Multiplate and TEG platelet mapping in a population of severely injured trauma patients.

OBJECTIVES: The objectives of this study were to compare thromboelastography platelet mapping (TEG PM) with impedance aggregometry (Multiplate, MP) in a single trauma population and relate their results clinically. BACKGROUND: Platelet function as measured by thromboelastography and impedance aggregometry demonstrates significant reductions that persist for days following traumatic injury. However, no study compares these devices and the correlation between them is not known. METHODS: In level 1 trauma patients, TEG PM and MP were conducted at their initial presentation to the emergency department. Within-device repeatability and between-device association were determined using correlation analyses. Demographic variables, Injury Severity Score, blood product transfusion, laboratory test results and mortality rate were recorded. RESULTS: Ninety-two patients were enrolled. Within-device repeatability was high for TEG PM and MP for arachidonic acid (AA) and adenosine diphosphate (ADP) activation pathways. When comparing TEG PM with MP, results correlated poorly in the ADP pathway (Spearman's rho = 0·11, P = 0·44) and moderately in the AA pathway (Spearman's rho = 0·56, P < 0·0001). TEG PM was predictive of blood product transfusion and correlated with increased base deficit, whereas MP was only predictive of mortality. CONCLUSIONS: Intra-device variability was low for TEG PM and MP, but the two point-of-care devices measuring platelet function correlate poorly with each other in injured trauma patients. Each device also had different clinical associations.

External validation of a smartphone app model to predict the need for massive transfusion using five different definitions.

BACKGROUND: Previously, a model to predict massive transfusion protocol (MTP) (activation) was derived using a single-institution data set. The PRospective, Observational, Multicenter, Major Trauma Transfusion database was used to externally validate this model's ability to predict both MTP activation and massive transfusion (MT) administration using multiple MT definitions. METHODS: The app model was used to calculate the predicted probability of MTP activation or MT delivery. The five definitions of MT used were: (1) 10 units packed red blood cells (PRBCs) in 24 hours, (2) Resuscitation Intensity score ≥ 4, (3) critical administration threshold, (4) 4 units PRBCs in 4 hours; and (5) 6 units PRBCs in 6 hours. Receiver operating curves were plotted to compare the predicted probability of MT with observed outcomes. RESULTS: Of 1,245 patients in the data set, 297 (24%) met definition 1, 570 (47%) met definition 2, 364 (33%) met definition 3, 599 met definition 4 (49.1%), and 395 met definition 5 (32.4%). Regardless of the outcome (MTP activation or MT administration), the predictive ability of the app model was consistent: when predicting activation of the MTP, the area under the curve for the model was 0.694 and when predicting MT administration, the area under the curve ranged from 0.695 to 0.711. CONCLUSION: Regardless of the definition of MT used, the app model demonstrates moderate ability to predict the need for MT in an external, homogenous population. Importantly, the app allows the model to be iteratively recalibrated ("machine learning") and thus could improve its predictive capability as additional data are accrued. LEVEL OF EVIDENCE: Diagnostic test study/Prognostic study, level III.

Primary skin closure after damage control laparotomy.

BACKGROUND: Damage control laparotomy (DCL) is used widely in the management of patients with traumatic injuries but carries significant morbidity. Surgical-site infection (SSI) also carries potential morbidity, increased costs and prolonged hospital stay. The aim of this study was to determine whether primary skin closure after DCL increases the risk of SSI. METHODS: This was a retrospective institutional review of injured patients undergoing DCL between 2004 and 2012. Outcomes of patients who had primary skin closure at the time of fascial closure were compared with those of patients whose skin wound was left open to heal by secondary intention. The association between skin closure and SSI was evaluated using propensity score-adjusted multivariable logistic regression. RESULTS: Of 510 patients who underwent DCL, primary fascial closure was achieved in 301. Among these, 111 (36.9 per cent) underwent primary skin closure and in 190 (63.1 per cent) the skin wound was left open. Fascial closure at the initial take-back surgery was associated with having skin closure (P < 0.001), and colonic injury was associated with leaving the skin open (P = 0.002). On multivariable analysis, primary skin closure was associated with an increased risk of abdominal SSI (P = 0.020), but not fascial dehiscence (P = 0.446). Of patients receiving skin closure, 85.6 per cent did not develop abdominal SSI and were spared the morbidity of managing an open wound at discharge. CONCLUSION: Primary skin closure after DCL is appropriate but may be associated with an increased risk of SSI.

