Safety of Bioplasma FDP and Hemopure in rhesus macaques after 30% hemorrhage.

Objectives: Prehospital transfusion can be life-saving when transport is delayed but conventional plasma, red cells, and whole blood are often unavailable out of hospital. Shelf-stable products are needed as a temporary bridge to in-hospital transfusion. Bioplasma FDP (freeze-dried plasma) and Hemopure (hemoglobin-based oxygen carrier; HBOC) are products with potential for prehospital use. In vivo use of these products together has not been reported. This study assessed the safety of intravenous administration of HBOC+FDP, relative to normal saline (NS), in rhesus macaques (RM). Methods: After 30% blood volume removal and 30 minutes in shock, animals were resuscitated with either NS or two units (RM size adjusted) each of HBOC+FDP during 60 minutes. Sequential blood samples were collected. After neurological assessment, animals were killed at 24 hours and tissues collected for histopathology. Results: Due to a shortage of RM during the COVID-19 pandemic, the study was stopped after nine animals (HBOC+FDP, seven; NS, two). All animals displayed physiologic and tissue changes consistent with hemorrhagic shock and recovered normally. There was no pattern of cardiovascular, blood gas, metabolic, coagulation, histologic, or neurological changes suggestive of risk associated with HBOC+FDP. Conclusion: There was no evidence of harm associated with the combined use of Hemopure and Bioplasma FDP. No differences were noted between groups in safety-related cardiovascular, pulmonary, renal or other organ or metabolic parameters. Hemostasis and thrombosis-related parameters were consistent with expected responses to hemorrhagic shock and did not differ between groups. All animals survived normally with intact neurological function. Level of evidence: Not applicable.

The Effect of Prehospital Clinical Trial-Related Procedures on Scene Interval, Cognitive Load, and Error: A Randomized Simulation Study.

INTRODUCTION: Globally, very few settings have undertaken prehospital randomized controlled trials. Given this lack of experience, there is a risk that such trials in these settings may result in protocol deviations, increased prehospital intervals, and increased cognitive load, leading to error. Ultimately, this may affect patient safety and mortality. The aim of this study was to assess the effect of trial-related procedures on simulated scene interval, self-reported cognitive load, medical errors, and time to action. METHODS: This was a prospective simulation study. Using a cross-over design, ten teams of prehospital clinicians were allocated to three separate simulation arms in a random order. Simulations were: (1) Eligibility assessment and administration of freeze-dried plasma (FDP) and a hemoglobin-based oxygen carrier (HBOC), (2) Eligibility assessment and administration of HBOC, (3) Eligibility assessment and standard care. All simulations also required clinical management of hemorrhagic shock. Simulated scene interval, error rates, cognitive load (measured by NASA Task Load Index), and competency in clinical care (assessed using the Simulation Assessment Tool Limiting Assessment Bias (SATLAB)) were measured. Mean differences between simulations with and without trial-related procedures were sought using one-way ANOVA or Kruskal-Wallis test. A p-value of <0.05 within the 95% confidence interval was considered significant. RESULTS: Thirty simulations were undertaken, representing our powered sample size. The mean scene intervals were 00:16:56 for Simulation 1 (FDP and HBOC), 00:17:22 for Simulation 2 (HBOC only), and 00:14:24 for Simulation 3 (standard care). Scene interval did not differ between the groups (p = 0.27). There were also no significant differences in error rates (p = 0.28) or cognitive load (p = 0.67) between the simulation groups. There was no correlation between cognitive load and error rates (r = 0.15, p = 0.42). Competency was achieved in all the assessment criteria for all simulation groups. CONCLUSION: In a simulated environment, eligibility screening, performance of trial-related procedures, and clinical management of patients with hemorrhagic shock can be completed competently by prehospital advanced life support clinicians without delaying transport or emergency care. Future prehospital clinical trials may use a similar approach to help ensure graded and cautious implementation of clinical trial procedures into prehospital emergency care systems.

Increasing hemoglobin concentration with an artificial oxygen carrier improves severe anemia-induced degraded cognitive function.

ABSTRACT: Before death, patients commonly experience impaired consciousness for a significant period, frequently preventing family and others from final interactions with the patient. Some of these episodes of cognitive impairment may be treatable, with treatment not offered owing to the perception of ultimate futility or expense, or both. One of the causes of terminal loss of consciousness or decreased lucidity can be inadequate cerebral oxygen delivery. We report five cases from four institutions where an infusion of a hemoglobin-based oxygen carrier to patients who were unconscious or not lucid owing to acute severe anemia (hemoglobin range, 2.1-5.2 g/dL) resulted in awakening or lucidity. We review briefly human cognitive function and anemia and remark about the use of a hemoglobin-based oxygen carrier for acute severe anemia when red cell transfusion is not an option.

