Addition of aspirin to venous thromboembolism chemoprophylaxis safely decreases venous thromboembolism rates in trauma patients.

Background: Trauma patients exhibit a multifactorial hypercoagulable state and have increased risk of venous thromboembolism (VTE). Despite early and aggressive chemoprophylaxis (CP) with various heparin compounds ("standard" CP; sCP), VTE rates remain high. In high-quality studies, aspirin has been shown to decrease VTE in postoperative elective surgical and orthopedic trauma patients. We hypothesized that inhibiting platelet function with aspirin as an adjunct to sCP would reduce the risk of VTE in trauma patients. Methods: We performed a retrospective observational study of prospectively collected data from all adult patients admitted to an American College of Surgeons Level I Trauma center from January 2012 to June 2015 to evaluate the addition of aspirin (sCP+A) to sCP regimens for VTE mitigation. Cox proportional hazard models were used to assess the potential benefit of adjunctive aspirin for symptomatic VTE incidence. Results: 10,532 patients, median age 44 (IQR 28 to 62), 68% male, 89% blunt mechanism of injury, with a median Injury Severity Score (ISS) of 12 (IQR 9 to 19), were included in the study. 8646 (82%) of patients received only sCP, whereas 1886 (18%) patients received sCP+A. The sCP+A cohort displayed a higher median ISS compared with sCP (13 vs 11; p<0.01). The overall median time of sCP initiation was hospital day 1 (IQR 0.8 to 2) and the median day for aspirin initiation was hospital day 3 (IQR 1 to 6) for the sCP+A cohort. 353 patients (3.4%) developed symptomatic VTE. Aspirin administration was independently associated with a decreased relative hazard of VTE (HR 0.57; 95% CI 0.36 to 0.88; p=0.01). There were no increased bleeding or wound complications associated with sCP+A (point estimate 1.23, 95% CI 0.68 to 2.2, p=0.50). Conclusion: In this large trauma cohort, adjunctive aspirin was independently associated with a significant reduction in VTE and may represent a potential strategy to safely mitigate VTE risk in trauma patients. Further prospective studies evaluating the addition of aspirin to heparinoid-based VTE chemoprophylaxis regimens should be sought. Level of evidence: Level III/therapeutic.

Thromboelastography-Based Profiling of Coagulation Status in Patients Undergoing Bariatric Surgery: Analysis of 422 Patients.

INTRODUCTION/PURPOSE: Some clinical indicators suggest hypercoagulability/hyperaggregability in patients with morbid obesity. Thromboelastography (TEG®) has been used to profile coagulation status in surgical patients. We aimed to assess coagulation profiles in patients with morbid obesity undergoing bariatric surgery by correlating demographic and patient characteristics to pre-operative TEG® values. MATERIALS AND METHODS: Pre-operative TEG® values from 422 patients undergoing bariatric surgery were evaluated. TEG® results were analyzed by gender, use of medications known to alter the coagulation profile, and body mass index (BMI). RESULTS: Patients have a mean of 45.03 ± 11.8 years, female (76.3%), and with a mean BMI of 42 kg/m 1. The overall coagulation profile of female patients was significantly different from males, even in the sub-cohort without use of medications known to alter coagulation. The majority of patients (94%) with a G value > 15 dynes/cm 1 (clot strength) were female. In females, there was no association between BMI and TEG® values; however, in men, there was a statistically significant difference in TEG® values for those with BMI < 40 kg/m 1 compared to those with BMI > 50 kg/m2. CONCLUSIONS: TEG®-based analysis of coagulation profiles offers unique insights. Compared to laboratory normal values (R time, angle, maximal amplitude, and G values), patients with morbid obesity may have a tendency for hypercoagulability/hyperaggregability, with mean values at the higher limit. A significant hypercoagulable difference in TEG® values was identified in female as compared to male patients. Male patients with a BMI greater than 50 kg/m2 were also found to be increasingly hypercoagulable.

Trends in potentially preventable trauma deaths between 2005-2006 and 2012-2013.

