular mechanism of heat stress leading to heat illness may provide information to develop better therapeutic interventions, risk assessment strategies, and early biomarkers of organ damage. microRNA (miRNA) are promising candidates for therapeutic targets and biomarkers for a variety of clinical conditions since there is the potential for high specificity for individual tissues and unique cellular functions. The objective of this study was to identify differentially expressed microRNAs and their putative mRNA targets in the heart, liver, kidney, and lung in rats at three time points: during heat stress (i.e., when core temperature reached 41.8 °C), or following a 24 or 48 h recovery period. RESULTS: Rats did not show histological evidence of tissue pathology until 48 h after heat stress, with 3 out of 6 rats showing cardiac inflammation and renal proteinosis at 48 h. The three rats with cardiac and renal pathology had 86, 7, 159, and 37 differentially expressed miRNA in the heart, liver, kidney, or lung, respectively compared to non-heat stressed control animals. During heat stress one differentially expressed miRNA was found in the liver and five in the lung, with no other modulated miRNA after 24 h or 48 h in animals with no evidence of organ injury. Pathway enrichment analysis revealed enrichment in functional pathways associated with heat stress, with the greatest effects observed in animals with histological evidence of cardiac and renal damage at 48 h. Inhibiting miR-21 in cultured cardiomyocytes increased the percent apoptotic cells five hours after heat stress from 70.9 ± 0.8 to 84.8 ± 2.2%. CONCLUSIONS: Global microRNA and transcriptomics analysis suggested that perturbed miRNA due to heat stress are involved in biological pathways related to organ injury, energy metabolism, the unfolded protein response, and cellular signaling. These miRNA may serve as biomarkers of organ injury and potential pharmacological targets for preventing heat illness or organ injury.

The Role of the Human Microbiome in Chemical Toxicity.

There is overwhelming evidence that the microbiome must be considered when evaluating the toxicity of chemicals. Disruption of the normal microbial flora is a known effect of toxic exposure, and these disruptions may lead to human health effects. In addition, the biotransformation of numerous compounds has been shown to be dependent on microbial enzymes, with the potential for different host health outcomes resulting from variations in the microbiome. Evidence suggests that such metabolism of environmental chemicals by enzymes from the host's microbiota can affect the toxicity of that chemical to the host. Chemical-microbial interactions can be categorized into two classes: Microbiome Modulation of Toxicity (MMT) and Toxicant Modulation of the Microbiome (TMM). MMT refers to transformation of a chemical by microbial enzymes or metabolites to modify the chemical in a way that makes it more or less toxic. TMM is a change in the microbiota that results from a chemical exposure. These changes span a large magnitude of effects and may vary from microbial gene regulation, to inhibition of a specific enzyme, to the death of the microbes. Certain microbiomes or microbiota may become associated with different health outcomes, such as resistance or susceptibility to exposure to certain toxic chemicals, the ability to recover following a chemical-induced injury, the presence of disease-associated phenotypes, and the effectiveness of immune responses. Future work in toxicology will require an understanding of how the microbiome interacts with toxicants to fully elucidate how a compound will affect a diverse, real-world population.

A Comparison of Aromatherapy to Standard Care for Relief of PONV and PDNV in Ambulatory Surgical Patients.

PURPOSE: To determine effectiveness of aromatherapy (AT) compared with standard care (SC) for postoperative and postdischarge nausea and vomiting (PONV/PDNV) in ambulatory surgical patients. DESIGN: Prospective randomized study. METHODS: Patients (n = 254) received either SC or AT for PONV and interviewed for effectiveness of PDNV. Machine learning methods (eight algorithms) were used to evaluate. FINDING: Of patients (64 of 221) that experienced PONV, 52% were in the AT group and 48% in the SC group. The majority were satisfied with treatment (timely, P = .60; effectiveness, P = .86). Of patients that experienced PDNV, treatment was 100% effective in the AT group and 67% in the SC group. The cforest algorithm was used to develop a model for predicting PONV with literature-based risk factors (0.69 area under the curve). CONCLUSIONS: AT is an effective way to manage PONV/PDNV. Gender and age were the most important predictors of PONV.

Mining kidney toxicogenomic data by using gene co-expression modules.

