Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock.

BACKGROUND: After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting. METHODS: To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport. The primary outcome was mortality at 30 days. RESULTS: A total of 501 patients were evaluated: 230 patients received plasma (plasma group) and 271 received standard-care resuscitation (standard-care group). Mortality at 30 days was significantly lower in the plasma group than in the standard-care group (23.2% vs. 33.0%; difference, -9.8 percentage points; 95% confidence interval, -18.6 to -1.0%; P=0.03). A similar treatment effect was observed across nine prespecified subgroups (heterogeneity chi-square test, 12.21; P=0.79). Kaplan-Meier curves showed an early separation of the two treatment groups that began 3 hours after randomization and persisted until 30 days after randomization (log-rank chi-square test, 5.70; P=0.02). The median prothrombin-time ratio was lower in the plasma group than in the standard-care group (1.2 [interquartile range, 1.1 to 1.4] vs. 1.3 [interquartile range, 1.1 to 1.6], P<0.001) after the patients' arrival at the trauma center. No significant differences between the two groups were noted with respect to multiorgan failure, acute lung injury-acute respiratory distress syndrome, nosocomial infections, or allergic or transfusion-related reactions. CONCLUSIONS: In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation. (Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).

Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is the leading cause of death and disability due to trauma. Early administration of tranexamic acid may benefit patients with TBI. Objective: To determine whether tranexamic acid treatment initiated in the out-of-hospital setting within 2 hours of injury improves neurologic outcome in patients with moderate or severe TBI. Design, Setting, and Participants: Multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada from May 2015 to November 2017. Eligible participants (N = 1280) included out-of-hospital patients with TBI aged 15 years or older with Glasgow Coma Scale score of 12 or less and systolic blood pressure of 90 mm Hg or higher. Interventions: Three interventions were evaluated, with treatment initiated within 2 hours of TBI: out-of-hospital tranexamic acid (1 g) bolus and in-hospital tranexamic acid (1 g) 8-hour infusion (bolus maintenance group; n = 312), out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo 8-hour infusion (bolus only group; n = 345), and out-of-hospital placebo bolus and in-hospital placebo 8-hour infusion (placebo group; n = 309). Main Outcomes and Measures: The primary outcome was favorable neurologic function at 6 months (Glasgow Outcome Scale-Extended score >4 [moderate disability or good recovery]) in the combined tranexamic acid group vs the placebo group. Asymmetric significance thresholds were set at 0.1 for benefit and 0.025 for harm. There were 18 secondary end points, of which 5 are reported in this article: 28-day mortality, 6-month Disability Rating Scale score (range, 0 [no disability] to 30 [death]), progression of intracranial hemorrhage, incidence of seizures, and incidence of thromboembolic events. Results: Among 1063 participants, a study drug was not administered to 96 randomized participants and 1 participant was excluded, resulting in 966 participants in the analysis population (mean age, 42 years; 255 [74%] male participants; mean Glasgow Coma Scale score, 8). Of these participants, 819 (84.8%) were available for primary outcome analysis at 6-month follow-up. The primary outcome occurred in 65% of patients in the tranexamic acid groups vs 62% in the placebo group (difference, 3.5%; [90% 1-sided confidence limit for benefit, -0.9%]; P = .16; [97.5% 1-sided confidence limit for harm, 10.2%]; P = .84). There was no statistically significant difference in 28-day mortality between the tranexamic acid groups vs the placebo group (14% vs 17%; difference, -2.9% [95% CI, -7.9% to 2.1%]; P = .26), 6-month Disability Rating Scale score (6.8 vs 7.6; difference, -0.9 [95% CI, -2.5 to 0.7]; P = .29), or progression of intracranial hemorrhage (16% vs 20%; difference, -5.4% [95% CI, -12.8% to 2.1%]; P = .16). Conclusions and Relevance: Among patients with moderate to severe TBI, out-of-hospital tranexamic acid administration within 2 hours of injury compared with placebo did not significantly improve 6-month neurologic outcome as measured by the Glasgow Outcome Scale-Extended. Trial Registration: ClinicalTrials.gov Identifier: NCT01990768.

Iliac Vascular Injury in the Absence of a Pelvic Fracture.