BACKGROUND: Most studies of trauma deaths include non-preventable deaths, potentially limiting successful intervention efforts. In this study we aimed to compare the potentially preventable trauma deaths between 2 time periods at our institution. METHODS: Trauma patients who died in our hospital in 2005-2006 or 2012-2013 were included, non-preventable deaths were excluded from analysis. The Mann-Whitney and chi square test were used to compare variables between both time periods. RESULTS: 80% of deaths were non-preventable. Between the study time periods there was a decrease in potentially preventable deaths, from 29% to 12%, p < 0.001. Head injury deaths significantly decreased (40.6%-24.6%, p = 0.03), while hemorrhage deaths were stable during both time periods (47.6%-43.1%, p = 0.55). CONCLUSION: Potentially preventable trauma deaths decreased during the study period. Hemorrhage remains constant as the leading cause of potentially preventable deaths. Continued research to improve survival from hemorrhage is warranted.

The trauma center is too late: Major limb trauma without a pre-hospital tourniquet has increased death from hemorrhagic shock.

BACKGROUND: To date, no civilian studies have demonstrated that pre-hospital (PH) tourniquets improve survival. We hypothesized that late, trauma center (TC) tourniquet use would increase death from hemorrhagic shock compared to early (PH) placement. METHODS: All patients arriving to a Level 1, urban TC between October 2008 and January 2016 with a tourniquet placed before (T-PH) or after arrival to the TC (T-TC) were evaluated. Cases were assigned the following designations: indicated (absolute indication [vascular injury requiring repair/ligation, operation within 2 hours for extremity injury, or traumatic amputation] or relative indication [major musculoskeletal/soft tissue injury requiring operation 2-8 hours after arrival, documented large blood loss]) or non-indicated. Outcomes were death from hemorrhagic shock, physiology upon arrival to the TC, and massive transfusion requirements. After univariate analysis, logistic regression was carried out to assess independent predictors of death from hemorrhagic shock. RESULTS: A total of 306 patients received 326 tourniquets for injuries to 157 upper and 147 lower extremities. Two hundred eighty-one (92%) had an indication for placement. Seventy percent of patients had a blunt mechanism of injury. T-TC patients arrived with a lower systolic blood pressure (SBP, 101 [86, 123] vs. 125 [100, 145] mm Hg, p < 0.001), received more transfusions in the first hour of arrival (55% vs. 34%, p = 0.02), and had a greater mortality from hemorrhagic shock (14% vs. 3.0%, p = 0.01). When controlling for year of admission, mechanism of injury and shock upon arrival (SBP ≤90 mm Hg or HR ≥120 bpm or base deficit ≤ 4) indicated T-TC had a 4.5-fold increased odds of death compared to T-PH (OR 4.5, 95% CI 1.23-16.4, p = 0.02). CONCLUSIONS: Waiting until TC arrival to control hemorrhage with a tourniquet was associated with worsened blood pressure and increased transfusion within the first hour of arrival. In routine civilian trauma patients, delaying to T-TC was associated with 4.5-fold increased odds of mortality from hemorrhagic shock. LEVEL OF EVIDENCE: Level IV.

Early chemoprophylaxis is associated with decreased venous thromboembolism risk without concomitant increase in intraspinal hematoma expansion after traumatic spinal cord injury.