BACKGROUND: Acute kidney injury (AKI) caused by drug and toxicant ingestion is a serious clinical condition associated with high mortality rates. We currently lack detailed knowledge of the underlying molecular mechanisms and biological networks associated with AKI. In this study, we carried out gene co-expression analyses using DrugMatrix-a large toxicogenomics database with gene expression data from rats exposed to diverse chemicals-and identified gene modules associated with kidney injury to probe the molecular-level details of this disease. RESULTS: We generated a comprehensive set of gene co-expression modules by using the Iterative Signature Algorithm and found distinct clusters of modules that shared genes and were associated with similar chemical exposure conditions. We identified two module clusters that showed specificity for kidney injury in that they 1) were activated by chemical exposures causing kidney injury, 2) were not activated by other chemical exposures, and 3) contained known AKI-relevant genes such as Havcr1, Clu, and Tff3. We used the genes in these AKI-relevant module clusters to develop a signature of 30 genes that could assess the potential of a chemical to cause kidney injury well before injury actually occurs. We integrated AKI-relevant module cluster genes with protein-protein interaction networks and identified the involvement of immunoproteasomes in AKI. To identify biological networks and processes linked to Havcr1, we determined genes within the modules that frequently co-express with Havcr1, including Cd44, Plk2, Mdm2, Hnmt, Macrod1, and Gtpbp4. We verified this procedure by showing that randomized data did not identify Havcr1 co-expression genes and that excluding up to 10 % of the data caused only minimal degradation of the gene set. Finally, by using an external dataset from a rat kidney ischemic study, we showed that the frequently co-expressed genes of Havcr1 behaved similarly in a model of non-chemically induced kidney injury. CONCLUSIONS: Our study demonstrated that co-expression modules and co-expressed genes contain rich information for generating novel biomarker hypotheses and constructing mechanism-based molecular networks associated with kidney injury.

Mathematical modeling of the heat-shock response in HeLa cells.

The heat-shock response is a key factor in diverse stress scenarios, ranging from hyperthermia to protein folding diseases. However, the complex dynamics of this physiological response have eluded mathematical modeling efforts. Although several computational models have attempted to characterize the heat-shock response, they were unable to model its dynamics across diverse experimental datasets. To address this limitation, we mined the literature to obtain a compendium of in vitro hyperthermia experiments investigating the heat-shock response in HeLa cells. We identified mechanisms previously discussed in the experimental literature, such as temperature-dependent transcription, translation, and heat-shock factor (HSF) oligomerization, as well as the role of heat-shock protein mRNA, and constructed an expanded mathematical model to explain the temperature-varying DNA-binding dynamics, the presence of free HSF during homeostasis and the initial phase of the heat-shock response, and heat-shock protein dynamics in the long-term heat-shock response. In addition, our model was able to consistently predict the extent of damage produced by different combinations of exposure temperatures and durations, which were validated against known cellular-response patterns. Our model was also in agreement with experiments showing that the number of HSF molecules in a HeLa cell is roughly 100 times greater than the number of stress-activated heat-shock element sites, further confirming the model's ability to reproduce experimental results not used in model calibration. Finally, a sensitivity analysis revealed that altering the homeostatic concentration of HSF can lead to large changes in the stress response without significantly impacting the homeostatic levels of other model components, making it an attractive target for intervention. Overall, this model represents a step forward in the quantitative understanding of the dynamics of the heat-shock response.

Hydrogen sulfide improves resuscitation via non-hibernatory mechanisms in a porcine shock model.

