Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

Objectives: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported. Methods: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography angle <60. Univariate and multivariable analyses assessed risk factors for HYPOFIB. Inverse probability of treatment weighting analyses assessed the relationship between cryoprecipitate administration and outcomes. Results: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood, <1%, 2%, and 7% were HYPOFIB. HYPOFIB patients were younger, had higher head Abbreviated Injury Scale value, and had worse coagulopathy and shock. HYPOFIB had lower survival (48% vs 82%, p<0.001), shorter time to death (median 28 (7, 50) vs 36 (14, 140) hours, p=0.012), and were more likely to die from head injury (72% vs 51%, p<0.001). Risk factors for HYPOFIB included increased age (OR (95% CI) 0.98 (0.96 to 0.99), p=0.03), head injury severity (OR 1.24 (1.06 to 1.46), p=0.009), lower arrival pH (OR 0.01 (0.001 to 0.20), p=0.002), and elevated prehospital red blood cell to platelet ratio (OR 1.20 (1.02 to 1.41), p=0.03). Among HYPOFIB patients, there was no difference in survival for those that received early cryoprecipitate (within 2 hours; 40 vs 47%; p=0.630). On inverse probability of treatment weighted analysis, early cryoprecipitate did not benefit the full cohort (OR 0.52 (0.43 to 0.65), p<0.001), nor the HYPOFIB subgroup (0.28 (0.20 to 0.39), p<0.001). Conclusions: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced resuscitation. Previously reported higher rates may be partially due to unbalanced resuscitation and/or delay in resuscitation initiation. Routine empiric inclusion of concentrated fibrinogen replacement in MTPs is not supported by the currently available data. Level of evidence: Level III.

An assessment of the safety, hemostatic efficacy, and clinical impact of low-titer group O whole blood in children and adolescents.

BACKGROUND: Low-titer group O whole blood (LTOWB) use has been associated with improved survival and less blood transfusions in adult trauma patients. Its use in pediatric trauma has been shown to be safe when using leukoreduced, LTOWB with anti-A, anti-B antibody titers of <1:50. We set out to evaluate the safety, hemostatic potential, and impact on pediatric outcomes at a center using non-leukoreduced, LTOWB with anti-A, anti-B antibody titers of <1:200. METHODS: Patients younger than 18 years, who received emergency-release, uncrossed matched blood, and presented to our trauma center from November 2017 to April 2021 were included. Patients were divided into those receiving any LTOWB and those receiving only RBC and or plasma (COMP). Primary outcome was 30-day survival. RESULTS: One hundred sixty-four patients received emergency release blood products. Of these, 73 received at least one unit of LTOWB. The LTOWB group were younger (14 years vs. 13 years), more likely to be male (87% vs. 49%), and to have sustained penetrating trauma (44% vs. 23%); all p < 0.05. Low-titer group O whole blood patients received more blood than their COMP counterparts prior to arrival. Serial hemolysis panels (K+, bilirubin, LDH, haptoglobin) obtained at 24 hours, 48 hours, and 72 hours were similar between groups; all p > 0.05. There was no difference in survival by univariate analysis but after adjusting for inverse probability of treatment weights there was an observed association between WB administration and improved survival, with an odds ratio of 2.48 (1.15-5.47). CONCLUSION: Non-leukoreduced, LTOWB in anti-A/anti-B antibody titers of <1:200 appear safe in children and adolescents. While patients receiving LTOWB had more evidence of shock, higher torso injury severity, and received more prehospital blood products, there may be a mortality benefit with whole blood. Larger, multicenter studies are needed. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Quantification of Circulating Cell Free Mitochondrial DNA in Extracellular Vesicles with PicoGreen™ in Liquid Biopsies: Fast Assessment of Disease/Trauma Severity.