BACKGROUND: After traumatic spinal cord injury (SCI), there is increased risk of venous thromboembolism (VTE), but chemoprophylaxis (PPX) may cause expansion of intraspinal hematoma (ISH). METHODS: Single-center retrospective study of adult trauma patients from 2012 to 2015 with SCI. EXCLUSION CRITERIA: VTE diagnosis, death, or discharge within 48 hours. Patients were dichotomized based on early (≤48 hours) heparinoid and/or aspirin PPX. Intraspinal hematoma expansion was diagnosed intraoperatively or by follow-up radiology. We used multivariable Cox proportional hazards to estimate the effect of PPX on risk of VTE and ISH expansion controlling for age, injury severity score (ISS), complete SCI, and mechanism as static covariates and operative spine procedure as a time-varying covariate. RESULTS: Five hundred one patients with SCI were dichotomized into early PPX (n = 260 [52%]) and no early PPX (n = 241 [48%]). Early PPX patients were less likely blunt injured (91% vs 97%) and had fewer operative spine interventions (65% vs 80%), but age (median, 43 vs 49 years), ISS (median 24 vs 21), admission ISH (47% vs 44%), and VTE (5% vs 9%) were similar. Cox analysis found that early heparinoids was associated with reduced VTE (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.84) and reduced pulmonary embolism (PE) (HR, 0.20; 95% CI, 0.06-0.69). The estimated number needed to treat with heparinoids was 10 to prevent one VTE and 13 to prevent one PE at 30 days. Early aspirin was not associated with reduced VTE or PE. Seven patients (1%) had ISH expansion, of which four were on PPX at the time of expansion. Using heparinoid and aspirin as time-varying covariates, neither heparinoids (HR, 1.90; 95% CI, 0.32-11.41) nor aspirin (HR, 3.67; 95% CI, 0.64-20.88) was associated with ISH expansion. CONCLUSION: Early heparinoid therapy was associated with decreased VTE and PE risk in SCI patients without concomitant increase in ISH expansion. LEVEL OF EVIDENCE: Therapeutic, level IV.

Survey of Parent Experiences in Prenatal Visits for Infants With Cleft Lip and Palate.

OBJECTIVE: The purpose of this study was to identify the factors that influence the parent's choice of cleft team/surgeon. DESIGN: A 10-question survey was used to elucidate factors that influenced parents in choosing their cleft surgeon. No identifiers of the origin of the study were used to improve parent objectivity. SETTING: The setting for this study was an online survey. PARTICIPANTS: Participants in this study were the parents of children who were born with cleft lip and/or palate. INTERVENTIONS: Parents were contacted anonymously via national, established social media websites that were independently run by the parents themselves. MAIN OUTCOME MEASURES: The main outcome measures were information regarding choice of cleft team/surgeon, source of patient referrals, and use of online media in decision making. RESULTS: A total of 112 responses were received. Of the parents, 77% sought prenatal evaluation with at least one cleft surgeon. Maternal-fetal medicine specialists were the most frequent (42%) referral source, followed by primary obstetricians (14%) and pediatricians (12%). The surgeon/cleft team's experience level and overall personality were ranked as the most important, whereas the least important was distance traveled. Of the parents, 95% used the Internet or social media for research prior to their prenatal visit; 96% of the parents found the prenatal visit helpful, and the most useful topics discussed were treatments (surgical, nonsurgical) and feeding techniques. CONCLUSION: This study identifies factors used to choose a cleft team/surgeon. Parents are more concerned with the experience level, reputation, and environment of the cleft team/surgeon than the distance traveled to get to the center.

Trends in 1029 trauma deaths at a level 1 trauma center: Impact of a bleeding control bundle of care.

BACKGROUND: Over the last decade the age of trauma patients and injury mortality has increased. At the same time, many centers have implemented multiple interventions focused on improved hemorrhage control, effectively resulting in a bleeding control bundle of care. The objective of our study was to analyze the temporal distribution of trauma-related deaths, the factors that characterize that distribution and how those factors have changed over time at our urban level 1 trauma center. METHODS: Records at an urban Level 1 trauma center were reviewed. Two time periods (2005-2006 and 2012-2013) were included in the analysis. Mortality rates were directly adjusted for age, gender and mechanism of injury. The Mann-Whitney and chi square tests were used to compare variables between periods, with significance set at 0.05. RESULTS: 7080 patients (498 deaths) were examined in 2005-2006, while 8767 patients (531 deaths) were reviewed in 2012-2013. The median age increased 6 years, with a similar increase in those who died. In patients that died, no differences by gender, race or ethnicity were observed. Fall-related deaths are now the leading cause of death. Traumatic brain injury (TBI) and hemorrhage accounted for >91% of all deaths. TBI (61%) and multiple organ failure or sepsis (6.2%) deaths were unchanged, while deaths associated with hemorrhage decreased from 36% to 25% (p<0.01). Across time periods, 26% of all deaths occurred within one hour of hospital arrival, while 59% occurred within 24h. Unadjusted mortality dropped from 7.0% to 6.1 (p=0.01) and in-hospital mortality dropped from 6.0% to 5.0% (p<0.01). Adjusted mortality dropped 24% from 7.6% (95% CI: 6.9-8.2) to 5.8% (95% CI: 5.3-6.3) and in-hospital mortality decreased 30% from 6.6% (95% CI: 6.0-7.2) to 4.7 (95% CI: 4.2-5.1). CONCLUSIONS: Over the same time frame of this study, increases in trauma death across the globe have been reported. This single-site study demonstrated a significant reduction in mortality, attributable to decreased hemorrhagic death. It is possible that efforts focused on hemorrhage control interventions (a bleeding control bundle) resulted in this reduction. These changing factors provide guidance on future prevention and intervention efforts.