BACKGROUND: Hydrogen sulfide (H2S) has been demonstrated to induce a "suspended animation-like" state in rodent models by reversible inhibition of cellular respiration and marked metabolic suppression and has been proposed as a potential pharmacologic adjunct to resuscitation from shock states. There are few data currently available about the mechanisms and efficacy of H2S in larger animals or humans. We examined H2S as a pharmacologic adjunct to resuscitation in a porcine model of severe traumatic shock. METHODS: Twenty-one adult swine were assigned to three study arms: sham, H2S, and saline vehicle controls (SC). All pigs underwent laparotomy and instrumentation, and the two study arms then underwent a 35% controlled hemorrhage followed by 50 min of truncal ischemia via aortic cross-clamp. H2S (5 mg/kg) or saline was administered immediately before reperfusion, followed by 6 h of resuscitation. Resuscitation requirements, laboratory parameters, end-organ histology, and inflammatory product gene expression (by reverse transcription-polymerase chain reaction) were measured and compared between groups. RESULTS: All animals survived to the 6-h postresuscitation time point. Both treatment arms demonstrated severe shock characterized by fluid and vasopressor requirements, metabolic acidosis, and hypotension compared with sham animals. Animals treated with H2S demonstrated significantly lower resuscitative requirements (total epinephrine 727 versus 3052 µg; P < 0.05), decreased fluid requirements, and lower serum lactate levels (7 versus 10 mmol/L) versus SC. Cardiac output was slightly decreased with H2S treatment but all other hemodynamic and metabolic parameters were equivalent between H2S and C groups. Serum liver and kidney biomarkers were unchanged, but administration of H2S was associated with a significant improvement in histopathologic liver and kidney injury scores compared with SC (both P < 0.05). Both study groups demonstrated significantly increased gene expression of hypoxia-inducible factor 1α and nitric oxide synthase (endogenous nitric oxide synthase, inducible nitric oxide synthase [iNOS]2, iNOS3) relative to sham animals. However, H2S was associated with increased expression of hypoxia-inducible factor 1α and decreased iNOS2 levels compared with SC. CONCLUSIONS: Administration of H2S in a large-animal model of severe traumatic shock resulted in a significant decrease in resuscitative requirements, decreased metabolic acidosis, and less end-organ histologic injury compared with standard resuscitation. H2S did not induce profound metabolic suppression as seen in rodents, and appears to have alternative mechanisms of action in large animals.

Longitudinal analysis of maternal plasma apolipoproteins in pregnancy: a targeted proteomics approach.

Minimally invasive diagnostic tests are needed in obstetrics to identify women at risk for complications during delivery. The apolipoproteins fluctuate in complexity and abundance in maternal plasma during pregnancy and could be incorporated into a blood test to evaluate this risk. The objective of this study was to examine the relative plasma concentrations of apolipoproteins and their biochemically modified subtypes (i.e. proteolytically processed, sialylated, cysteinylated, dimerized) over gestational time using a targeted mass spectrometry approach. Relative abundance of modified and unmodified apolipoproteins A-I, A-II, C-I, C-II, and C-III was determined by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in plasma prospectively collected from 11 gravidas with uncomplicated pregnancies at 4-5 gestational time points per patient. Apolipoproteins were readily identifiable by spectral pattern. Apo C-III(2) and Apo C-III(1) (doubly and singly sialylated Apo C-III subtypes) increased with gestational age (r(2)>0.8). Unmodified Apo A-II, Apo C-I, and Apo C-III(0) showed no correlation (r(2) = 0.01-0.1). Pro-Apo C-II did not increase significantly until third trimester (140 ± 13% of first trimester), but proteolytically cleaved, mature Apo C-II increased in late pregnancy (702 ± 130% of first trimester). Mature Apo C-II represented 6.7 ± 0.9% of total Apo C-II in early gestation and increased to 33 ± 4.5% in third trimester. A label-free, semiquantitative targeted proteomics approach was developed using LTQ-Orbitrap mass spectrometry to confirm the relative quantitative differences observed by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry in Apo C-III and Apo C-II isoforms between first and third trimesters. Targeted apolipoprotein screening was applied to a cohort of term and preterm patients. Modified Apo A-II isoforms were significantly elevated in plasma from mothers who delivered prematurely relative to term controls (p = 0.02). These results support a role for targeted proteomics profiling approaches in monitoring healthy pregnancies and assessing risk of adverse obstetric outcomes.

Detection of dichlorvos adducts in a hepatocyte cell line.