The analysis of circulating cell free DNA (ccf-DNA) is an emerging diagnostic tool for the detection and monitoring of tissue injury, disease progression, and potential treatment effects. Currently, most of ccf-DNA in tissue and liquid biopsies is analysed with real-time quantitative PCR (qPCR) that is primer- and template-specific, labour intensive and cost-inefficient. In this report we directly compare the amounts of ccf-DNA in serum of healthy volunteers, and subjects presenting with various stages of lung adenocarcinoma, and survivors of traumatic brain injury using qPCR and quantitative PicoGreen™ fluorescence assay. A significant increase of ccf-DNA in lung adenocarcinoma and traumatic brain injury patients, in comparison to the group of healthy human subjects, was found using both analytical methods. However, the direct correlation between PicoGreen™ fluorescence and qPCR was found only when mitochondrial DNA (mtDNA)-specific primers were used. Further analysis of the location of ccf-DNA indicated that the majority of DNA is located within lumen of extracellular vesicles (EVs) and is easily detected with mtDNA-specific primers. We have concluded that due to the presence of active DNases in the blood, the analysis of DNA within EVs has the potential of providing rapid diagnostic outcomes. Moreover, we speculate that accurate and rapid quantification of ccf-DNA with PicoGreen™ fluorescent probe used as a point of care approach could facilitate immediate assessment and treatment of critically ill patients.

Limitations of Available Blood Products for Massive Transfusion During Mass Casualty Events at US Level 1 Trauma Centers.

INTRODUCTION: Exsanguination remains a leading cause of preventable death in traumatically injured patients. To better treat hemorrhagic shock, hospitals have adopted massive transfusion protocols (MTPs) which accelerate the delivery of blood products to patients. There has been an increase in mass casualty events (MCE) worldwide over the past two decades. These events can overwhelm a responding hospital's supply of blood products. Using a computerized model, this study investigated the ability of US trauma centers (TCs) to meet the blood product requirements of MCEs. METHODS: Cross-sectional survey data of on-hand blood products were collected from 16 US level-1 TCs. A discrete event simulation model of a TC was developed based on historic data of blood product consumption during MCEs. Each hospital's blood bank was evaluated across increasingly more demanding MCEs using modern MTPs to guide resuscitation efforts in massive transfusion (MT) patients. RESULTS: A total of 9,000 simulations were performed on each TC's data. Under the least demanding MCE scenario, the median size MCE in which TCs failed to adequately meet blood product demand was 50 patients (IQR 20-90), considering platelets. Ten TCs exhaust their supply of platelets prior to red blood cells (RBCs) or plasma. Disregarding platelets, five TCs exhausted their supply of O- packed RBCs, six exhausted their AB plasma supply, and five had a mixed exhaustion picture. CONCLUSION: Assuming a TC's ability to treat patients is limited only by their supply of blood products, US level-1 TCs lack the on-hand blood products required to adequately treat patients following a MCE. Use of non-traditional blood products, which have a longer shelf life, may allow TCs to better meet the blood product requirement needs of patients following larger MCEs.

An Assessment of Research Priorities to Dampen the Pendulum Swing of Burn Resuscitation.

On June 17 to 18, 2019, the American Burn Association, in conjunction with Underwriters Laboratories, convened a group of experts on burn resuscitation in Washington, DC. The goal of the meeting was to identify and discuss novel research and strategies to optimize the process of burn resuscitation. Patients who sustain a large thermal injury (involving >20% of the total body surface area [TBSA]) face a sequence of challenges, beginning with burn shock. Over the last century, research has helped elucidate much of the underlying pathophysiology of burn shock, which places multiple organ systems at risk of damage or dysfunction. These studies advanced the understanding of the need for fluids for resuscitation. The resultant practice of judicious and timely infusion of crystalloids has improved mortality after major thermal injury. However, much remains unclear about how to further improve and customize resuscitation practice to limit the morbidities associated with edema and volume overload. Herein, we review the history and pathophysiology of shock following thermal injury, and propose some of the priorities for resuscitation research. Recommendations include: studying the utility of alternative endpoints to resuscitation, reexamining plasma as a primary or adjunctive resuscitation fluid, and applying information about inflammation and endotheliopathy to target the underlying causes of burn shock. Undoubtedly, these future research efforts will require a concerted effort from the burn and research communities.

Hemostatic potential of cold-stored non-leukoreduced whole blood over time: An assessment of platelet function and thrombin generation for optimal shelf life.

