In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days ...later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background In trauma, most hemorrhagic deaths occur within the first 6 hours. This study examined the effect on survival of high ratios of fresh frozen plasma (FFP) and platelets (PLTs) to ...packed red blood cells (PRBCs) in the first 6 hours. Methods Records of 466 massive transfusion trauma patients (≥10 U of PRBCs in 24 hours) at 16 level 1 trauma centers were reviewed. Transfusion ratios in the first 6 hours were correlated with outcome. Results All groups had similar baseline characteristics. Higher 6-hour ratios of FFP:PRBCs and PLTs:PRBCs lead to improved 6-hour mortality (from 37.3 in the lowest ratio group to 15.7 in the middle ratio group to 2.0% in the highest ratio group and 22.8% to 19.0% to 3.2%, respectively) and in-hospital mortality (from 54.9 to 41.1 to 25.5% and 43.7% to 46.8% to 27.4%, respectively). Initial higher ratios of FFP:PRBCs and PLTs:PRBCs decreased overall PRBC transfusion. Conclusions The early administration of high ratios of FFP and platelets improves survival and decreases overall PRBC need in massively transfused patients. The largest difference in mortality occurs during the first 6 hours after admission, suggesting that the early administration of FFP and platelets is critical.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Impaired coagulation is associated with elevated risk of mortality in trauma patients. Prior studies have demonstrated increased mortality in patients with hyperfibrinolysis (HF) and fibrinolysis ...shutdown (SD). In addition, prior studies have demonstrated no effect of tranexamic acid (TXA) on fibrinolysis phenotypes. We examined the association of admission fibrinolysis phenotype with traumatic brain injury (TBI) patient outcomes.
Data were extracted from a placebo-controlled multicenter clinical trial. Patients ≥15 years with TBI (Glasgow Coma Scale score, 3-12) and systolic blood pressure ≥90 mm Hg were randomized in the out-of-hospital setting to receive placebo bolus/placebo infusion (Placebo), 1 gram (g) TXA bolus/1 g TXA infusion (bolus maintenance BM); or 2 g TXA bolus/placebo infusion (bolus only BO). Fibrinolysis phenotypes on admission were determined by clot lysis at 30 minutes (LY30): SD, ≤0.8%; physiologic, 0.9% to 2.9%; HF, ≥3%. Logistic regression was used to control for age, sex, penetrating injury, Injury Severity Score, maximum head AIS, and TXA treatment group.
Seven hundred forty-seven patients met inclusion criteria. Fibrinolysis shutdown was the most common phenotype in all treatment groups and was associated with increased age, Injury Severity Score, and presence of intracranial hemorrhage (ICH). Inpatient mortality was 15.2% for SD and HF, and 10.6% for physiologic ( p = 0.49). No differences in mortality, disability rating scale at 6 months, acute kidney injury, acute respiratory distress syndrome, or multi-organ failure were noted between fibrinolysis phenotypes.
SD is the most common phenotype expressed in moderate to severe TBI. In TBI, there is no association between fibrinolysis phenotype and mortality or other major complications.
Prognostic and Epidemiological; Level IV.
OBJECTIVE:To identify causes and timing of mortality in trauma patients to determine targets for future studies.
BACKGROUND:In trials conducted by the Resuscitation Outcomes Consortium in patients ...with traumatic hypovolemic shock (shock) or traumatic brain injury (TBI), hypertonic saline failed to improve survival. Selecting appropriate candidates is challenging.
METHODS:Retrospective review of patients enrolled in multicenter, randomized trials performed from 2006 to 2009. Inclusion criteria were as followsinjured patients, age 15 years or more with hypovolemic shock systolic blood pressure (SBP) ≤ 70 mm Hg or SBP 71–90 mm Hg with heart rate ≥ 108) or severe TBI Glasgow Coma Score (GCS) ≤ 8. Initial fluid administered was 250 mL of either 7.5% saline with 6% dextran 70, 7.5% saline or 0.9% saline.