Contributions of severe burn and disuse to bone structure and strength in rats.

Burn and disuse results in metabolic and bone changes associated with substantial and sustained bone loss. Such loss can lead to an increased fracture incidence and osteopenia. We studied the independent effects of burn and disuse on bone morphology, composition and strength, and microstructure of the bone alterations 14days after injury. Sprague-Dawley rats were randomized into four groups: Sham/Ambulatory (SA), Burn/Ambulatory (BA), Sham/Hindlimb Unloaded (SH) and Burn/Hindlimb Unloaded (BH). Burn groups received a 40% total body surface area full-thickness scald burn. Disuse by hindlimb unloading was initiated immediately following injury. Bone turnover was determined in plasma and urine. Femur biomechanical parameters were measured by three-point bending tests and bone microarchitecture was determined by micro-computed tomography (uCT). On day 14, a significant reduction in body mass was observed as a result of burn, disuse and a combination of both. In terms of bone health, disuse alone and in combination affected femur weight, length and bone mineral content. Bending failure energy, an index of femur strength, was significantly reduced in all groups and maximum bending stress was lower when burn and disuse were combined. Osteocalcin was reduced in BA compared to the other groups, indicating influence of burn. The reductions observed in femur weight, BMC, biomechanical parameters and indices of bone formation are primarily responses to the combination of burn and disuse. These results offer insight into bone degradation following severe injury and disuse.

Increased platelet:RBC ratios are associated with improved survival after massive transfusion.

BACKGROUND: Several recent military and civilian trauma studies demonstrate that improved outcomes are associated with early and increased use of plasma-based resuscitation strategies. However, outcomes associated with platelet transfusions are poorly characterized. We hypothesized that increased platelet:red blood cells (RBC) ratios would decrease hemorrhagic death and improve survival after massive transfusion (MT). METHODS: A transfusion database of patients transported from the scene to 22 Level I Trauma Centers over 12 months in 2005 to 2006 was reviewed. MT was defined as receiving ≥ 10 RBC units within 24 hours of admission. To mitigate survival bias, 25 patients who died within 60 minutes of arrival were excluded from analysis. Six random donor platelet units were considered equal to a single apheresis platelet unit. Admission and outcome data associated with the low (>1:20), medium (1:2), and high (1:1) platelet:RBC ratios were examined. These groups were based on the median value of the tertiles for the ratio of platelets:RBC units. RESULTS: Two thousand three hundred twelve patients received at least one unit of blood and 643 received an MT. Admission vital signs, INR, temperature, pH, Glasgow Coma Scale, Injury Severity Score, and age were similar between platelet ratio groups. The average admission platelet counts were lower in the patients who received the high platelet:RBC ratio versus the low ratio (192 vs. 216, p = 0.03). Patients who received MT were severely injured, with a mean (± standard deviation) Injury Severity Score of 33 ± 16 and received 22 ± 15 RBCs and 11 ± 14 platelets within 24 hours of injury. Increased platelet ratios were associated with improved survival at 24 hours and 30 days (p < 0.001 for both). Truncal hemorrhage as a cause of death was decreased (low: 67%, medium: 60%, high: 47%, p = 0.04). Multiple organ failure mortality was increased (low: 7%, medium: 16%, high: 27%, p = 0.003), but overall 30-day survival was improved (low: 52%, medium: 57%, high: 70%) in the high ratio group (medium vs. high: p = 0.008; low vs. high: p = 0.007). CONCLUSION: Similar to recently published military data, transfusion of platelet:RBC ratios of 1:1 was associated with improved early and late survival, decreased hemorrhagic death and a concomitant increase in multiple organ failure-related mortality. Based on this large retrospective study, increased and early use of platelets may be justified, pending the results of prospective randomized transfusion data.

High ratios of plasma and platelets to packed red blood cells do not affect mortality in nonmassively transfused patients.