OBJECTIVES: Cold-stored low-titer whole blood (WB) is becoming increasingly used as the preferred product for initial hemorrhagic shock resuscitation. The purpose of this study was to identify whether the current 21-day shelf life is the optimal duration for storage of WB, maintaining hemostatic efficacy. METHODS: Five units of fresh low-titer group O WB (non-leukoreduced) were acquired from our regional blood center. These units were stored at 4°C for up to 21 days as per current clinical storage guidelines in our emergency department. Hemostatic parameters were measured in vitro at 0 days, 7 days, 14 days, and 21 days. Assessments of hemostatic potential included cell count, rapid thrombelastography (r-TEG) and kaolin thrombelastography (TEG), multiplate impedance aggregometry, and calibrated automated thrombogram (CAT). Univariate analysis, including one-way analysis of variance with repeated measures, was performed (STATA 12.1). RESULTS: Compared with baseline product (0 days), both platelet count and platelet function of WB showed sharp decreases at 7 days and again at 14 days. Platelet function deterioration was noted by r-TEG c (MA), TEG-MA, and multiplate arachidonic acid and adenosine diphosphate (all p < 0.001). With respect to clot initiation, r-TEG ACT and TEG R-time were similar over the 21-day shelf life (p = 0.058 and p = 0.620, respectively). Thrombin generation assessed by CAT demonstrated stable endogenous thrombin potential over the course of storage (p = 0.162), but increased peak thrombin generation and quicker time to peak generation after 7 days. CONCLUSION: While the platelet function of WB degrades significantly at 7 days (and again at 14 days), clot initiation remains stable over time, and thrombin generation appears to be improved at 7 days. This study supports a current storage limit for cold-stored, low-titer WB of 14 days.

Managing emerging mutagenicity risks: Late stage mutagenic impurity control within the atovaquone second generation synthesis.

The mutagenic-impurity control strategy for a second generation manufacturing route to the non-mutagenic antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required. Following a thorough review of process purging detail, spiking and purging experimentation, and an understanding of the process parameters to which they were exposed an ICH M7 Option 4 approach could be justified for their control. The development of two 1H NMR spectroscopy methods for measurement of these impurities is also described as well as a proposed summary table for describing the underlying rationale for ICH M7 control rationales to regulators. This manuscript demonstrates that process purging of potential mutagenic impurities can be realised even when they are introduced in the later stages of a process and highlights the importance of scientific understanding rather than relying on a stage-counting approach.

Prevalence and Impact of Admission Acute Traumatic Coagulopathy on Treatment Intensity, Resource Use, and Mortality: An Evaluation of 956 Severely Injured Children and Adolescents.

BACKGROUND: Acute coagulopathy of trauma in children is of potential importance to clinical outcomes, but knowledge is limited and has only been investigated using conventional coagulation testing. The purpose of this study was to assess the prevalence and impact of arrival coagulopathy, determined by viscoelastic hemostatic testing, in severely injured children. STUDY DESIGN: Pediatric patients (younger than 17 years of age) who were admitted January 2010 to May 2016 and met highest-level trauma activation were included. Patients were divided into 2 groups (coagulopathy and controls) based on arrival rapid thrombelastography values. Coagulopathy was defined as the presence of any of the following on rapid thrombelastography: activated clotting time ≥128 seconds, α-angle ≤65 degrees, maximum amplitude ≤55 mm, and lysis at 30 minutes from 20-mm amplitude ≥3%. Logistic regression was used to adjust for age, sex, blood pressure, mechanism, and injury severity. RESULTS: Nine hundred and fifty-six patients met inclusion; 507 (57%) were coagulopathic and 449 (43%) were not (noncoagulopathic and control cohort). Coagulopathic patients were younger (median 14 vs 15 years) and more likely to be male (68% vs 60%) and Hispanic (38% vs 31%) (all p < 0.05). Coagulopathic patients received more RBC and plasma transfusions and had fewer ICU and ventilator-free days and higher mortality (12% vs 3%; all p < 0.05). Of these 956, 197 (21%) sustained severe brain injury-123 (62%) were coagulopathic and 74 (38%) were noncoagulopathic. The mortality difference was even greater for coagulopathic head injuries (31% vs 10%; p = 0.002). Adjusting for confounders, admission coagulopathy was an independent predictor of death, with an odds ratio of 3.67 (95% CI 1.768 to 7.632; p < 0.001). CONCLUSIONS: Almost 60% of severely injured children and adolescents arrive with evidence of acute traumatic coagulopathy. The presence of admission coagulopathy is associated with high mortality in children, especially among those with head injuries.