Safety and Appropriateness of Tourniquets in 105 Civilians.

BACKGROUND: The United States military considers tourniquets to be effective for controlling bleeding from major limb trauma. The purpose of this study was to assess whether tourniquets are safely applied to the appropriate civilian patient with major limb trauma of any etiology. METHODS: Following IRB approval, patients arriving to a level-1 trauma center between October 2008 and May 2013 with a prehospital (PH) or emergency department (ED) tourniquet were reviewed. Cases were assigned the following designations: absolute indication (operation within 2 hours for limb injury, vascular injury requiring repair/ligation, or traumatic amputation); relative indication (major musculoskeletal/soft-tissue injury requiring operation 2-8 hours after arrival, documented large blood loss); and non-indicated. Patients with absolute or relative indications for tourniquet placement were defined as indicated, while the remaining were designated as non-indicated. Complications potentially associated with tourniquets, including amputation, acute renal failure, compartment syndrome, nerve palsies, and venous thromboembolic events, were adjudicated by orthopedic, hand or trauma surgical staff. Univariate analysis was performed to compare patients with indicated versus non-indicated tourniquet placement. RESULTS: A total of 105 patients received a tourniquet for injuries sustained via sharp objects, i.e., glass or knives (32%), motor vehicle collisions (30%), or other mechanisms (38%). A total of 94 patients (90%) had indicated tourniquet placement; 41 (44%) of which had a vascular injury. Demographics, mechanism, transport, and vitals were similar between patients that had indicated or non-indicated tourniquet placement. 48% of the indicated tourniquets placed PH were removed in the ED, compared to 100% of the non-indicated tourniquets (p < 0.01). The amputation rate was 32% among patients with indicated tourniquet placement (vs. 0%; p = 0.03). Acute renal failure (3.2 vs. 0%, p = 0.72), compartment syndrome (2.1 vs. 0%, p = 0.80), nerve palsies (5.3 vs. 0%; p = 0.57), and venous thromboembolic events (9.1 vs. 8.5%; p = 0.65) and were similar in patients that had indicated compared to non-indicated tourniquet placement. After adjudication, no complication was a result of tourniquet use. CONCLUSION: The current study suggests that PH and ED tourniquets are used safely and appropriately in civilians with major limb trauma that occur via blunt and penetrating mechanisms.

Beyond Blood Culture and Gram Stain Analysis: A Review of Molecular Techniques for the Early Detection of Bacteremia in Surgical Patients.

