Heather F. Pidcoke

Ten-year analysis of transfusion in Operation Iraqi Freedom and Operation Enduring Freedom: increased plasma and platelet use correlates with improved survival.

BACKGROUND The Joint Theater Trauma Registry database, begun early in Operation Iraqi Freedom and Operation Enduring Freedom, created a comprehensive repository of information that facilitated research efforts and produced rapid changes in clinical care. New clinical practice guidelines were adopted throughout the last decade. The damage-control resuscitation clinical practice guideline sought to provide high-quality blood products in support of tissue perfusion and hemostasis. The goal was to reduce death from hemorrhagic shock in patients with severe traumatic bleeding. This 10-year review of the Joint Theater Trauma Registry database reports the military’s experience with resuscitation and coagulopathy, evaluates the effect of increased plasma and platelet (PLT)–to–red blood cell ratios, and analyzes other recent changes in practice. METHODS Records of US active duty service members at least 18 years of age who were admitted to a military hospital from March 2003 to February 2012 were entered into a database. Those who received at least one blood product (n = 3,632) were included in the analysis. Data were analyzed with respect to interactions within and between categories (demographics, admission characteristics, hospital course, and outcome). Transfusions were analyzed with respect to time, survival, and effect of increasing transfusion ratios. RESULTS Coagulopathy was prevalent upon presentation (33% with international normalized ratio ≥ 1.5), correlated with increased mortality (fivefold higher), and was associated with the need for massive transfusion. High transfusion ratios of fresh frozen plasma and PLT to red blood cells were correlated with higher survival but not decreased blood requirement. Survival was most correlated with PLT ratio, but high fresh frozen plasma ratio had an additive effect (PLT odds ratio, 0.22). CONCLUSION This 10-year evaluation supports earlier studies reporting the benefits of damage-control resuscitation strategies in military casualties requiring massive transfusion. The current analysis suggests that defects in PLT function may contribute to coagulopathy of trauma. LEVEL OF EVIDENCE Epidemiologic study, level IV.

Hemostatic function of apheresis platelets stored at 4 °C and 22 °C

ABSTRACT Introduction: Platelet refrigeration decreases the risk of bacterial contamination and may preserve function better than standard-of-care room temperature (RT) storage. Benefits could include lower transfusion-related complications, decreased costs, improved hemostasis in acutely bleeding patients, and extended shelf life. In this study, we compared the effects of 22°C and 4°C storage on the functional and activation status of apheresis platelets. Methods: Apheresis platelets (n = 5 per group) were stored for 5 days at 22°C with agitation (RT) versus at 4°C with agitation (4°C + AG) and without (4°C). Measurements included platelet counts, mean platelet volume, blood gas analytes, aggregation response, thromboelastography, thromboxane B2 and soluble CD40 ligand release, activation markers, and microparticle formation. Results: Sample pH levels were within acceptable limits for storage products (pH 6.2–7.4). Platelet glucose metabolism (P < 0.05), aggregation response (adenosine diphosphate: RT 0; 4°C + AG 5.0 ± 0.8; 4°C 5.6 ± 0.9; P < 0.05), and clot strength (maximum amplitude: RT 58 ± 2; 4°C + AG 63 ± 2; 4°C 67 ± 2; P < 0.05) were better preserved at 4°C compared with RT storage. Refrigerated samples were more activated compared with RT (P < 0.05), although thromboxane B2 (P < 0.05) and soluble CD40 ligand release (P < 0.05) were higher at RT. Agitation did not improve the quality of 4°C-stored samples. Conclusions: Apheresis platelets stored at 4°C maintain more viable metabolic characteristics, are hemostatically more effective, and release fewer proinflammatory mediators than apheresis platelets stored at RT over 5 days. Given the superior bacteriologic safety of refrigerated products, these data suggest that cold-stored platelets may improve outcomes for acutely bleeding patients.

Anemia causes hypoglycemia in intensive care unit patients due to error in single-channel glucometers: Methods of reducing patient risk