Purposeful variable selection and stratification to impute missing Focused Assessment with Sonography for Trauma data in trauma research.

BACKGROUND: The Focused Assessment with Sonography for Trauma (FAST) examination is an important variable in many retrospective trauma studies. The purpose of this study was to devise an imputation method to overcome missing data for the FAST examination. Owing to variability in patients' injuries and trauma care, these data are unlikely to be missing completely at random, raising concern for validity when analyses exclude patients with missing values. METHODS: Imputation was conducted under a less restrictive, more plausible missing-at-random assumption. Patients with missing FAST examinations had available data on alternate, clinically relevant elements that were strongly associated with FAST results in complete cases, especially when considered jointly. Subjects with missing data (32.7%) were divided into eight mutually exclusive groups based on selected variables that both described the injury and were associated with missing FAST values. Additional variables were selected within each group to classify missing FAST values as positive or negative, and correct FAST examination classification based on these variables was determined for patients with nonmissing FAST values. RESULTS: Severe head/neck injury (odds ratio [OR], 2.04), severe extremity injury (OR, 4.03), severe abdominal injury (OR, 1.94), no injury (OR, 1.94), other abdominal injury (OR, 0.47), other head/neck injury (OR, 0.57), and other extremity injury (OR, 0.45) groups had significant ORs for missing data; the other group's OR was not significant (OR, 0.84). All 407 missing FAST values were imputed, with 109 classified as positive. Correct classification of nonmissing FAST results using the alternate variables was 87.2%. CONCLUSION: Purposeful imputation for missing FAST examinations based on interactions among selected variables assessed by simple stratification may be a useful adjunct to sensitivity analysis in the evaluation of imputation strategies under different missing data mechanisms. This approach has the potential for widespread application in clinical and translational research, and validation is warranted.

Determination of resting energy expenditure after severe burn.

The purpose of this study was to evaluate the accuracy of nine predictive equations for calculating energy expenditure in severely burned adult subjects. The selected equations have been reported as commonly used or determined to be the most accurate. This prospective, observational study was conducted on adult subjects admitted between October 2007 and July 2010 with ≥ 20% TBSA full-thickness burns (excluding electrical burns or severe head injury). Indirect calorimetry measurements were conducted as a convenience sample during the first 30 days after injury. Demographic data were collected, and resting energy expenditure was calculated using the nine selected predictive equations and compared to measured energy expenditure (MEE) using descriptive and comparative statistics. Data were collected on 31 subjects with an average age of 46 ± 19 years and %TBSA burn of 48 ± 21%. For all equations, slopes and intercepts were significantly different from the line of identity when compared with MEE. A calorie-dependent bias was present for all equations, in that lower calorie range was overestimated and the higher calorie range was underestimated. Only the Carlson and Milner equations had results that were not significantly different from the MEE and mean differences that were not significant in all burn size ranges. None of the equations had a strong correlation with MEE. Of the equations available, the Milner and Carlson equations are the most satisfactory in predicting resting energy expenditure in severely burned adults when indirect calorimetry is unavailable.

Early femur fracture fixation is associated with a reduction in pulmonary complications and hospital charges: a decade of experience with 1,376 diaphyseal femur fractures.