BACKGROUND: Sepsis from bacteremia occurs in 250,000 cases annually in the United States, has a mortality rate as high as 60%, and is associated with a poorer prognosis than localized infection. Because of these high figures, empiric antibiotic administration for patients with systemic inflammatory response syndrome (SIRS) and suspected infection is the second most common indication for antibiotic administration in intensive care units (ICU)s. However, overuse of empiric antibiotics contributes to the development of opportunistic infections, antibiotic resistance, and the increase in multi-drug-resistant bacterial strains. The current method of diagnosing and ruling out bacteremia is via blood culture (BC) and Gram stain (GS) analysis. METHODS: Conventional and molecular methods for diagnosing bacteremia were reviewed and compared. The clinical implications, use, and current clinical trials of polymerase chain reaction (PCR)-based methods to detect bacterial pathogens in the blood stream were detailed. RESULTS: BC/GS has several disadvantages. These include: some bacteria do not grow in culture media; others do not GS appropriately; and cultures can require up to 5 d to guide or discontinue antibiotic treatment. PCR-based methods can be potentially applied to detect rapidly, accurately, and directly microbes in human blood samples. CONCLUSIONS: Compared with the conventional BC/GS, particular advantages to molecular methods (specifically, PCR-based methods) include faster results, leading to possible improved antibiotic stewardship when bacteremia is not present.

Prehospital triage of trauma patients using the Random Forest computer algorithm.

BACKGROUND: Overtriage not only wastes resources but also displaces the patient from their community and causes delay of treatment for the more seriously injured. This study aimed to validate the Random Forest computer model (RFM) as means of better triaging trauma patients to level 1 trauma centers. METHODS: Adult trauma patients with "medium activation" presenting via helicopter to a level 1 trauma center from May 2007 to May 2009 were included. The "medium activation" trauma patient is alert and hemodynamically stable on scene but has either subnormal vital signs or accumulation of risk factors that may indicate a potentially serious injury. Variables included in the RFM analysis were demographics, mechanism of injury, prehospital fluid, medications, vitals, and disposition. Statistical analysis was performed via the Random Forest algorithm to compare our institutional triage rate to rates determined by the RFM. RESULTS: A total of 1653 patients were included in this study, of which 496 were used in the testing set of the RFM. In our testing set, 33.8% of patients brought to our level 1 trauma center could have been managed at a level 3 trauma center, and 88% of patients who required a level 1 trauma center were identified correctly. In the testing set, there was an overtriage rate of 66%, whereas using the RFM, we decreased the overtriage rate to 42% (P < 0.001). There was an undertriage rate of 8.3%. The RFM predicted patient disposition with a sensitivity of 89%, specificity of 42%, negative predictive value of 92%, and positive predictive value of 34%. CONCLUSIONS: Although prospective validation is required, it appears that computer modeling potentially could be used to guide triage decisions, allowing both more accurate triage and more efficient use of the trauma system.

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.

A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers.

The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of these efforts involves a complicated mixture of science, ethics, and business. This review focuses on clinical trials of the three hemoglobin-based oxygen carriers (HBOC) that have progressed to Phase II or III clinical trials: He-mAssist (Baxter; Deerfield, IL, US), PolyHeme (Northfield; Evanston, IL, US), and Hemopure (Biopure; Cambridge, MA, US). Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions. To date, the results from these perioperative studies have not led to regulatory approval. All three companies instead chose to focus their efforts on large trials of trauma patients in the pre-hospital setting.Baxter abandoned the development of HemAssist after a trial in the U.S. was prematurely halted when the first 100 patients showed significantly increased mortality rates as compared to patients treated with blood products. Northfield's PolyHeme trial demonstrated a non-significant trend towards increased mortality and a very modest reduction in the subsequent need for blood. The testing of Biopure's Hemopure for trauma patients has been halted for several years because of FDA concerns over trial design and study justification. Ethical concerns have also been raised regarding the design and implementation of all HBOC clinical trials.Thus, the available evidence suggests that HemAssist, Polyheme, and Hemopure are associated with a significant level of cardiovascular dysfunction. The next generation of HBOCs remains under development.