Objective: Intensive insulin therapy in the critically ill reduces mortality but carries the risk of increased hypoglycemia. Point-of-care blood glucose analysis is standard; however, anemia causes falsely high values and potentially masks hypoglycemia. Permissive anemia is practiced routinely in most intensive care units. We hypothesized that point-of-care glucometer error due to anemia is prevalent, can be corrected mathematically, and correction uncovers occult hypoglycemia during intensive insulin therapy. Design: The study has both retrospective and prospective phases. We reviewed data to verify the presence of systematic error, determine the source of error, and establish the prevalence of anemia. We confirmed our findings by reproducing the error in an in vitro model. Prospective data were used to develop a correction formula validated by the Monte Carlo method. Correction was implemented in a burn intensive care unit and results were evaluated after 9 mos. Setting: Burn and trauma intensive care units at a single research institution. Patients/Subjects: Samples for in vitro studies were taken from healthy volunteers. Samples for formula development were from critically ill patients who received intensive insulin therapy. Interventions: Insulin doses were calculated based on predicted serum glucose values from corrected point-of-care glucometer measurements. Measurements and Main Results: Time-matched point-of-care glucose, laboratory glucose, and hematocrit values. We previously found that anemia (hematocrit <34%) produces systematic error in glucometer measurements. The error was correctible with a mathematical formula developed and validated, using prospectively collected data. Error of uncorrected point-of-care glucose ranged from 19% to 29% (p < .001), improving to ≤5% after mathematical correction of prospective data. Comparison of data pairs before and after correction formula implementation demonstrated a 78% decrease in the prevalence of hypoglycemia in critically ill and anemic patients treated with insulin and tight glucose control (p < .001). Conclusions: A mathematical formula that corrects erroneous point-of-care glucose values due to anemia in intensive care unit patients reduces the prevalence of hypoglycemia during intensive insulin therapy.

Refrigerated platelets for the treatment of acute bleeding: a review of the literature and reexamination of current standards.

Abstract This review is a synopsis of the decisions that shaped global policy on platelet (PLT) storage temperature and a focused appraisal of the literature on which those discussions were based. We hypothesize that choices were centered on optimization of preventive PLT transfusion strategies, possibly to the detriment of the therapeutic needs of acutely bleeding patients. Refrigerated PLTs are a better hemostatic product, and they are safer in that they are less prone to bacterial contamination. They were abandoned during the 1970s because of the belief that clinically effective PLTs should both be hemostatically functional and survive in circulation for several days as indicated for prophylactic transfusion; however, clinical practice may be changing. Data from two randomized controlled trials bring into question the concept that stable autologous stem cell transplant patients with hypoproliferative thrombocytopenia should continue to receive prophylactic transfusions. At the same time, new findings regarding the efficacy of cold PLTs and their potential role in treating acute bleeding have revived the debate regarding optimal PLT storage temperature. In summary, a “one-size-fits-all” strategy for PLT storage may not be adequate, and a reexamination of whether cold-stored PLTs should be offered as a widely available therapeutic product may be indicated.

Validation of lower body negative pressure as an experimental model of hemorrhage.

Lower body negative pressure (LBNP), a model of hemorrhage (Hem), shifts blood to the legs and elicits central hypovolemia. This study compared responses to LBNP and actual Hem in sedated baboons. Arterial pressure, pulse pressure (PP), central venous pressure (CVP), heart rate, stroke volume (SV), and +dP/dt were measured. Hem steps were 6.25%, 12.5%, 18.75%, and 25% of total estimated blood volume. Shed blood was returned, and 4 wk after Hem, the same animals were subjected to four LBNP levels which elicited equivalent changes in PP and CVP observed during Hem. Blood gases, hematocrit (Hct), hemoglobin (Hb), plasma renin activity (PRA), vasopressin (AVP), epinephrine (EPI), and norepinephrine (NE) were measured at baseline and maximum Hem or LBNP. LBNP levels matched with 6.25%, 12.5%, 18.75%, and 25% hemorrhage were -22 ± 6, -41 ± 7, -54 ± 10, and -71 ± 7 mmHg, respectively (mean ± SD). Hemodynamic responses to Hem and LBNP were similar. SV decreased linearly such that 25% Hem and matching LBNP caused a 50% reduction in SV. Hem caused a decrease in Hct, Hb, and central venous oxygen saturation (ScvO2). In contrast, LBNP increased Hct and Hb, while ScvO2 remained unchanged. Hem caused greater elevations in AVP and NE than LBNP, while PRA, EPI, and other hematologic indexes did not differ between studies. These results indicate that while LBNP does not elicit the same effect on blood cell loss as Hem, LBNP mimics the integrative cardiovascular response to Hem, and validates the use of LBNP as an experimental model of central hypovolemia associated with Hem.

Error rates resulting from anemia can be corrected in multiple commonly used point-of-care glucometers

BACKGROUND A point-of-care (POC) glucometer (G1) used for critical care at our institution is inaccurate in the presence of low hematocrit (HCT) values. The purpose of this study was to analyze error rates of three additional POC glucometer brands and determine mathematical correction formulas for each. METHODS Blood samples (n = 196) from a cohort of surgical, trauma, medical, cardiothoracic, and burn intensive care unit patients were tested on three commonly used POC glucometer brands (G2-G4). Results were compared with reference laboratory values, and correction compared with the validated formula for G1. A mathematical formula specific to each glucometer type was derived from glucose measurements, associated HCT values, and the degree of difference relative to laboratory results. RESULTS POC glucometer results were consistently elevated compared with reference laboratory values. Glucometer error rates for HCT </= 25% ranged from 15.4% to 22.3% for the three types. Error rates for 25% < HCT < 34% ranged from 16.4% to 18.4%. A correction formula for each glucometer based on the natural log transformation of the HCT predicted reference values with a mean error rate of -0.54% +/- 5.6% for G2, -0.6% +/- 5.5% for G3, and 0.2% +/- 8.0% for G4. Correction was similar to that previously established for G1 (-0.01% +/- 4.8). CONCLUSIONS Significant error rates because of HCT effect were found in all glucometer models tested with accurate prediction of reference values with a simple mathematical formula.