The toxicity of dichlorvos (DDVP), an organophosphate (OP) pesticide, classically results from modification of the serine in the active sites of cholinesterases. However, DDVP also forms adducts on unrelated targets such as transferrin and albumin, suggesting that DDVP could cause perturbations in cellular processes by modifying noncholinesterase targets. Here we identify novel DDVP-modified targets in lysed human hepatocyte-like cells (HepaRG) using a direct liquid chromatography-mass spectrometry (LC-MS) assay of cell lysates incubated with DDVP or using a competitive pull-down experiments with a biotin-linked organophosphorus compound (10-fluoroethoxyphosphinyl-N-biotinamidopentyldecanamide; FP-biotin), which competes with DDVP for similar binding sites. We show that DDVP forms adducts to several proteins important for the cellular metabolic pathways and differentiation, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin. We validated the results using purified proteins and enzymatic assays. The study not only identified novel DDVP-modified targets but also suggested that the modification directly inhibits the enzymes. The current approach provides information for future hypothesis-based studies to understand the underlying mechanism of toxicity of DDVP in non-neuronal tissues. The MS data have been deposited to the ProteomeXchange with identifier PXD001107.

Patterns of gene expression associated with recovery and injury in heat-stressed rats.

BACKGROUND: The in vivo gene response associated with hyperthermia is poorly understood. Here, we perform a global, multiorgan characterization of the gene response to heat stress using an in vivo conscious rat model. RESULTS: We heated rats until implanted thermal probes indicated a maximal core temperature of 41.8°C (Tc,Max). We then compared transcriptomic profiles of liver, lung, kidney, and heart tissues harvested from groups of experimental animals at Tc,Max, 24 hours, and 48 hours after heat stress to time-matched controls kept at an ambient temperature. Cardiac histopathology at 48 hours supported persistent cardiac injury in three out of six animals. Microarray analysis identified 78 differentially expressed genes common to all four organs at Tc,Max. Self-organizing maps identified gene-specific signatures corresponding to protein-folding disorders in heat-stressed rats with histopathological evidence of cardiac injury at 48 hours. Quantitative proteomics analysis by iTRAQ (isobaric tag for relative and absolute quantitation) demonstrated that differential protein expression most closely matched the transcriptomic profile in heat-injured animals at 48 hours. Calculation of protein supersaturation scores supported an increased propensity of proteins to aggregate for proteins that were found to be changing in abundance at 24 hours and in animals with cardiac injury at 48 hours, suggesting a mechanistic association between protein misfolding and the heat-stress response. CONCLUSIONS: Pathway analyses at both the transcript and protein levels supported catastrophic deficits in energetics and cellular metabolism and activation of the unfolded protein response in heat-stressed rats with histopathological evidence of persistent heat injury, providing the basis for a systems-level physiological model of heat illness and recovery.

Alteration in circulating metabolites during and after heat stress in the conscious rat: potential biomarkers of exposure and organ-specific injury.

BACKGROUND: Heat illness is a debilitating and potentially life-threatening condition. Limited data are available to identify individuals with heat illness at greatest risk for organ damage. We recently described the transcriptomic and proteomic responses to heat injury and recovery in multiple organs in an in vivo model of conscious rats heated to a maximum core temperature of 41.8°C (Tc,Max). In this study, we examined changes in plasma metabolic networks at Tc,Max, 24, or 48 hours after the heat stress stimulus. RESULTS: Circulating metabolites were identified by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry. Bioinformatics analysis of the metabolomic data corroborated proteomics and transcriptomics data in the tissue at the pathway level, supporting modulations in metabolic networks including cell death or catabolism (pyrimidine and purine degradation, acetylation, sulfation, redox alterations and glutathione metabolism, and the urea cycle/creatinine metabolism), energetics (stasis in glycolysis and tricarboxylic acid cycle, ß-oxidation), cholesterol and nitric oxide metabolism, and bile acids. Hierarchical clustering identified 15 biochemicals that differentiated animals with histopathological evidence of cardiac injury at 48 hours from uninjured animals. The metabolic networks perturbed in the plasma corroborated the tissue proteomics and transcriptomics pathway data, supporting a model of irreversible cell death and decrements in energetics as key indicators of cardiac damage in response to heat stress. CONCLUSIONS: Integrating plasma metabolomics with tissue proteomics and transcriptomics supports a diagnostic approach to assessing individual susceptibility to organ injury and predicting recovery after heat stress.

A safety and feasibility analysis on the use of cold-stored platelets in combat trauma.