Lower hemoglobin concentration decreases time to death in severely anemic patients for whom blood transfusion is not an option.

BACKGROUND: Anemia in patients who decline transfusion has been associated with increased morbidity and mortality. We hypothesized that the time to death decreases with increasing severity of anemia in patients for whom transfusion is not an option. METHODS: With institutional review board approval, a retrospective review of registered adult blood refusal patients with at least one hemoglobin (Hb) value of 12.0 g/dL or less during hospital admission at a single institution from January 2004 to September 2015 was performed. The association of nadir Hb category and time to death (all-cause 30-day mortality) was determined using Kaplan-Meier plots, log rank tests, and Cox proportional hazard models. We investigated if there was a nadir Hb level between the values of 5.0 and 6.0 g/dL at which mortality risk significantly increased and then categorized nadir Hb by the traditional cut points and the newly identified "critical" cut point. RESULTS: The study population included 1,011 patients. The Cox proportional hazard models showed a more than 50% increase in hazard of death per 1 g/dL decrease in Hb (adjusted hazard ratio [confidence interval], 1.55 [1.40-1.72]; p < 0.001). A Hb value of 5.0 g/dL was identified as defining "critical anemia." We found a strong association between anemia severity level and mortality (p < 0.001). Time to death was shorter (median, 2 days) in patients with critical anemia than in those having higher Hb (median time to death of 4 or 6 days, in severe or moderate anemia). CONCLUSION: In anemic patients unable to be transfused, critical anemia was associated with a significantly and clinically important reduced time to death. LEVEL OF EVIDENCE: Prognostic, level III.

Reassessment of the Need for an Oxygen Carrier for the Treatment of Traumatic Hemorrhage When Blood is not an Option.

Approximately 10 years ago, the development of hemoglobin-based oxygen carriers (HBOCs) was largely stalled after two large phase 3 clinical trials failed to achieve licensure primarily because the safety profile was viewed as unsatisfactory when HBOCs were compared with red cells. Concerns were also raised that HBOCs, as a class, had inherent toxicities. Since then, clinical experience with HBOCs in expanded access programs and under licensure in South Africa has demonstrated that HBOCs can be used safely and effectively. In recent years, clinical studies have demonstrated that prehospital blood transfusion improves survival in severely injured patients with hemorrhage, especially when transport times are longer than 20 to 30 min. Yet, logistical constraints still limit use of blood products in the prehospital setting. As the urgent need for oxygen-carrying capacity for trauma patients for whom red cells are not available is becoming much more apparent, it is imperative that we reexamine the possibility of using HBOCs when red blood cell transfusion is not an option.

The need for dried plasma - a national issue.

Recent studies have demonstrated that early transfusion of plasma or RBCs improves survival in patients with severe trauma and hemorrhagic shock. Time to initiate transfusion is the critical factor. It is essential that transfusion begin in the prehospital environment when transport times are longer than approximately 15 to 20 minutes. Unfortunately, logistic constraints severely limit the use of blood products in the prehospital setting, especially in military, remote civilian, and mass disaster circumstances, where the need can be most acute. US military requirements for logistically supportable blood products are projected to increase dramatically in future conflicts. Although dried plasma products have been available and safely used in a number of countries for over 20 years, there is no dried plasma product commercially available in the United States. A US Food and Drug Administration-approved dried plasma is urgently needed. Considering the US military, disaster preparedness, and remote civilian trauma perspectives, this is an urgent national health care issue.

Severe anemia associated with increased risk of death and myocardial ischemia in patients declining blood transfusion.