BACKGROUND: Administration of high transfusion ratios in patients not requiring massive transfusion might be harmful. We aimed to determine the effect of high ratios of fresh frozen plasma (FFP) and platelets (PLT) to packed red blood cells (PRBC) in nonmassively transfused patients. METHODS: Records of 1,788 transfused trauma patients who received <10 units of PRBC in 24 hours at 23 United States Level I trauma centers were reviewed. The relationship between ratio category (low and high) and in-hospital mortality was assessed with propensity-adjusted multivariate proportional hazards models. RESULTS: At baseline, patients transfused with a high FFP:PRBC ratio were younger, had a lower Glasgow Coma Scale score, and a higher Injury Severity Score. Those receiving a high PLT:PRBC ratio were older. The risk of in-hospital mortality did not vary significantly with FFP:PRBC ratio category. Intensive care unit (ICU)-free days, hospital-free days, and ventilator-free days did not vary significantly with FFP:PRBC ratio category. ICU-free days and ventilator-free days were significantly decreased among patients in the high (≥1:1) PLT:PRBC category, and hospital-free days did not vary significantly with PLT:PRBC ratio category. The analysis was repeated using 1:2 as the cutoff for high and low ratios. Using this cutoff, there was still no difference in mortality with either FFP:PRBC ratios or platelet:PRBC ratios. However, patients receiving a >1:2 ratio of FFP:PRBCs or a >1:2 ratio PLT:PRBCs had significantly decreased ICU-free days and ventilator-free days. CONCLUSIONS: FFP:PRBC and PLT:PRBC ratios were not associated with in-hospital mortality. Depending on the threshold analyzed, a high ratio of FFP:PRBC and PLT:PRBC transfusion was associated with fewer ICU-free days and fewer ventilator-free days, suggesting that the damage control infusion of FFP and PLT may cause increased morbidity in nonmassively transfused patients and should be rapidly terminated when it becomes clear that a massive transfusion will not be required.

A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients.

BACKGROUND: Platelets play a central role in hemostasis after trauma. However, the platelet count of most trauma patients does not fall below the normal range (100-450 × 10(9)/L), and as a result, admission platelet count has not been adequately investigated as a predictor of outcome. The purpose of this study was to examine the relationship between admission platelet count and outcomes after trauma. METHODS: A retrospective cohort study of 389 massively transfused trauma patients. Regression methods and the Kruskal-Wallis test were used to test the association between admission platelet count and 24-hour mortality and units of packed red blood cells (PRBCs) transfused. RESULTS: For every 50 × 10(9)/L increase in admission platelet count, the odds of death decreased 17% at 6 hours (p = 0.03; 95% confidence interval [CI], 0.70-0.99) and 14% at 24 hours (p = 0.02; 95% CI, 0.75-0.98). The probability of death at 24 hours decreased with increasing platelet count. For every 50 × 10(9)/L increase in platelet count, patients received 0.7 fewer units of blood within the first 6 hours (p = 0.01; 95% CI, -1.3 to -0.14) and one less unit of blood within the first 24 hours (p = 0.002; 95% CI, -1.6 to -0.36). The mean number of units of PRBCs transfused within the first 6 hours and 24 hours decreased with increasing platelet count. CONCLUSIONS: Admission platelet count was inversely correlated with 24-hour mortality and transfusion of PRBCs. A normal platelet count may be insufficient after severe trauma, and as a result, these patients may benefit from a lower platelet transfusion threshold. Future studies of platelet number and function after injury are needed.

Effect of high product ratio massive transfusion on mortality in blunt and penetrating trauma patients.

BACKGROUND: Recent data suggest that massively transfused patients have lower mortality rates when high ratios (>1:2) of plasma or platelets to red blood cells (RBCs) are used. Blunt and penetrating trauma patients have different injury patterns and may respond differently to resuscitation. This study was performed to determine whether mortality after high product ratio massive transfusion is different in blunt and penetrating trauma patients. METHODS: Patients receiving 10 or more units of RBCs in the first 24 hours after admission to one of 23 Level I trauma centers were analyzed. Baseline physiologic and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (≥ 1:2) and low (<1:2) ratios of plasma or platelets to RBCs was calculated for blunt and penetrating trauma patients. RESULTS: The cohort contained 703 patients. Blunt injury patients receiving a high ratio of plasma or platelets to RBCs had lower 24-hour mortality (22% vs. 31% for plasma, p = 0.007; 20% vs. 30% for platelets, p = 0.032), but there was no difference in 30-day mortality (40% vs. 44% for plasma, p = 0.085; 37% vs. 44% for platelets, p = 0.063). Patients with penetrating injuries receiving a high plasma:RBC ratio had lower 24-hour mortality (21% vs. 37%, p = 0.005) and 30-day mortality (29% vs. 45%, p = 0.005). High platelet:RBC ratios did not affect mortality in penetrating patients. CONCLUSION: Use of high plasma:RBC ratios during massive transfusion may benefit penetrating trauma patients to a greater degree than blunt trauma patients. High platelet:RBC ratios did not benefit either group.