This case study presents a rare iliac vascular injury in the absence of a pelvic fracture. A 36-year-old man sustained a blunt injury after being stuck by a motor vehicle. The only positive computed tomographic finding was in the pelvis that showed a 4 × 2-cm left retroperitoneal soft-tissue collection, appearing to encompass the left common and left external iliac veins. A pelvic venogram was obtained on Day 2 revealing a focal injury to the left external iliac vein with 60% narrowing. The patient was treated with clopidogrel and acetylsalicylic acid and discharged from the hospital to his home 3 days later. A follow-up pelvic venogram in 6 weeks later showed complete healing of previously visualized left external iliac venous injury without any residual stenosis.

Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways.

In the normal heart, leptin modulates cardiac metabolism. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that leptin signaling increases glucose metabolism and attenuates injury in the acutely infarcted heart. Mice with (ObR(+/+)) and without (ObR(-/-)) cardiomyocyte specific expression of leptin receptor (ObR) were randomly assigned to experimental MI or sham procedure, and studied 3 days later. ObR(+/+) and ObR(-/-) sham mice were not significantly different in any measured outcome. However, after MI, ObR(-/-) mice had greater cardiac dysfunction, left ventricular dilation, and levels of oxidative stress. These worse indices of cardiac injury in ObR(-/-) mice were associated with attenuated signal transducer and activator of transcription (STAT) 3, phosphatidylinositol-3-kinase (PI3K), and Akt signaling, decreased malonyl CoA content, and reduced mitochondrial pyruvate dehydrogenase and electron transport Complex I, II and IV activities. Furthermore, ObR(-/-) mice maintained high rates of cardiac fatty acid oxidation after MI, whereas ObR(+/+) mice demonstrated a switch away from fatty acid oxidation to glucose metabolism. Restoration of cardiac STAT3, PI3K and Akt activity and mitochondrial function in ObR(-/-) mice post-MI was accomplished by ciliary neurotrophic factor (CNTF), an established STAT3 activator, administered immediately after MI. Moreover, CNTF therapy resulted in mitigation of cardiac structural and functional injury, attenuated levels of oxidative stress, and rescued glucose metabolism in the infarcted ObR(-/-) heart. These data demonstrate that impaired cardiac leptin signaling results in metabolic inflexibility for glucose utilization in the face of cardiac stress, and greater morbidity after MI. Further, these studies show that cardiac glucose metabolism can be restored in leptin-resistant hearts by CNTF-mediated activation of survival kinases, resulting in multiple improved structural and functional outcomes post-MI.

Association of Prehospital Plasma Transfusion With Survival in Trauma Patients With Hemorrhagic Shock When Transport Times Are Longer Than 20 Minutes: A Post Hoc Analysis of the PAMPer and COMBAT Clinical Trials.

Importance: Both military and civilian clinical practice guidelines include early plasma transfusion to achieve a plasma to red cell ratio approaching 1:1 to 1:2. However, it was not known how early plasma should be given for optimal benefit. Two recent randomized clinical trials were published, with apparently contradictory results. The Prehospital Air Medical Plasma (PAMPer) clinical trial showed a nearly 30% reduction in mortality with plasma transfusion in the prehospital environment, while the Control of Major Bleeding After Trauma (COMBAT) clinical trial showed no survival improvement. Objective: To facilitate a post hoc combined analysis of the COMBAT and PAMPer trials to examine questions that could not be answered by either clinical trial alone. We hypothesized that prehospital transport time influenced the effects of prehospital plasma on 28-day mortality. Design, Setting, and Participants: A total of 626 patients in the 2 clinical trials were included. Patients with trauma and hemorrhagic shock were randomly assigned to receive either standard care or 2 U of thawed plasma followed by standard care in the prehospital environment. Data analysis was performed between September 2018 and January 2019. Interventions: Prehospital transfusion of 2 U of plasma compared with crystalloid-based resuscitation. Main Outcomes and Measures: The main outcome was 28-day mortality. Results: In this post hoc analysis of 626 patients (467 men [74.6%] and 159 women [25.4%]; median [interquartile range] age, 42 [27-57] years) who had trauma with hemorrhagic shock, a Cox regression analysis showed a significant overall survival benefit for plasma (hazard ratio [HR], 0.65; 95% CI, 0.47-0.90; P = .01) after adjustment for injury severity, age, and clinical trial cohort (COMBAT or PAMPer). A significant association with prehospital transport time was detected (from arrival on scene to arrival at the trauma center). Increased mortality was observed in patients in the standard care group when prehospital transport was longer than 20 minutes (HR, 2.12; 95% CI, 1.05-4.30; P = .04), while increased mortality was not observed in patients in the prehospital plasma group (HR, 0.78; 95% CI, 0.40-1.51; P = .46). No serious adverse events were associated with prehospital plasma transfusion. Conclusions and Relevance: These data suggest that prehospital plasma is associated with a survival benefit when transport times are longer than 20 minutes and that the benefit-risk ratio is favorable for use of prehospital plasma. Trial Registration: ClinicalTrials.gov identifiers: NCT01838863 (COMBAT) and NCT01818427 (PAMPer).

