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.

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.

Transfusion-related acute lung injury: incidence and risk factors.

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti-human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

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.

Balancing potential risks and benefits of hemoglobin-based oxygen carriers.

Hemoglobin-based oxygen carriers (HBOCs) are thought to have an adverse risk:benefit profile when compared to that of transfusing stored red blood cells (RBCs). However, there are clinical circumstances when RBC transfusion is not an option (e.g., patient refusal, unavailability owing to issues of compatibility or remote location). For these circumstances assessment of the risks of an HBOC should be compared to the risks of untransfused acute anemia. In this article we compare the risk of allowing a patient with severe anemia to have a further small decrease in hemoglobin (Hb) concentration to the risk of infusing an HBOC. We conclude that at Hb concentrations less than 6 g/dL, the risk of a further decrease in Hb concentration greatly exceeds the risk of HBOC infusion. Thus, we suggest that there may be a place for use of HBOCs when RBC transfusion is not an option.

Safety of modern starches used during surgery.

Various hydroxyethyl starch (HES) preparations have been used for decades to augment blood volume. There has been concern recently regarding possible adverse outcomes when using HES in the intensive care setting, especially in patients with septic shock. However, the pharmacokinetic and pharmacodynamic properties of HES preparations depend on their chemical composition and source material. Thus, different clinical conditions could result in differing effectiveness and safety for these preparations. Consequently, we assessed the safety of tetrastarches when used during surgery, using a formal search, that yielded 59 primary full publications of studies that met a priori inclusion criteria and randomly allocated 4529 patients with 2139 patients treated with tetrastarch compared with 2390 patients treated with a comparator. There were no indications that the use of tetrastarches during surgery induces adverse renal effects as assessed by change or absolute concentrations of serum creatinine or need for renal replacement therapy (39 trials, 3389 patients), increased blood loss (38 trials, 3280 patients), allogeneic erythrocyte transfusion (20 trials, 2151 patients; odds ratio for HES transfusion 0.73 [95% confidence interval = 0.61-0.87], P = 0.0005), or increased mortality (odds ratio for HES mortality = 0.51 [0.24-1.05], P = 0.079).

Fresh red blood cell transfusion and short-term pulmonary, immunologic, and coagulation status: a randomized clinical trial.

RATIONALE: Transfusion-related pulmonary complications are leading causes of morbidity and mortality attributed to transfusion. Observational studies suggest an important role for red blood cell (RBC) storage duration in these adverse outcomes. OBJECTIVES: To evaluate the impact of RBC storage duration on short-term pulmonary function as well as immunologic and coagulation status in mechanically ventilated patients receiving RBC transfusion. METHODS: This is a double-blind, randomized, clinical trial comparing fresh (≤5 d of storage) versus standard issue single-unit RBC transfusion in adult intubated and mechanically ventilated patients. The primary outcome is the change in pulmonary gas exchange as assessed by the partial pressure of arterial oxygen to fraction of inspired oxygen concentration ratio (ΔPa(O(2))/Fi(O(2))). Secondary outcomes include changes in immune and coagulation status. MEASUREMENTS AND MAIN RESULTS: Fifty patients were randomized to receive fresh RBCs and an additional 50 patients to standard issue RBCs. Median storage age was 4.0 days (interquartile range, 3.0-5.0) and 26.5 days (interquartile range, 21.0-36.0) in the fresh RBC group and standard issue RBC group, respectively. No differences were noted in the primary outcome of ΔPa(O(2))/Fi(O(2)) (difference between the mean ΔPa(O(2))/Fi(O(2)) in the standard issue RBC group vs. the fresh RBC group, -11.5; 95% confidence interval, -35.3 to 12.3; P = 0.22). Similarly, no significant differences were noted in markers of immunologic or coagulation status. CONCLUSIONS: In this randomized clinical trial, no differences were noted in early measures of pulmonary function or in immunologic or coagulation status when comparing fresh versus standard issue single-unit RBC transfusion. Clinical trial registered with ClinicalTrials.gov (NCT00751322).

Two septic transfusion reactions presenting as transfusion-related acute lung injury from a split plateletpheresis unit.

OBJECTIVES: We report two simultaneous cases of Staphylococcus aureus sepsis initially consistent with and diagnosed as transfusion-related acute lung injury. The sepsis in both cases resulted from transfusion of two split products from a single contaminated plateletpheresis unit. In each case, the platelets were given along with numerous other blood products during posterior spine surgery. The discussion includes presentation, clinical course, diagnosis, and similarities between sepsis and transfusion-related acute lung injury. The cases and discussion highlight the importance of considering sepsis as part of the differential for any patient believed to have transfusion-related acute lung injury with clinical features of sepsis. DATA SOURCES: Data were collected from the patients' electronic medical records and the hospital laboratory medicine database. CONCLUSIONS: Our cases highlight the importance of vigilant investigation in patients suspected of transfusion-related acute lung injury, as septic transfusions are easily missed and may mimic or coexist with transfusion-related acute lung injury. Sepsis should be strongly considered whenever clinical features such as hypotension, leucopenia, and fever are noted in patients with suspected transfusion-related acute lung injury. In comparison to patients receiving red blood cells or plasma, platelet transfusion recipients are at a greater risk for sepsis from a contaminated unit. Patients developing sepsis from a contaminated blood product may meet the clinical definition of transfusion-related acute lung injury. In such cases, if the clinical syndrome is attributed solely to transfusion-related acute lung injury and bacterial sepsis is not suspected, the correct diagnosis may be missed or delayed. Consequently, appropriate treatment for sepsis would also be delayed or not provided and likely result in increased morbidity and mortality.

Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans.

BACKGROUND: Transfusion can cause severe acute lung injury, although most transfusions do not seem to induce complications. We tested the hypothesis that transfusion can cause mild pulmonary dysfunction that has not been noticed clinically and is not sufficiently severe to fit the definition of transfusion-related acute lung injury. METHODS: We studied 35 healthy, normal volunteers who donated 1 U of blood 4 weeks and another 3 weeks before 2 study days separated by 1 week. On study days, 2 U of blood were withdrawn while maintaining isovolemia, followed by transfusion with either the volunteer's autologous fresh red blood cells (RBCs) removed 2 hours earlier or their autologous stored RBCs (random order). The following week, each volunteer was studied again, transfused with the RBCs of the other storage duration. The primary outcome variable was the change in alveolar to arterial difference in oxygen partial pressure (AaDo(2)) from before to 60 minutes after transfusion with fresh or older RBCs. RESULTS: Fresh RBCs and RBCs stored for 24.5 days equally (P = 0.85) caused an increase of AaDo(2) (fresh: 2.8 mm Hg [95% confidence interval: 0.8-4.8; P = 0.007]; stored: 3.0 mm Hg [1.4-4.7; P = 0.0006]). Concentrations of all measured cytokines, except for interleukin-10 (P = 0.15), were less in stored leukoreduced (LR) than stored non-LR packed RBCs; however, vascular endothelial growth factor was the only measured in vivo cytokine that increased more after transfusion with LR than non-LR stored packed RBCs. Vascular endothelial growth factor was the only cytokine tested with in vivo concentrations that correlated with AaDo(2). CONCLUSION: RBC transfusion causes subtle pulmonary dysfunction, as evidenced by impaired gas exchange for oxygen, supporting our hypothesis that lung impairment after transfusion includes a wide spectrum of physiologic derangements and may not require an existing state of altered physiology. These data do not support the hypothesis that transfusion of RBCs stored for >21 days is more injurious than that of fresh RBCs.