BACKGROUND: There are limited data on morbidity and mortality in severely anemic patients for whom blood transfusion is not an option, with most data coming only from surgical patients and no data on the rate of myocardial ischemia associated with severe anemia. We sought to determine rates of all-cause mortality and myocardial ischemia in severely anemic hospitalized patients declining transfusion. STUDY DESIGN AND METHODS: With institutional review board approval, we conducted a retrospective review of all hospital admissions for adult blood refusal patients between January 2004 and September 2015 at a single institution. Severe anemia was defined as hemoglobin (Hb) level of not more than 8.0 g/dL at any time during hospital admission. Outcomes measured included all-cause mortality within 30 days of nadir Hb and myocardial ischemia as defined by abnormal troponin (>0.10 ng/mL). We studied the association of patient's nadir Hb with outcomes via multivariable repeated measures generalized estimating equations (GEEs). RESULTS: Of 1306 blood refusal patients with hospital admissions during the study period, 263 had at least one admission with Hb level of not more than 8.0 g/dL. The rate of all-cause mortality within 30 days was 19.8%, and the multivariable GEE model indicated a 55% increase in odds of mortality per 1 g/dL decrease in nadir Hb (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.25-1.91; p < 0.0001). Rate of myocardial ischemia was 10.5% and in the multivariable model risk increased with decreasing nadir Hb (per 1 g/dL decrease; OR, 1.42; 95% CI, 1.07-1.90; p = 0.016). CONCLUSIONS: Severe anemia is associated with increased myocardial ischemia and mortality in patients declining transfusion, with risk increasing with decreasing nadir Hb.

Evaluating Pulmonary Function: An Assessment of PaO2/FIO2.

OBJECTIVES: PaO2/FIO2 is used commonly for diagnosis of lung injury (acute respiratory distress syndrome and transfusion-related acute lung injury), for assessment of pulmonary disease course and therapy, and in pulmonary transplantation for evaluation of donor lungs and clinical outcome. It was developed for convenience, without formal mathematical and graphic assessment to validate its suitability for these purposes. DESIGN: We examined, mathematically and graphically, the relationship of PaO2/FIO2 to FIO2 at constant normal and several degrees of increased intrapulmonary shunting (QS/QT), assessing the impact of intra- and extrapulmonary factors on the relationship and thus the reliability of PaO2/FIO2. MEASUREMENTS AND MAIN RESULTS: The relationship of PaO2/FIO2 varies at all shunt fractions but most with QS/QT from 0.1 to 0.3 with FIO2 approximately greater than 0.4. At higher QS/QT, the relationship is more constant and changes less with FIO2 more than 0.4. Hemoglobin concentration and arterial-venous oxygen content difference have large effects that can confound interpretation of PaO2/FIO2. Barometric pressure has a substantial effect; PCO2, base excess, and respiratory quotient have small effects. CONCLUSIONS: At high QS/QT with FIO2 more than 0.4, the relationship of PaO2/FIO2 to FIO2 is relatively constant. However, with QS/QT of 0.1-0.3, PaO2/FIO2 changes substantially with FIO2. Understanding the important effects of nonpulmonary factors (especially hemoglobin concentration and arterial-venous oxygen content difference) should enhance appropriate clinical use, interpretation of PaO2/FIO2, and interpretation of previous publications and future studies (especially those seeking to assess effects of anemia or transfusion on lung function). The ratio of PaO2/FIO2 is a good tool for some, but not many clinical circumstances, and is insufficiently robust for most research applications.

A Clinical Trial to Detect Subclinical Transfusion-induced Lung Injury during Surgery.

BACKGROUND: Transfusion-related acute lung injury incidence remains the leading cause of posttransfusion mortality. The etiology may be related to leukocyte antibodies or biologically active compounds in transfused plasma, injuring susceptible recipient's lungs. The authors have hypothesized that transfusion could have less severe effects that are not always appreciated clinically and have shown subtly decreased pulmonary oxygen gas transfer in healthy volunteers after transfusion of fresh and 21-day stored erythrocytes. In this study, the authors tested the same hypothesis in surgical patients. METHODS: Ninety-one patients undergoing elective major spine surgery with anticipated need for erythrocyte transfusion were randomly allocated to receive their first transfusion of erythrocytes as cell salvage (CS), washed stored, or unwashed stored. Clinicians were not blinded to group assignment. Pulmonary gas transfer and mechanics were measured 5 min before and 30 min after erythrocyte transfusion. RESULTS: The primary outcome variable, gas transfer, as assessed by change of PaO2/FIO2, with erythrocyte transfusion was not significant in any group (mean ± SD; CS: 9 ± 59; washed: 10 ± 26; and unwashed: 15 ± 1) and did not differ among groups (P = 0.92). Pulmonary dead space (VD/VT) decreased with CS transfusion (-0.01 ± 0.04; P = 0.034) but did not change with other erythrocytes; the change from before to after erythrocyte transfusion did not differ among groups (-0.01 to +0.01; P = 0.28). CONCLUSIONS: The authors did not find impaired gas exchange as assessed by PaO2/FIO2 with transfused erythrocytes that did or did not contain nonautologous plasma. This clinical trial did not support the hypothesis of erythrocyte transfusion-induced gas exchange deficit that had been found in healthy volunteers.