A high fresh frozen plasma: packed red blood cell transfusion ratio decreases mortality in all massively transfused trauma patients regardless of admission international normalized ratio.

BACKGROUND: Coagulopathy is present in 25% to 38% of trauma patients on arrival to the hospital, and these patients are four times more likely to die than trauma patients without coagulopathy. Recently, a high ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBCs) has been shown to decrease mortality in massively transfused trauma patients. Therefore, we hypothesized that patients with elevated International Normalized Ratio (INR) on arrival to the hospital may benefit more from transfusion with a high ratio of FFP:PRBC than those with a lower INR. METHODS: Retrospective multicenter cohort study of 437 massively transfused trauma patients was conducted to determine whether the effect of the ratio of FFP:PRBC on death at 24 hours is modified by a patient's admission INR on arrival to the hospital. Contingency tables and logistic regression were used. RESULTS: Trauma patients who arrived to the hospital with an elevated INR had a greater risk of death than those with a lower INR. However, as the ratio of FFP:PRBC transfused increased, mortality decreased similarly between the INR quartiles. CONCLUSIONS: The mortality benefit from a high FFP:PRBC ratio is similar for all massively transfused trauma patients. This is contrary to the current belief that only coagulopathic trauma patients benefit from a high FFP:PRBC ratio. Furthermore, it is unnecessary to determine whether INR is elevated before transfusing a high FFP:PRBC ratio. Future studies are needed to determine the mechanism by which a high FFP:PRBC ratio decreases mortality in all massively transfused trauma patients.

Profoundly abnormal initial physiologic and biochemical data cannot be used to determine futility in massively transfused trauma patients.

BACKGROUND: Improvements in prehospital care and resuscitation have led to increases in the number of severely injured patients who are salvageable. Massive transfusion has been increasingly used. Patients often present with markedly abnormal physiologic and biochemical data. The purpose of this study was to identify objective data that can be used to identify clinical futility in massively transfused trauma patients to allow for early termination of resuscitative efforts. METHODS: A multicenter database was used. Initial physiologic and biochemical data were obtained, and mortality was determined for patients in the 5th and 10th percentiles for each variable. Raw data from the extreme outliers for each variable were also examined to determine whether a point of excessive mortality could be identified. Injury scoring data were also analyzed. A classification tree model was used to look for variable combinations that predict clinical futility. RESULTS: The cohort included 704 patients. Overall mortality was 40.2%. The highest mortality rates were seen in patients in the 10th percentile for lactate (77%) and pH (72%). Survivors at the extreme ends of the distribution curves for each variable were not uncommon. The classification tree analysis failed to identify any biochemical and physiologic variable combination predictive of >90% mortality. Patients older than 65 years with severe head injuries had 100% mortality. CONCLUSION: Consideration should be given to withholding massive transfusion for patients older than 65 years with severe head injuries. Otherwise we did not identify any objective variables that reliably predict clinical futility in individual cases. Significant survival rates can be expected even in patients with profoundly abnormal physiologic and biochemical data.

A predictive model for mortality in massively transfused trauma patients.

BACKGROUND: Improvements in trauma systems and resuscitation have increased survival in severely injured patients. Massive transfusion has been increasingly used in the civilian setting. Objective predictors of mortality have not been well described. This study examined data available in the early postinjury period to identify variables that are predictive of 24-hour- and 30-day mortality in massively transfused trauma patients. METHODS: Massively transfused trauma patients from 23 Level I centers were studied. Variables available on patient arrival that were predictive of mortality at 24 hours were entered into a logistic regression model. A second model was created adding data available 6 hours after injury. A third model evaluated mortality at 30 days. Receiver operating characteristic curves and the Hosmer-Lemeshow test were used to assess model quality. RESULTS: Seven hundred four massively transfused patients were analyzed. The model best able to predict 24-hour mortality included pH, Glasgow Coma Scale score, and heart rate, with an area under the receiver operating characteristic curve (AUROC) of 0.747. Addition of the 6-hour red blood cell requirement increased the AUROC to 0.769. The model best able to predict 30-day mortality included the above variables plus age and Injury Severity Score with an AUROC of 0.828. CONCLUSION: Glasgow Coma Scale score, pH, heart rate, age, Injury Severity Score, and 6-hour red blood cell transfusion requirement independently predict mortality in massively transfused trauma patients. Models incorporating these data have only a modest ability to predict mortality and should not be used to justify withholding massive transfusion in individual cases.