Chronic intermittent hypoxia increases left ventricular contractility in C57BL/6J mice.

Intermittent hypoxia (IH) commonly occurs in patients with obstructive sleep apnea and can cause a wide range of pathology, including reduced left ventricular (LV) ejection fraction in rats as determined by echocardiography, in rodent models. We utilized echocardiography and pressure-volume (PV) loop analyses to determine whether LV contractility was decreased in inbred C57BL/6J mice exposed to IH and whether blockade of beta-adrenergic receptors modified the response to hypoxia. Adult male 9- to 10-wk-old mice were exposed to 4 wk of IH (nadir inspired O(2) 5-6% at 60 cycles/h for 12 h during the light period) or intermittent air (IA) as control. A second group of animals were exposed to the same regimen of IH or IA, but in the presence of nonspecific beta-blockade with propranolol. Cardiac function was assessed by echocardiography and PV loop analyses, and mRNA and protein expression in ventricular homogenates was determined. Contrary to our expectations, we found with PV loop analyses that LV ejection fraction (63.4 +/- 3.5 vs. 50.5 +/- 2.6%, P = 0.015) and other measures of LV contractility were increased in IH-exposed animals compared with IA controls. There were no changes in contractile proteins, atrial natriuretic peptide levels, LV posterior wall thickness, or heart weight with IH exposure. However, cAMP levels were elevated after IH, and propranolol administration attenuated the increase in LV contractility induced by IH exposure. We conclude that, contrary to our hypothesis, 4 wk of IH exposure in C57BL/6J mice causes an increase in LV contractility that occurs independent of ventricular hypertrophy and is, in part, mediated by activation of cardiac beta-adrenergic pathways.

Implementation of a prehospital air medical thawed plasma program: Is it even feasible?

BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) trial demonstrated a 30-day survival benefit among hypotensive trauma patients treated with prehospital plasma during air medical transport. We characterized resources, costs and feasibility of air medical prehospital plasma program implementation. METHODS: We performed a secondary analysis using data derived from the recent PAMPer trial. Intervention patients received thawed plasma (5-day shelf life). Unused plasma units were recycled back to blood bank affiliates, when possible. Distribution method and capability of recycling varied across sites. We determined the status of plasma units deployed, utilized, wasted, and returned. We inventoried thawed plasma use and annualized costs for distribution and recovery. RESULTS: The PAMPer trial screened 7,275 patients and 5,103 plasma units were deployed across 22 air medical bases during a 42-month period. Only 368 (7.2%) units of this total thawed plasma pool were provided to plasma randomized PAMPer patients. Of the total plasma pool, 3,716 (72.8%) units of plasma were returned to the blood bank with the potential for transfusion prior to expiration and 1,019 (20.0%) thawed plasma units were deemed wasted for this analysis. The estimated average annual cost of implementation of a thawed plasma program per air medical base at an average courier distance would be between US $24,343 and US $30,077, depending on the ability to recycle plasma and distance of courier delivery required. CONCLUSION: A prehospital plasma program utilizing thawed plasma is resource intensive. Plasma waste can be minimized depending on trauma center and blood bank specific logistics. Implementation of a thawed plasma program can occur with financial cost. Products with a longer shelf life, such as liquid plasma or freeze-dried plasma, may provide a more cost-effective prehospital product relative to thawed plasma. LEVEL OF EVIDENCE: Therapeutic, level III.

A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial.