RESULTS:A total of 2061 subjects were enrolled (809 shock, 1252 TBI) and 571 (27.7%) died. Survivors were younger than nonsurvivors 30 (interquartile range 23) vs 42 (34) and had a higher GCS, though similar hemodynamics. Most deaths occurred despite ongoing resuscitation. Forty-six percent of deaths in the TBI cohort were within 24 hours, compared with 82% in the shock cohort and 72% in the cohort with both shock and TBI. Median time to death was 29 hours in the TBI cohort, 2 hours in the shock cohort, and 4 hours in patients with both. Sepsis and multiple organ dysfunction accounted for 2% of deaths.
CONCLUSIONS:Most deaths from trauma with shock or TBI occur within 24 hours from hypovolemic shock or TBI. Novel resuscitation strategies should focus on early deaths, though prevention may have a greater impact.
To determine the effect of blood component ratios in massive transfusion (MT), we hypothesized that increased use of plasma and platelet to red blood cell (RBC) ratios would result in decreased early ...hemorrhagic death and this benefit would be sustained over the ensuing hospitalization.
Civilian guidelines for massive transfusion (MT > or =10 units of RBC in 24 hours) have typically recommend a 1:3 ratio of plasma:RBC, whereas optimal platelet:RBC ratios are unknown. Conversely, military data shows that a plasma:RBC ratio approaching 1:1 improves long term outcomes in MT combat casualties. There is little consensus on optimal platelet transfusions in either civilian or military practice. At present, the optimal combinations of plasma, platelet, and RBCs for MT in civilian patients is unclear.
Records of 467 MT trauma patients transported from the scene to 16 level 1 trauma centers between July 2005 and June 2006 were reviewed. One patient who died within 30 minutes of admission was excluded. Based on high and low plasma and platelet to RBC ratios, 4 groups were analyzed.
Among 466 MT patients, survival varied by center from 41% to 74%. Mean injury severity score varied by center from 22 to 40; the average of the center means was 33. The plasma:RBC ratio ranged from 0 to 2.89 (mean +/- SD: 0.56 +/- 0.35) and the platelets:RBC ratio ranged from 0 to 2.5 (0.55 +/- 0.50). Plasma and platelet to RBC ratios and injury severity score were predictors of death at 6 hours, 24 hours, and 30 days in multivariate logistic models. Thirty-day survival was increased in patients with high plasma:RBC ratio (> or =1:2) relative to those with low plasma:RBC ratio (<1:2) (low: 40.4% vs. high: 59.6%, P < 0.01). Similarly, 30-day survival was increased in patients with high platelet:RBC ratio (> or =1:2) relative to those with low platelet:RBC ratio (<1:2) (low: 40.1% vs. high: 59.9%, P < 0.01). The combination of high plasma and high platelet to RBC ratios were associated with decreased truncal hemorrhage, increased 6-hour, 24-hour, and 30-day survival, and increased intensive care unit, ventilator, and hospital-free days (P < 0.05), with no change in multiple organ failure deaths. Statistical modeling indicated that a clinical guideline with mean plasma:RBC ratio equal to 1:1 would encompass 98% of patients within the optimal 1:2 ratio.
Current transfusion practices and survival rates of MT patients vary widely among trauma centers. Conventional MT guidelines may underestimate the optimal plasma and platelet to RBC ratios. Survival in civilian MT patients is associated with increased plasma and platelet ratios. Massive transfusion practice guidelines should aim for a 1:1:1 ratio of plasma:platelets:RBCs.