A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers

The complications associated with acquiring and storing whole blood for transfusions have launched substantial efforts to develop a blood substitute. The history of these efforts involves a complicated mixture of science, ethics, and business. This review focuses on clinical trials of the three hemoglobin-based oxygen carriers (HBOC) that have progressed to Phase II or III clinical trials: HemAssist (Baxter; Deerfield, IL, US), PolyHeme (Northfield; Evanston, IL, US), and Hemopure (Biopure; Cambridge, MA, US). Published animal studies and clinical trials carried out in a perioperative setting have demonstrated that these products successfully transport and deliver oxygen, but all may induce hypertension and lead to unexpectedly low cardiac outputs. Overall, these studies suggest that HBOCs resulted in only modest blood saving during and after surgery, no improvement in mortality and an increased incidence of adverse reactions. To date, the results from these perioperative studies have not led to regulatory approval. All three companies instead chose to focus their efforts on large trials of trauma patients in the pre-hospital setting. Baxter abandoned the development of HemAssist after a trial in the U.S. was prematurely halted when the first 100 patients showed significantly increased mortality rates as compared to patients treated with blood products. Northfield's PolyHeme trial demonstrated a non-significant trend towards increased mortality and a very modest reduction in the subsequent need for blood. The testing of Biopure's Hemopure for trauma patients has been halted for several years because of FDA concerns over trial design and study justification. Ethical concerns have also been raised regarding the design and implementation of all HBOC clinical trials. Thus, the available evidence suggests that HemAssist, Polyheme, and Hemopure are associated with a significant level of cardiovascular dysfunction. The next generation of HBOCs ...

PKA and ERK, but not PKC, in the amygdala contribute to pain-related synaptic plasticity and behavior.

The laterocapsular division of the central nucleus of the amygdala (CeLC) has emerged as an important site of pain-related plasticity and pain modulation. Glutamate and neuropeptide receptors in the CeLC contribute to synaptic and behavioral changes in the arthritis pain model, but the intracellular signaling pathways remain to be determined. This study addressed the role of PKA, PKC, and ERK in the CeLC. Adult male Sprague-Dawley rats were used in all experiments. Whole-cell patch-clamp recordings of CeLC neurons were made in brain slices from normal rats and from rats with a kaolin/carrageenan-induced monoarthritis in the knee (6 h postinduction). Membrane-permeable inhibitors of PKA (KT5720, 1 microM; cAMPS-Rp, 10 microM) and ERK (U0126, 1 microM) activation inhibited synaptic plasticity in slices from arthritic rats but had no effect on normal transmission in control slices. A PKC inhibitor (GF109203x, 1 microM) and an inactive structural analogue of U0126 (U0124, 1 microM) had no effect. The NMDA receptor-mediated synaptic component was inhibited by KT5720 or U0126; their combined application had additive effects. U0126 did not inhibit synaptic facilitation by forskolin-induced PKA-activation. Administration of KT5720 (100 microM, concentration in microdialysis probe) or U0126 (100 microM) into the CeLC, but not striatum (placement control), inhibited audible and ultrasonic vocalizations and spinal reflexes of arthritic rats but had no effect in normal animals. GF109203x (100 microM) and U0124 (100 microM) did not affect pain behavior. The data suggest that in the amygdala PKA and ERK, but not PKC, contribute to pain-related synaptic facilitation and behavior by increasing NMDA receptor function through independent signaling pathways.

Closed-loop control of fluid therapy for treatment of hypovolemia.

Closed-loop algorithms and resuscitation systems are being developed to control IV infusion rate during early resuscitation of hypovolemia. Although several different physiologic variables have been suggested as an endpoint to guide fluid therapy, blood pressure remains the most used variable for the initial assessment of hemorrhagic shock and the treatment response to volume loading. Closed-loop algorithms use a controller function to alter infusion rate inversely to blood pressure. Studies in hemorrhaged conscious sheep suggest that: (1) a small reduction in target blood pressure can result in a significant reduction in volume requirement; (2) nonlinear algorithms may reduce the risk of increased internal bleeding during resuscitation; (3) algorithm control functions based on proportional-integral, fuzzy logic, or nonlinear decision tables were found to restore and maintain blood pressure equally well. Proportional-integral and fuzzy logic algorithms reduced mean fluid volume requirements compared with the nonlinear decision table; and (4) several algorithms have been constructed to the specific mechanism of injury and the volume expansion properties of different fluids. Closed-loop systems are undergoing translation from animal to patient studies. Future smart resuscitation systems will benefit from new noninvasive technologies for monitoring blood pressure and the development of computer controlled high flow intravenous pumps.