BACKGROUND: Damage-control resuscitation has come full circle, with the use of whole blood and balanced components. Lack of platelet availability may limit effective damage-control resuscitation. Platelets are typically stored and transfused at room temperature and have a short shelf-life, while cold-stored platelets (CSPs) have the advantage of a longer shelf-life. The US military introduced CSPs into the battlefield surgical environment in 2016. This study is a safety analysis for the use of CSPs in battlefield trauma. METHODS: The Department of Defense Trauma Registry and Armed Services Blood Program databases were queried to identify casualties who received room-temperature-stored platelets (RSPs) or both RSPs and CSPs between January 1, 2016, and February 29, 2020. Characteristics of recipients of RSPs and RSPs-CSPs were compared and analyzed. RESULTS: A total of 274 patients were identified; 131 (47.8%) received RSPs and 143 (52.2%) received RSPs-CSPs. The casualties were mostly male (97.1%), similar in age (31.7 years), with a median Injury Severity Score of 22. There was no difference in survival for recipients of RSPs (88.5%) versus RSPs-CSPs (86.7%; p = 0.645). Adverse events were similar between the two cohorts. Blood products received were higher in the RSPs-CSPs cohort compared with the RSPs cohort. The RSPs-CSPs cohort had more massive transfusion (53.5% vs. 33.5%, p = 0.001). A logistic regression model demonstrated that use of RSPs-CSPs was not associated with mortality, with an adjusted odds ratio of 0.96 (p > 0.9; 95% confidence interval, 0.41-2.25). CONCLUSION: In this safety analysis of RSPs-CSPs compared with RSPs in a combat setting, survival was similar between the two groups. Given the safety and logistical feasibility, the results support continued use of CSPs in military environments and further research into how to optimize resuscitation strategies. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

A 20-year retrospective analysis of deep venous thrombosis and pulmonary embolism among combat casualties requiring damage-control laparotomy at US military Role 2 surgical units.

BACKGROUND: Combat casualties receiving damage-control laparotomy at forward deployed, resource-constrained US military Role 2 (R2) surgical units require multiple evacuations, but the added risk of venous thromboembolism (VTE) in this population has not been defined. To fill this gap, we retrospectively analyzed 20 years of Department of Defense Trauma Registry data to define the VTE rate in this population. METHODS: Department of Defense Trauma Registry from 2002 to 2023 was queried for US military combat casualties requiring damage-control laparotomy at R2. All deaths were excluded in subsequent analysis. Rates of VTE were assessed, and subgroup analysis was performed on patients requiring massive transfusion. RESULTS: Department of Defense Trauma Registry (n = 288) patients were young (mean age, 25 years) and predominantly male (98%) with severe (mean Injury Severity Score, 26), mostly penetrating injury (76%) and high mortality. Venous thromboembolism rate was high: 15.8% (DVT, 10.3%; pulmonary embolism, 7.1%). In the massively transfused population, the VTE rate was even higher (26.7% vs. 10.2%, p < 0.001). CONCLUSION: This is the first report that combat casualties requiring damage-control laparotomy at R2 have such high VTE rates. Therefore, for military casualties, we propose screening ultrasound upon arrival to each subsequent capable echelon of care and low threshold for initiating thromboprophylaxis. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

The thin red line: Blood planning factors and the enduring need for a robust military blood system to support combat operations.

ABSTRACT: Battlefield lessons learned are forgotten; the current name for this is the Walker Dip. Blood transfusion and the need for a Department of Defense Blood Program are lessons that have cycled through being learned during wartime, forgotten, and then relearned during the next war. The military will always need a blood program to support combat and contingency operations. Also, blood supply to the battlefield has planning factors that have been consistent over a century. In 2024, it is imperative that we codify these lessons learned. The linchpins of modern combat casualty care are optimal prehospital care, early whole blood transfusion, and forward surgical care. This current opinion comprised of authors from all three military Services, the Joint Trauma System, the Armed Services Blood Program, blood SMEs and the CCC Research Program discuss two vital necessities for a successful military trauma system: (1) the need for an Armed Services Blood Program and (2) Planning factors for current and future deployed military ere is no effective care for wounded soldiers, and by extension there is no effective military medicine.

Flutamide fails to reduce resuscitation requirements in a porcine ischemia-reperfusion model.