Glucose variability is associated with high mortality after severe burn.

BACKGROUND Hyperglycemia is associated with increased mortality in the severely injured; intensive insulin protocols reduce mortality, improve wound healing, and decrease susceptibility to infection. High glucose variability creates challenges to glycemic control and may be a marker of poor outcome. We wondered whether glycemic variability alone might identify patients at higher risk of death. METHODS Burn patients admitted in 2005 with >20% total body surface area burned, >or=100 glucose measurements, and one hypo- and hyperglycemic event were included in the analysis; all were treated with intensive insulin (glycemic target: 80-110 mg/dL). Glycemic variability was the sum of percent excursions (defined as values <80 mg/dL or >110 mg/dL); variability above the mean was considered high. RESULTS Individual average variability in the 49 subjects was 50% +/- 8% (range, 30-65%); the average number of glucose measurements per patient was 840 (range, 103-5314). Percent excursions in those with high (n = 26) compared with low (n = 23) variability scores was 56% +/- 6% and 43% +/- 5% (p < 0.001), respectively. No difference was found between groups in injury severity score, age, total body surface area burned, full thickness burns, gender, or inhalation injury. Both groups were similar for days of ventilator support, intensive care unit stay, and hospital stay. Mortality in the highly variable group was twice that of the less variable group (50% vs. 22%, p = 0.041). CONCLUSIONS High glucose variability (>50% of values outside 80-110 mg/dL) is associated with increased mortality in the severely burned. Individuals with frequent excursions outside the glucose target range of 80 mg/dL to 110 mg/dL are at greater risk of death.

Whole blood for hemostatic resuscitation of major bleeding.

Recent combat experience reignited interest in transfusing whole blood (WB) for patients with life‐threatening bleeding. US Army data indicate that WB transfusion is associated with improved or comparable survival compared to resuscitation with blood components. These data complement randomized controlled trials that indicate that platelet (PLT)‐containing blood products stored at 4°C have superior hemostatic function, based on reduced bleeding and improved functional measures of hemostasis, compared to PLT‐containing blood products at 22°C.

Effect of cold storage on shear-induced platelet aggregation and clot strength.

BACKGROUND Platelets (PLTs) participate in hemostasis and save lives following trauma. PLTs for transfusion are maintained at room temperature (RT, 22°C), limiting viability to 5 days because of metabolic compromise and high risk of bacterial contamination. RT storage may result in weaker clots, delaying hemorrhage control, whereas cold storage (4°C) could permit longer PLT shelf life and result in a more hemostatic product. In this study, we characterized the effect of storage temperature on shear-induced PLT aggregation, clot formation, and strength. METHODS PLTs obtained from phlebotomized blood or by apheresis were stored at RT or 4°C for 5 days, and PLT aggregation and clot strength were assessed at 37°C. We studied PLT aggregation at steady and complex patterns of shear rates (500–2,500 per second) by flow cytometry, and the kinetics of clot formation and strength were measured using turbidity and dynamic mechanical analysis, respectively. RESULTS PLT aggregation was higher in 4°C-stored samples on Day 5 compared with fresh or RT-stored samples at all shear rates tested (fresh vs. 4°C and RT vs. 4°C, p < 0.05). PLTs stored at 4°C for 5 days formed significantly stronger clots compared with fresh or RT-stored samples as quantified by turbidity and elastic moduli measurements (fresh vs. 4°C and RT vs. 4°C, p < 0.05). CONCLUSION Our results show that cold-stored PLTs are more responsive to aggregation stimuli and form stronger clots, presumably because of thicker fibrin strands. These data suggest that the superior functionality of cold-stored PLTs may support faster hemostasis for acutely bleeding in trauma patients compared with RT-stored PLTs.

Storage of platelets at 4°C in platelet additive solutions prevents aggregate formation and preserves platelet functional responses

Platelet (PLT) storage has been limited to 5 days at room temperature due to metabolic decline and risk for bacterial contamination. Refrigeration preserves PLT metabolism and function as well as limits bacterial growth; however, cold storage of PLTs also leads to aggregate formation. We hypothesized that storage of PLT concentrates at 4°C leads to glycoprotein (GP)IIb‐IIIa activation and thus aggregate formation through fibrinogen binding and that this could be prevented by storing PLTs in PLT additive solution (PAS) without compromising PLT function.