BACKGROUND: Early fixation (<24 hour) of femur fractures with an intramedullary nail (IMN) has been associated with a decreased incidence of pulmonary complication (PC) in stable trauma patients. Early fixation is in accordance with the "two-hit" hypothesis, that is, an increase in proinflammatory markers during Days 3 to 5 after injury, increases the risk of developing a PC. We hypothesized that early IMN fixation of femur fractures would be associated with a decreased incidence of PC, hospital stay, and overall charges. METHODS: A retrospective review of all trauma patients with diaphyseal femur fractures was performed from January 2000 through December 2010 at an academic Level 1 trauma center. The cohort was divided into those who underwent early fixation (<24 hours) and delayed fixation (≥24 hours). Multivariable logistic regression modeling was used to adjust for the anatomic (Injury Severity Score [ISS]) and physiologic (Revised Trauma Score [RTS]) severity of injury. The primary outcome of interest was PC, defined as the presence of pneumonia (PNA), pulmonary embolism, or adult respiratory distress syndrome. Continuous variables are expressed as mean (SD). The analysis was repeated for patients with an ISS of greater than 15 and an ISS of greater than 25. RESULTS: During the study period, 1,755 patients were admitted with a diaphyseal femur fracture, of whom 1,376 patients underwent primary IMN. A total of 1,032 (75%) underwent early fixation (median, 7.4 hours; interquartile range [IQR], 3.7-12.9 hours), and 344 (25%) underwent delayed fixation (median, 40.9 hours; IQR, 31.0-64.9 hours). The early fixation group had lower ISS (median [IQR], 10 [10-19] vs. 17.5 [10-27]; p < 0.001) and a higher RTS (median [IQR], 7.84 [7.84-7.84] vs. 7.84 [7.84-7.84]; p < 0.001). PC were reduced in the early fixation group, (3.9% vs. 13.4%, p < 0.001). Specifically, there was a decreased incidence of PNA (2% vs. 11%, p < 0.001), pulmonary embolism (2% vs. 4%, p < 0.21), and adult respiratory distress syndrome (0.002% vs. 0.02%, p < 0.001). After adjustment for anatomic (ISS) and physiologic (RTS) indices of injury severity, early fixation was independently associated with a reduction in PC (odds ratio, 0.43; 95% confidence interval, 0.25-0.72; p = 0.002). The early fixation group also had a decrease in hospital length of stay (median [IQR], 6 [4-11] vs. 10 [6-17]; p < 0.001), ventilator days (median [IQR], 0 [0-0] vs. 0 [0-4]; p < 0.001), and hospital charges (median [IQR], $59,561 [$38,618-$106,780] vs. $97,018 [48,249-205,570]; p < 0.001). Mortality was low in both groups (0.4% vs. 1.7%, p < 0.01). Similar results were seen in patients with an ISS of greater than 15 and ISS of greater than 25. CONCLUSION: Controlling for anatomic and physiologic severity of injury, early femoral IMN was associated with an almost 60% reduction in odds of developing PCs. Early fixation was also associated with a reduction ventilator days, hospital length of stay, and overall hospital charges. As the list of "never events" continues to expand and improving quality of care while reducing costs is emphasized, early (<24 hours) definitive operative intervention seems to decrease complications, achieve early hospital discharge, and reduce hospital charges. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients.

OBJECTIVE: Injury and shock lead to alterations in conventional coagulation tests (CCTs). Recently, rapid thrombelastography (r-TEG) has become recognized as a comprehensive assessment of coagulation abnormalities. We have previously shown that admission r-TEG results are available faster than CCTs and predict pulmonary embolism. We hypothesized that r-TEGs more reliably predict blood component transfusion than CCTs. METHODS: Consecutive patients admitted between September 2009 and February 2011 who met the highest-level trauma activations were included. All had admission r-TEG and CCTs. We correlated r-TEG values [activated clotting time (ACT), r, k, α, maximal amplitude (MA), LY30] with their corresponding CCTs [prothrombin time (PT)/activated partial thromboplastin time (aPTT), international normalized ratio (INR), platelet count and fibrinogen] for transfusion requirements. Charges were calculated for each test. Demographics, vital signs, and injury severity were recorded. RESULTS: We studied 1974 major trauma activations. The median injury severity score was 17 [interquartile range 9-26]; 25% were in shock; 28% were transfused; and 6% died within 24 hours. Overall, r-TEG correlated with CCTs. When controlling for age, injury mechanism, weighted-Revised Trauma Score, base excess and hemoglobin, ACT-predicted red blood cell (RBC) transfusion, and the α-angle predicted massive RBC transfusion better than PT/aPTT or INR (P < 0.001). The α-angle was superior to fibrinogen for predicting plasma transfusion (P < 0.001); MA was superior to platelet count for predicting platelet transfusion (P < 0.001); and LY-30 (rate of amplitude reduction 30 minutes after the MA is reached) documented fibrinolysis. These correlations improved for transfused, shocked or head injured patients. The charge for r-TEG ($317) was similar to the 5 CCTs ($286). CONCLUSIONS: The r-TEG data was clinically superior to results from 5 CCTs. In addition, r-TEG identified patients with an increased risk of early RBC, plasma and platelet transfusions, and fibrinolysis. Admission CCTs can be replaced with r-TEG.