Gender-based differences in mortality in response to high product ratio massive transfusion.

BACKGROUND: Recent data suggest that patients undergoing massive transfusion have lower mortality rates when ratios of plasma and platelets to red blood cells (RBCs) of ≥ 1:2 are used. This has not been examined independently in women and men. A gender dichotomy in outcome after severe injury is known to exist. This study examined gender-related differences in mortality after high product ratio massive transfusion. METHODS: A retrospective study was conducted using a database containing massively transfused trauma patients from 23 Level I trauma centers. Baseline demographic, physiologic, and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (≥ 1:2) or low (<1:2) ratios of plasma or platelets to RBCs was compared in women and men independently. RESULTS: Seven hundred four patients were analyzed. In males, mortality was lower for patients receiving a high plasma:RBC ratio at 24 hours (20.6% vs. 33.0% for low ratio, p = 0.005) and at 30 days (34.9% vs. 42.8%, p = 0.032). Males receiving a high platelet:RBC ratio also had lower 24-hour mortality (17.6% vs. 31.5%, p = 0.004) and 30-day mortality (32.1% vs. 42.2%, p = 0.045). Females receiving high ratios of plasma or platelets to RBCs had no improvement in 24-hour mortality (p = 0.119 and 0.329, respectively) or 30-day mortality (p = 0.199 and 0.911, respectively). Use of high product ratio transfusions did not affect 24-hour RBC requirements in males or females. CONCLUSION: Use of high plasma:RBC or platelet:RBC ratios in massive transfusion may benefit men more than women. This may be due to gender-related differences in coagulability. Further study is needed to determine whether separate protocols for women and men should be established.

Specific abbreviated injury scale values are responsible for the underestimation of mortality in penetrating trauma patients by the injury severity score.

BACKGROUND: The Injury Severity Score (ISS) is widely used as a method for rating severity of injury. The ISS is the sum of the squares of the three worst Abbreviated Injury Scale (AIS) values from three body regions. Patients with penetrating injuries tend to have higher mortality rates for a given ISS than patients with blunt injuries. This is thought to be secondary to the increased prevalence of multiple severe injuries in the same body region in patients with penetrating injuries, which the ISS does not account for. We hypothesized that the mechanism-based difference in mortality could be attributed to certain ISS ranges and specific AIS values by body region. METHODS: Outcome and injury scoring data were obtained from transfused patients admitted to 23 Level I trauma centers. ISS values were grouped into categories, and a logistic regression model was created. Mortality for each ISS category was determined and compared with the ISS 1 to 15 group. An interaction term was added to evaluate the effect of mechanism. Additional logistic regression models were created to examine each AIS category individually. RESULTS: There were 2,292 patients in the cohort. An overall interaction between ISS and mechanism was observed (p = 0.049). Mortality rates between blunt and penetrating patients with an ISS between 25 and 40 were significantly different (23.6 vs. 36.1%; p = 0.022). Within this range, the magnitude of the difference in mortality was far higher for penetrating patients with head injuries (75% vs. 37% for blunt) than truncal injuries (26% vs. 17% for blunt). Penetrating trauma patients with an AIS head of 4 or 5, AIS abdomen of 3, or AIS extremity of 3 all had adjusted mortality rates higher than blunt trauma patients with those values. CONCLUSION: Significant differences in mortality between blunt and penetrating trauma patients exist at certain ISS and AIS category values. The mortality difference is greatest for head injured patients.

Variations between level I trauma centers in 24-hour mortality in severely injured patients requiring a massive transfusion.