BACKGROUND: Hemorrhagic shock and subsequent resuscitation can lead to ischemia-reperfusion injury, followed by multiorgan failure and death. Flutamide, a vasoactive nonsteroidal antiandrogen compound, is thought to improve tissue and organ perfusion. We tested whether administration of flutamide-cyclodextrin (FLU-CYD) alters physiologic parameters or resuscitation requirements in a porcine model of severe acidosis and shock secondary to combined hemorrhage + ischemia-reperfusion injury. METHODS AND MATERIALS: Fifteen male pigs underwent a 35% blood-volume hemorrhage. Ischemia was induced by cross-clamping the supraceliac aorta for 50 min followed by reperfusion and resuscitation. FLU-CYD complex was administered during aortic clamping. Fluid resuscitation and epinephrine were titrated by protocol to maintain mean arterial pressure ≥40 mm Hg for 6 h. Sequential laboratory results were obtained and serum levels of FLU and 2-hydroxy-flutamide (FLUOH) were measured by mass spectrometry. RESULTS: Mean requirements for injured control swine were 14.6 (± 1.21 standard error of the mean [SEM]) L crystalloid saline and 0.59 (± 0.29 SEM) g epinephrine, compared with 16.30 (± 1.33 SEM) L and 0.54 (± 0.16 SEM) g, respectively, in the FLU-CYD group (both P > 0.05). There were no significant differences in central hemodynamics between control and experimental groups. No significant differences for pH, bicarbonate, fibrinogen, or international normalized ratio were evident. FLU-CYD resuscitation was associated with a significant increase in lactate levels compared with controls (10.1 versus 5.7 mmol/L, P < 0.05). Histologic injury was significantly increased in the livers of FLU-CYD compared with sham (P = 0.022). High serum levels of FLU and the active metabolite FLUOH were measurable throughout the resuscitation period. CONCLUSIONS: Flutamide failed to show any benefit to resuscitation in a model of severe injury and was associated with increased acidosis, hemodilution, and liver injury compared with standard crystalloid resuscitation.

Beneficial effects of histone deacetylase inhibition with severe hemorrhage and ischemia-reperfusion injury.

BACKGROUND: Valproic acid (VPA) is a histone deacetylase inhibitor that may decrease cellular metabolic needs following traumatic injury. We hypothesized that VPA may have beneficial effects in preventing or reducing the cellular and metabolic sequelae of ischemia-reperfusion injury. METHODS: Twenty-eight Yorkshire swine underwent 35% blood volume hemorrhage, followed by a lethal truncal ischemia-reperfusion injury and 6 h of resuscitation. Physiologic and laboratory parameters were closely measured and the pigs divided into four groups: sham, control (injury protocol), VPA dosing before cross-clamp (VPA-B), and VPA dosing after cross-clamp (VPA-A). RESULTS: All animals developed significant coagulopathy, acidosis, and anemia. Animals receiving VPA-A had decreased acidosis and coagulopathy as measured by pH (P = 0.016) and international normalized ratio (P = 0.013) over the resuscitation. VPA-A pigs had a decreased requirement for crystalloid (P = 0.007) and epinephrine (P < 0.0001) during resuscitation. Pathologic analysis demonstrated decreased liver injury with VPA administration. VPA administration increased levels of acetylated proteins in liver and lung tissues, and was associated with increased expression of heat shock protein 70 versus controls. CONCLUSIONS: Valproic acid conferred a significant cardiovascular, metabolic, and pathologic protective effect in a model of severe injury. Earlier administration (VPA-B) was significantly less effective compared with dosing after initial hemorrhage control.

APPRAISE-HRI: AN ARTIFICIAL INTELLIGENCE ALGORITHM FOR TRIAGE OF HEMORRHAGE CASUALTIES.