Impact of policy change on US Army combat transfusion practices.

BACKGROUND: Clinical practice guidelines (CPGs) are used to keep providers up-to-date with the most recent literature and to guide in decision making. Adherence is typically improved although many have a muted impact. In March 2006, the US Army issued a damage control resuscitation CPG, encouraging 1:1 plasma:red blood cell (RBC) transfusions and limiting crystalloid use. The objective of this study was to determine whether the CPG was associated with a change in the transfusion practices in combat-wounded patients. METHODS: All US service members injured in Operation Iraqi Freedom/Operation Enduring Freedom who received massive transfusions (MTs; > or = 10 RBC in 24 hours) were queried from the US Army Institute of Surgical Research transfusion database. Whole blood, when used, was counted as 1 unit of RBC, fresh frozen plasma (FFP), and platelet. Subjects were divided into pre- and post-CPG cohorts. Primary outcomes were ratios of FFP:RBC and crystalloid use. RESULTS: A total of 777 MT patients were identified. The cohorts were similar in age (25 years +/- 6 years vs. 25 years +/- 6 years; p = ns) and injury severity scale score (24 +/- 12 vs. 25 +/- 12; p = ns). The post-CPG cohort was warmer (96.5 degrees F +/- 7.8 degrees F vs. 98.2 degrees F +/- 1.9 degrees F; p < 0.05) and was transfused more RBC, platelets, and plasma but received less crystalloid (17 units +/- 12 units vs. 19 units +/- 11 units, 1 unit +/- 2 units vs. 2 units +/- 3 units, 8 units +/- 8 units vs. 14 units +/- 11 units, 14 L +/- 14 L vs. 9 L +/- 13 L, respectively; p < 0.05). The post-CPG cohort also received a higher ratio transfusion (0.5 +/- 0.31 vs. 0.8 +/- 0.31; p < 0.05) representing a change in practice. Overall mortality was not different between the two groups (24 vs. 19%; p = 0.115). CONCLUSIONS: MT patients are now receiving a higher FFP:RBC ratio and less crystalloid after implementation of the CPG. Additionally, patients are now presenting normothermic and have higher hemoglobin levels. All of these changes are consistent with the principles of damage control resuscitation. Changes in practice were associated with implementation of the CPG, maturity of the battlefield, and increased availability of products.

Anemia causes hypoglycemia in intensive care unit patients due to error in single-channel glucometers: methods of reducing patient risk.

OBJECTIVE: Intensive insulin therapy in the critically ill reduces mortality but carries the risk of increased hypoglycemia. Point-of-care blood glucose analysis is standard; however, anemia causes falsely high values and potentially masks hypoglycemia. Permissive anemia is practiced routinely in most intensive care units. We hypothesized that point-of-care glucometer error due to anemia is prevalent, can be corrected mathematically, and correction uncovers occult hypoglycemia during intensive insulin therapy. DESIGN: The study has both retrospective and prospective phases. We reviewed data to verify the presence of systematic error, determine the source of error, and establish the prevalence of anemia. We confirmed our findings by reproducing the error in an in vitro model. Prospective data were used to develop a correction formula validated by the Monte Carlo method. Correction was implemented in a burn intensive care unit and results were evaluated after 9 mos. SETTING: Burn and trauma intensive care units at a single research institution. PATIENTS/SUBJECTS: Samples for in vitro studies were taken from healthy volunteers. Samples for formula development were from critically ill patients who received intensive insulin therapy. INTERVENTIONS: Insulin doses were calculated based on predicted serum glucose values from corrected point-of-care glucometer measurements. MEASUREMENTS AND MAIN RESULTS: Time-matched point-of-care glucose, laboratory glucose, and hematocrit values. We previously found that anemia (hematocrit <34%) produces systematic error in glucometer measurements. The error was correctible with a mathematical formula developed and validated, using prospectively collected data. Error of uncorrected point-of-care glucose ranged from 19% to 29% (p < .001), improving to < or = 5% after mathematical correction of prospective data. Comparison of data pairs before and after correction formula implementation demonstrated a 78% decrease in the prevalence of hypoglycemia in critically ill and anemic patients treated with insulin and tight glucose control (p < .001). CONCLUSIONS: A mathematical formula that corrects erroneous point-of-care glucose values due to anemia in intensive care unit patients reduces the prevalence of hypoglycemia during intensive insulin therapy.