BACKGROUND: Significant differences in outcomes have been demonstrated between Level I trauma centers. Usually these differences are ascribed to regional or administrative differences, although the influence of variation in clinical practice is rarely considered. This study was undertaken to determine whether differences in early mortality of patients receiving a massive transfusion (MT, ≥ 10 units pf RBCs within 24 hours of admission) persist after adjustment for patient and transfusion practice differences. We hypothesized differences among centers in 24-hour mortality could predominantly be accounted for by differences in transfusion practices as well as patient characteristics. METHODS: Data were retrospectively collected over a 1-year period from 15 Level I centers on patients receiving an MT. A purposeful variable selection strategy was used to build the final multivariable logistic model to assess differences between centers in 24-hour mortality. Adjusted odds ratios for each center were calculated. RESULTS: : There were 550 patients evaluated, but only 443 patients had complete data for the set of variables included in the final model. Unadjusted mortality varied considerably across centers, ranging from 10% to 75%. Multivariable logistic regression identified injury severity score (ISS), abbreviated injury scale (AIS) of the chest, admission base deficit, admission heart rate, and total units of RBC transfused, as well as ratios of plasma:RBC and platelet:RBC to be associated with 24-hour mortality. After adjusting for severity of injury and transfusion, treatment variables between center differences were no longer significant. CONCLUSIONS: In the defined population of patients receiving an MT, between-center differences in 24-hour mortality may be accounted for by severity of injury as well as transfusion practices.

The effect of FFP:RBC ratio on morbidity and mortality in trauma patients based on transfusion prediction score.

BACKGROUND AND OBJECTIVES: The empiric use of a high plasma to packed red-blood-cell [fresh frozen plasma:red-blood-cells (FFP:RBC)] ratio in trauma resuscitation for patients with massive bleeding has become well accepted without clear or objective indications. Increased plasma transfusion is associated with worse outcome in some patient populations. While previous studies analyse only patients who received a massive transfusion, this study analyses those that are at risk to receive a massive transfusion, based on the trauma-associated severe haemorrhage (TASH) score, to objectively determine which patients after severe trauma would benefit or have increased complications by the use of a high FFP:RBC ratio. METHODS: Multicentre retrospective study from the Trauma Registry of the German Trauma Society. Multivariate logistic regression and statistical risk adjustments utilized in analyses. RESULTS: A high ratio of FFP:RBC in the ≥15 TASH group was independently associated with survival, with an odds ratio of 2·5 (1·6-4·0), while the <15 TASH group was associated with increased multi-organ failure, 47% vs. 38%, (P<0·005). CONCLUSIONS: A predictive model of massive transfusion upon admission might be able to rapidly identify which severe trauma patients would benefit or have increased complications from the immediate application of a high ratio of FFP:RBCs. This study helps to identify the appropriate population for a prospective, interventional trial.

Tissue-specific variation in expression of prolactin receptor gene subtypes in hypergravity-exposed rats.

Prolactin (PRL) effects are mediated by membrane receptors (PRLR) of which the long (PRLR-L) and short form (PRLR-S) predominate. Our objective was to compare the distribution pattern of PRLR-L and PRLR-S transcripts and their ratio in adipose (AD), liver (LV), mammary (MG) and pituitary (PG) tissues of stationary (SC, n = 8) and hypergravity (HG, n = 8) exposed periparturient rats. Pregnant rats were exposed to 2 g force from day 11 of gestation (G11) through post partum day 1 (P1). PRLR-L mRNA expression compared to PRLR-S was greater (P < 0.001) in AD, MG and PG but was lower (P < 0.001) in LV in both HG and SC animals at P1. The ratio of PRLR-L/PRLR-S mRNA in the AD, LV, MG and PG was not different between HG and SC rats. In summary, these data reveal that the hypergravity-induced downregulation of PRLR is not directly triggered by deranged distribution of PRLR isoforms.

Metabolic consequences of muscle disuse atrophy.

In response to decreased usage, skeletal muscle undergoes an adaptive reductive remodeling. This adaptive response has been found with disuse during human spaceflight, rat spaceflight, rat hind-limb unloading, bed rest, and aging. The reductive remodeling of skeletal muscle with disuse is largely independent of the reason for the disuse. The process involves more than a transition from slow to fast myosin fiber types. There are associated metabolic changes including a fuel shift toward glycolysis, decreased capacity for fat oxidation, and energy substrate accumulation in the atrophied muscles. Glycolysis is very effective for high-intensity short-duration acute activities, but if sustained output is needed, an energy profile where fat use is favored rather than compromised is desirable. For astronauts, there is a need to maintain as much functional capacity as possible during spaceflight for extravehicular activities. The shift toward increased activity of the glycolytic enzymes in atrophied muscle is accommodated by an increase in gluconeogenic capacity in the liver.

Intensive exercise training suppresses testosterone during bed rest.