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
Background An early predictive model for massive transfusion (MT) is critical for management of combat casualties because of limited blood product availability, component preparation, and the time ...necessary to mobilize fresh whole blood donors. The purpose of this study was to determine which variables, available early after injury, are associated with MT. We hypothesized that International Normalized Ratio and penetrating mechanism would be predictive. Study Design We performed a retrospective cohort analysis in two combat support hospitals in Iraq. Patients who required MT were compared with patients who did not. Eight potentially predictive variables were subjected to univariate analysis. Variables associated with need for MT were then subjected to stepwise logistic regression. Results Two hundred forty-seven patients required MT and 311 did not. Mean Injury Severity Score was 22 in the MT group and 5 in the non-MT group (p < 0.001). Patients in the MT group received 17.9 U stored RBCs and 2.0 U fresh whole blood, versus 1.1 U RBCs and 0.2 U whole blood in the non-MT group (p < 0.001). Mortality was 39% in the MT group and 1% in the non-MT group (p < 0.001). Variables that independently predicted the need for MT were: hemoglobin ≤ 11 g/dL, International Normalized Ratio > 1.5, and a penetrating mechanism. The area under the receiver operator characteristic curve was 0.804 and Hosmer-Lemeshow goodness-of-fit test was 0.98. Conclusion MT after combat injury is associated with high mortality. Simple variables available early after admission allow accurate prediction of MT.
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GEOZS, NUK, OILJ, SBCE, SBJE, UL, UPUK
Abstract Background Traumatic diaphragmatic injury (TDI) is a rarely diagnosed injury in trauma. Previous studies have been limited in their evaluation of TDI because of small population size and ...center bias. Although injuries may be suspected based on penetrating mechanism, blunt injuries may be particularly difficult to detect. The American College of Surgeons National Trauma Data Bank is the largest trauma database in the United States. We hypothesized that we could identify specific injury patterns associated with blunt and penetrating TDIs. Methods We examined demographics, diagnoses, mechanism of injury, and outcomes for patients with TDI in 2012 as this is the largest and most recent dataset available. Comparisons were made using chi-square or independent samples t test. Results There were a total of 833,309 encounters in the National Trauma Data Bank in 2012. Three thousand eight hundred seventy-three patients had a TDI (.46%). Of those, 1,240 (33%) patients had a blunt mechanism and 2,543 (67%) had a penetrating mechanism. Patients with blunt TDI were older (44 ± 19 vs 31 ± 13 years, P < .001), had a higher injury severity score (33 ± 14 vs 24 ± 15, P < .001), and a higher mortality rate (19.8% vs 8.8%, P < .001). Compared with patients with penetrating injuries, those with blunt TDI were more likely to have injuries to the thoracic aorta (2.9% vs .5%, P < .001), lung (48.7% vs 28.1, P < .001), bladder (5.9% vs .7%, P < .001), and spleen (44.8% vs 29.1%, P < .001). Penetrating TDI was associated with liver and hollow viscus injuries. Conclusions Diaphragmatic injury is an uncommon but significant diagnosis in trauma patients. Blunt injuries may be more likely to be occult; however, a pattern of associated injuries to the aorta, lung, spleen, and bladder should prompt further workup for TDI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
ABSTRACTTraumatic hemorrhage is the leading cause of preventable death after trauma. Early transfusion of plasma and balanced transfusion have been shown to optimize survival, mitigate the acute ...coagulopathy of trauma, and restore the endothelial glycocalyx. There are a myriad of plasma formulations available worldwide, including fresh frozen plasma, thawed plasma, liquid plasma, plasma frozen within 24 h, and lyophilized plasma (LP). Significant equipoise exists in the literature regarding the optimal plasma formulation. LP is a freeze-dried formulation that was originally developed in the 1930s and used by the American and British military in World War II. It was subsequently discontinued due to risk of disease transmission from pooled donors. Recently, there has been a significant amount of research focusing on optimizing reconstitution of LP. Findings show that sterile water buffered with ascorbic acid results in decreased blood loss with suppression of systemic inflammation. We are now beginning to realize the creation of a plasma-derived formulation that rapidly produces the associated benefits without logistical or safety constraints. This review will highlight the history of plasma, detail the various types of plasma formulations currently available, their pathophysiological effects, impacts of storage on coagulation factors in vitro and in vivo, novel concepts, and future directions.
IMPORTANCE: Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), ...defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE: To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS: Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES: Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS: No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, −4.2% 95% CI, −9.6% to 1.1%; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, −3.7% 95% CI, −10.2% to 2.7%; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, −5.4% 95% CI, −10.4% to −0.5%; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE: Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01545232
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