ABSTRACT: Background: Hemorrhage remains the leading cause of death on the battlefield. This study aims to assess the ability of an artificial intelligence triage algorithm to automatically analyze vital-sign data and stratify hemorrhage risk in trauma patients. Methods: Here, we developed the APPRAISE-Hemorrhage Risk Index (HRI) algorithm, which uses three routinely measured vital signs (heart rate and diastolic and systolic blood pressures) to identify trauma patients at greatest risk of hemorrhage. The algorithm preprocesses the vital signs to discard unreliable data, analyzes reliable data using an artificial intelligence-based linear regression model, and stratifies hemorrhage risk into low (HRI:I), average (HRI:II), and high (HRI:III). Results: To train and test the algorithm, we used 540 h of continuous vital-sign data collected from 1,659 trauma patients in prehospital and hospital (i.e., emergency department) settings. We defined hemorrhage cases (n = 198) as those patients who received ≥1 unit of packed red blood cells within 24 h of hospital admission and had documented hemorrhagic injuries. The APPRAISE-HRI stratification yielded a hemorrhage likelihood ratio (95% confidence interval) of 0.28 (0.13-0.43) for HRI:I, 1.00 (0.85-1.15) for HRI:II, and 5.75 (3.57-7.93) for HRI:III, suggesting that patients categorized in the low-risk (high-risk) category were at least 3-fold less (more) likely to have hemorrhage than those in the average trauma population. We obtained similar results in a cross-validation analysis. Conclusions: The APPRAISE-HRI algorithm provides a new capability to evaluate routine vital signs and alert medics to specific casualties who have the highest risk of hemorrhage, to optimize decision-making for triage, treatment, and evacuation.

The Battle of the Titans-Comparing Resuscitation Between Five Major Burn Centers Using the Burn Navigator.

The goal of burn resuscitation is to provide the optimal amount of fluid necessary to maintain end-organ perfusion and prevent burn shock. The objective of this analysis was to examine how the Burn Navigator (BN), a clinical decision support tool in burn resuscitation, was utilized across five major burn centers in the United States, using an observational trial of 300 adult patients. Subject demographics, burn characteristics, fluid volumes, urine output, and resuscitation-related complications were examined. Two hundred eighty-five patients were eligible for analysis. There was no difference among the centers on mean age (45.5 ± 16.8 years), body mass index (29.2 ± 6.9), median injury severity score (18 [interquartile range: 9-25]), or total body surface area (TBSA) (34 [25.8-47]). Primary crystalloid infusion volumes at 24 h differed significantly in ml/kg/TBSA (range: 3.1 ± 1.2 to 4.5 ± 1.7). Total fluids, including colloid, drip medications, and enteral fluids, differed among centers in both ml/kg (range: 132.5 ± 61.4 to 201.9 ± 109.9) and ml/kg/TBSA (3.5 ± 1.0 to 5.3 ± 2.0) at 24 h. Post-hoc adjustment using pairwise comparisons resulted in a loss of significance between most of the sites. There was a total of 156 resuscitation-related complications in 92 patients. Experienced burn centers using the BN successfully titrated resuscitation to adhere to 24 h goals. With fluid volumes near the Parkland formula prediction and a low prevalence of complications, the device can be utilized effectively in experienced centers. Further study should examine device utility in other facilities and on the battlefield.

Higher Initial Formula for Resuscitation After Severe Burn Injury Means Higher 24-Hour Volumes.

Initial fluid infusion rates for resuscitation of burn injuries typically use formulas based on patient weight and total body surface area (TBSA) burned. However, the impact of this rate on overall resuscitation volumes and outcomes have not been extensively studied. The purpose of this study was to determine the impact of initial fluid rates on 24-hour volumes and outcomes using the Burn Navigator (BN). The BN database is composed of 300 patients with ≥20% TBSA, >40 kg that were resuscitated utilizing the BN. Four study arms were analyzed based on the initial formula-2 ml/kg/TBSA, 3 ml/kg/TBSA, 4 ml/kg/TBSA or the Rule of Ten. Total fluids infused at 24 hours after admission were compared as well as resuscitation-related outcomes. A total of 296 patients were eligible for analysis. Higher starting rates (4 ml/kg/TBSA) resulted in significantly higher volumes at 24 hours (5.2 ± 2.2 ml/kg/TBSA) than lower rates (2 ml/kg/TBSA resulted in 3.9 ± 1.4 ml/kg/TBSA). No shock was observed in the high resuscitation cohort, whereas the lowest starting rate exhibited a 12% incidence, lower than both the Rule of Ten and 3 ml/kg/TBSA arms. There was no difference in 7-day mortality across groups. Higher initial fluid rates resulted in higher 24-hour fluid volumes. The choice of 2ml/kg/TBSA as initial rate did not result in increased mortality or more complications. An initial rate of 2ml/kg/TBSA is a safe strategy.