BACKGROUND: Optimal resuscitation of hypotensive trauma patients has not been defined. This trial was performed to assess the feasibility and safety of controlled resuscitation (CR) versus standard resuscitation (SR) in hypotensive trauma patients. METHODS: Patients were enrolled and randomized in the out-of-hospital setting. Nineteen emergency medical services (EMS) systems in the Resuscitation Outcome Consortium participated. Eligible patients had an out-of-hospital systolic blood pressure (SBP) of 90 mm Hg or lower. CR patients received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg and additional 250-mL boluses to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or greater. The crystalloid protocol was maintained until hemorrhage control or 2 hours after hospital arrival. RESULTS: A total of 192 patients were randomized (97 CR and 95 SR). The CR and SR groups were similar at baseline. The mean (SD) crystalloid volume administered during the study period was 1.0 L (1.5) in the CR group and 2.0 L (1.4) in the SR group, a difference of 1.0 L (95% confidence interval [CI], 0.6-1.4). Intensive care unit-free days, ventilator-free days, renal injury, and renal failure did not differ between the groups. At 24 hours after admission, there were 5 deaths (5%) in the CR group and 14 (15%) in the SR group (adjusted odds ratio, 0.39; 95% CI, 0.12-1.26). Among patients with blunt trauma, 24-hour mortality was 3% (CR) and 18% (SR) with an adjusted odds ratio of 0.17 (0.03-0.92). There was no difference among patients with penetrating trauma (9% vs. 9%; adjusted odds ratio, 1.93; 95% CI, 0.19-19.17). CONCLUSION: CR is achievable in out-of-hospital and hospital settings and may offer an early survival advantage in blunt trauma. A large-scale, Phase III trial to examine its effects on survival and other clinical outcomes is warranted. LEVEL OF EVIDENCE: Therapeutic study, level I.

A high leucine diet mitigates cardiac injury and improves survival after acute myocardial infarction.

OBJECTIVE: Evidence suggests that branched chain amino acids (BCAAs) are beneficial in treating human disease. It is unknown, however, what impact BCAAs have on outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that the specific BCAA leucine mitigates cardiac injury and improves survival post-MI. MATERIALS/METHODS: 11-12 week old male C57BL/6 mice were subjected to experimental MI or sham procedure, and provided regular chow (RC; 1.5% leucine) or a high leucine diet (HLD; 5% leucine), and followed for 3½ or 28 days. All mice were studied by echocardiography and cardiac catheterization, and all hearts were collected for histologic measurements of hypertrophy, fibrosis and apoptosis. Inflammation, hypertrophic gene expression, signal transduction, and glucose, palmitate and leucine metabolism were also measured in 3½day hearts. RESULTS: Except for increased leucine and decreased glucose oxidation, an HLD had no effect on measured outcomes in sham mice. With MI, cardiac structure, function, and survival were significantly improved with an HLD. At 3½days post-MI, an HLD increased cardiac hypertrophic signaling and decreased inflammation. Cardiac leucine oxidation was decreased in RC mice post-MI, but significantly increased with an HLD. These changes in metabolism were accompanied by a significant increase in cardiac ATP content in the HLD group. Finally, at both 3½ and 28 days post-MI, an HLD increased compensatory hypertrophy, and attenuated cardiac fibrosis and apoptosis. CONCLUSIONS: An HLD increases compensatory hypertrophy, attenuates fibrosis and apoptosis, and positively modulates oxidative metabolism to improve cardiac structure, function, and survival post-MI.

Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice.

AIMS: the obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin signalling is unknown. Therefore, our objective was to generate a cardiomyocyte-specific leptin receptor knock-out (ObRKO) mouse to determine whether worse cardiac outcomes after MI result from impaired leptin signalling in cardiomyocytes. METHODS AND RESULTS: tamoxifen-inducible ObRKO mice were subjected to experimental MI or sham surgeries and studied after 1 month. After MI, ObRKO mice displayed a loss of cardiac signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) signalling. Worse survival and cardiac morbidity were also seen in the ObRKO mouse post-MI, including decreased contractile function and glycolytic metabolism, and increased left ventricular dilation, hypertrophy, collagen deposition, matrix metalloproteinase activity, apoptosis, and inflammation. Treatment of ObRKO mice post-MI with an ObR-independent AMPK activator improved cardiac function and restored many of these maladaptive processes to wild-type levels. CONCLUSION: these data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.