Assessment of cardiovascular regulation after burns by nonlinear analysis of the electrocardiogram.

Critical illness and hypovolemia are associated with loss of complexity of the R-to-R interval (RRI) of the electrocardiogram, whereas recovery is characterized by restoration thereof. Our goal was to investigate the dynamics of RRI complexity in burn patients. We hypothesized that the postburn period is associated with a state of low RRI complexity, and that successful resuscitation restores it. Electrocardiogram was acquired from 13 patients (age 55 +/- 5 years, total body surface area burned 36 +/- 6%, 11 +/- 5% full thickness) at 8, 12, 24, and 36 hours during postburn resuscitation. RRI complexity was quantified by approximate entropy (ApEn) and sample entropy (SampEn) that measure RRI signal irregularity, as well as by symbol distribution entropy and bit-per-word entropy that assess symbol sequences within the RRI signal. Data (in arbitrary units) are means +/- SEM. All patients survived resuscitation. Changes in heart rate and blood pressure were not significant. ApEn at 8 hours was abnormally low at 0.89 +/- 0.06. ApEn progressively increased after burn to 1.22 +/- 0.04 at 36 hours. SampEn showed similar significant changes. Symbol distribution entropy and bit-per-word entropy increased with resuscitation from 3.63 +/- 0.22 and 0.61 +/- 0.04 respectively at 8 hours postburn to 4.25 +/- 0.11 and 0.71 +/- 0.02 at 24 hours postburn. RRI complexity was abnormally low during the early postburn period, possibly reflecting physiologic deterioration. Resuscitation was associated with a progressive improvement in complexity as measured by ApEn and SampEn and complementary changes in other measures. Assessment of complexity may provide new insight into the cardiovascular response to burns.

The epidemiology and modern management of traumatic hemorrhage: US and international perspectives.

Trauma is a worldwide problem, with severe and wide ranging consequences for individuals and society as a whole. Hemorrhage is a major contributor to the dilemma of traumatic injury and its care. In this article we describe the international epidemiology of traumatic injury, its causes and its consequences, and closely examine the role played by hemorrhage in producing traumatic morbidity and mortality. Emphasis is placed on defining situations in which traditional methods of hemorrhage control often fail. We then outline and discuss modern principles in the management of traumatic hemorrhage and explore developing changes in these areas. We conclude with a discussion of outcome measures for the injured patient within the context of the epidemiology of traumatic injury.

Resting energy expenditure of rats acclimated to hypergravity.

BACKGROUND: The use of centrifugation at 1 G has been advocated as a control condition during spaceflight and as a countermeasure to compensate for the adverse effects of spaceflight. Rodents are the primary animal model for the study of the effects of spaceflight and will be used in the evaluation of centrifugation as a countermeasure and means of control at 1 G during flight. HYPOTHESIS: The present study was designed to assess whether resting energy expenditure (EER) of male rats was increased in relation to the magnitude of the level of gravity to which the animals were exposed. The influence of body mass and age on resting energy expenditure (EER) of male rats (n = 42, age 40-400 d) was determined following 2 wk of acclimation to 1, 2.3, or 4.1 G. Hypergravity environments were created by centrifugation. Measurements were made at the gravity level to which the animal was acclimated and during the lights-on period. RESULTS: In rats matched for body mass (approximately 400 g), mean O2 consumption and CO2 production were higher (18% and 27%, respectively) in the 2.3- and 4.1 -G groups than controls. Mean respiratory exchange ratio (RER) increased from 0.80 to 0.87. EER was increased from 47 +/- 0.1 kcal x d(-1) at 1 G, to 57 +/- 1.5 and 58 +/- 2.2 kcal x d(-1) at 2.3 and 4.1 G, respectively. There was no difference in EER between the hypergravity groups. When age differences were considered, EER (kcal x kg(-1) x d(-1)) with increased gravity was 40% higher than at 1 G. The increase in EER was not proportional over gravity levels. CONCLUSION: Acclimation of rats to hypergravity increases their EER, dependent on body mass and age, and may alter substrate metabolism. The increase in EER was not related to the level of gravity increase.