Spaceflight and prolonged bed rest (BR) alter plasma hormone levels inconsistently. This may be due, in part, to prescription of heavy exercise as a countermeasure for ameliorating the adverse effects of disuse. The initial project was to assess exercise programs to maintain aerobic performance and leg strength during BR. The present study evaluates the effect of BR and the performance of the prescribed exercise countermeasures on plasma steroid levels. In a 30-day BR study of male subjects, the efficacy of isotonic (ITE, n = 7) or isokinetic exercise (IKE, n = 7) training was evaluated in contrast to no exercise (n = 5). These exercise countermeasures protected aerobic performance and leg strength successfully. BR alone (no-exercise group) did not change steroidogenesis, as assessed by the plasma concentrations of cortisol, progesterone, aldosterone, and free (FT) and total testosterone (TT). In the exercise groups, both FT and TT were decreased (P < 0.05): FT during IKE from 24 +/- 1.7 to 18 +/- 2.0 pg/ml and during ITE from 21 +/- 1.5 to 18 +/- 1 pg/ml, and TT during IKE from 748 +/- 68 to 534 +/- 46 ng/dl and during ITE from 565 +/- 36 to 496 +/- 38 ng/dl. The effect of intensive exercise countermeasures on plasma testosterone was not associated with indexes of overtraining. The reduction in plasma testosterone associated with both the IKE and ITE countermeasures during BR supports our hypothesis that intensive exercise countermeasures may, in part, contribute to changes in plasma steroid concentrations during spaceflight.

Effects of disrupted beta1-integrin function on the skeletal response to short-term hindlimb unloading in mice.

The study was designed to determine whether beta1-integrin plays a role in mediating the acute skeletal response to mechanical unloading. Transgenic (TG) mice were generated to express a dominant negative form of beta1-integrin under the control of the osteocalcin promoter, which targets expression of the transgene to mature osteoblasts. At 63 days of age, wild-type (WT) and TG mice were subjected to hindlimb unloading by tail suspension for 1 wk. Pair-fed, normally loaded WT and TG mice served as age-matched controls. Bone samples from each mouse were processed for quantitative bone histomorphometry and biomechanical testing. The skeletal phenotype of TG mice was characterized by lower cancellous bone mass in the distal femoral metaphysis (-52%) and lumbar vertebral body (-20%), reduced curvature of the proximal tibia (-20%), and decreased bone strength (-20%) and stiffness (-23%) of the femoral diaphysis with relatively normal indexes of cancellous bone turnover. Hindlimb unloading for only 1 wk induced a 10% decline in tibial curvature and a 30% loss of cancellous bone in the distal femur due to a combination of increased bone resorption and decreased bone formation in both WT and TG mice. However, the strength and stiffness of the femoral diaphysis were unaffected by short-term hindlimb unloading in both genotypes. The observed increase in osteoclast surface was greater in unloaded TG mice (92%) than in unloaded WT mice (52%). Cancellous bone formation rate was decreased in unloaded WT (-29%) and TG (-15%) mice, but, in contrast to osteoclast surface, the genotype by loading interaction was not statistically significant. The results indicate that altered integrin function in mature osteoblasts may enhance the osteoclastic response to mechanical unloading but that it does not have a major effect on the development of cancellous osteopenia in mice during the early stages of hindlimb unloading.

Effects of hypergravity on mammary metabolic function: gravity acts as a continuum.

Mammary metabolic activity in pregnant rats is significantly increased in response to spaceflight. To determine whether changes in mammary metabolism are related to gravity load, we exposed pregnant rats to hypergravity and measured mammary metabolic activity. From days 11-20 of gestation (G), animals were centrifuged (20 rpm; 1.5, 1.75, or 2.0 x gravity) or were maintained at 1 G. On G20, five rats from each group were removed from the centrifuge and euthanized. The remaining dams (n = 5/treatment) were housed at 1 G until parturition. After 2 h of nursing by the pups, the postpartum dams were euthanized (G22). Glucose oxidation to CO2 and incorporation into lipids was measured. Mammary glands from dams euthanized on G20 revealed a strong negative correlation between metabolic rate and increased G load. Approximately 98% of the variation in glucose oxidation and 94% of the variation in glucose incorporation into lipids can be accounted for by differences in G load. Differences in metabolic activity disappeared in the postpartum dams. When we combined previous data from the microgravity with hypergravity environments and plotted the ratio of mammary metabolic rate vs. G load, there was a significant exponential relationship (r2 = 0.99). These data demonstrate a remarkable continuum of response across the microgravity and hypergravity environments and support the concept that gravitational load influences mammary tissue metabolism.