Data-Driven Blood Transfusion Thresholds for Severely Injured Patients During Blood Shortages.

INTRODUCTION: Crises like the COVID-19 pandemic create blood product shortages. Patients requiring transfusions are placed at risk and institutions may need to judiciously administer blood during massive blood transfusions protocols (MTP). The purpose of this study is to provide data-driven guidance for the modification of MTP when the blood supply is severely limited. METHODS: This is a retrospective cohort study of 47 Level I and II trauma centers (TC) within a single healthcare system whose patients received MTP from 2017 to 2019. All TC used a unifying MTP protocol for balanced blood product transfusions. The primary outcome was mortality as a function of volume of blood transfused and age. Hemoglobin thresholds and measures of futility were also estimated. Risk-adjusted analyses were performed using multivariable and hierarchical regression to account for confounders and hospital variation. RESULTS: Proposed MTP maximum volume thresholds for three age groupings are as follows: 60 units for ages 16-30 y, 48 units for ages 31-55 y, and 24 units for >55 y. The range of mortality under the transfusion threshold was 30%-36% but doubled to 67-77% when the threshold was exceeded. Hemoglobin concentration differences relative to survival were clinically nonsignificant. Prehospital measures of futility were prehospital cardiac arrest and nonreactive pupils. In hospital risk factors of futility were mid-line shift on brain CT and cardiopulmonary arrest. CONCLUSIONS: Establishing MTP threshold practices under blood shortage conditions, such as the COVID pandemic, could sustain blood availability by following relative thresholds for MTP use according to age groups and key risk factors.

Convalescent plasma associates with reduced mortality and improved clinical trajectory in patients hospitalized with COVID-19.

BACKGROUNDEvidence supporting convalescent plasma (CP), one of the first investigational treatments for coronavirus disease 2019 (COVID-19), has been inconclusive, leading to conflicting recommendations. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19.METHODSThe multicenter, electronic health records-based, retrospective study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare-affiliated community hospitals. Coarsened exact matching (1:k) was employed, resulting in a sample of 3774 CP and 10,687 comparison patients.RESULTSExamination of mortality using a shared frailty model, controlling for concomitant medications, date of admission, and days from admission to transfusion, demonstrated a significant association of CP with lower mortality risk relative to the comparison group (adjusted hazard ratio [aHR] = 0.71; 95% CI, 0.59-0.86; P < 0.001). Examination of patient risk trajectories, represented by 400 clinico-demographic features from our real-time risk model (RTRM), indicated that patients who received CP recovered more quickly. The stratification of days to transfusion revealed that CP within 3 days after admission, but not within 4 to 7 days, was associated with a significantly lower mortality risk (aHR = 0.53; 95% CI, 0.47-0.60; P < 0.001). CP serology level was inversely associated with mortality when controlling for its interaction with days to transfusion (HR = 0.998; 95% CI, 0.997-0.999; P = 0.013), yet it did not reach univariable significance.CONCLUSIONSThis large, diverse, multicenter cohort study demonstrated that CP, compared with matched controls, is significantly associated with reduced risk of in-hospital mortality. These observations highlight the utility of real-world evidence and suggest the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19.FUNDINGThis research was supported in whole by HCA Healthcare and/or an HCA Healthcare-affiliated entity, including Sarah Cannon and Genospace.

Assessment of left ventricular mass in mice: comparison between two-dimensional and m-mode echocardiography.

OBJECTIVE: M-mode echocardiography has been used extensively for estimating left ventricular (LV) mass in mice, but accuracy is limited by its unidimensional nature. This study tested whether two-dimensional (2-D) echocardiographic measurement of LV mass using area-length and truncated ellipsoid methods overcomes this limitation. METHODS: Twenty-five anesthetized FVB/N mice (Mus musculus) underwent high resolution (15 MHZ) two-dimensionally directed M-mode and 2-D echocardiography. End-diastolic epicardial and endocardial areas from short-axis views and the LV orthogonal long-axis views were measured, while LV mass was calculated by 2-D area-length and truncated ellipsoid methods. LV mass was calculated from M-mode using the uncorrected cube equation. Hearts were removed and weighed after completing the echocardiographic studies. The correlation and agreement between echocardiographic-determined LV mass and gravimetric LV weight were examined. RESULTS: LV mass using the area-length method correlated better with autopsy LV weight (r = 0.87, slope = 0.87, standard error of the estimate [SEE] = 12.4 mg, P < 0.001) than M-mode echocardiography (r = 0.85, slope = 0.71, SEE = 11.1 mg, P < 0.001), and the degree of agreement (bias +/- 2 SD) was better (10.2 +/- 25.1 mg vs 13.1 +/- 25.8 mg, P = NS). Although 2-D truncated ellipsoid LV mass showed a good correlation with necropsy LV weight (r = 0.87, slope = 0.78, SEE = 11.0 mg, P < 0.001), the agreement between the truncated ellipsoid estimates and LV weight was less than that between M-mode and gravimetric LV mass. CONCLUSIONS: The 2-D area-length method is an accurate method of LV mass determination in symmetrical ventricles and can be used as an alternative for in vivo measurement of LV mass in mice.

The myocardial performance index in patients with aortic stenosis.

OBJECTIVES: This study was designed to determine the effect of chronic afterload on a Doppler-derived myocardial performance index (MPI) combining both systolic and diastolic left ventricular dysfunction. METHODS: The study included 36 patients with a diagnosis of aortic stenosis and 36 normal subjects. Doppler-derived myocardial performance index (MPI), defined as the sum of the isovolumic contraction time and isovolumic relaxation time divided by ejection time, was measured from the mitral valve inflow and left ventricular outflow velocity patterns and was then related to the aortic valve area, valve gradient, and other echocardiographic variables. RESULTS: The values of the Doppler-derived MPI in the patients with aortic stenosis were significantly higher than those in the controls (0.54 +/- 0.20 vs 0.38 +/- 0.04, respectively; P < 0.001). Transmitral deceleration time and the E/A ratio ( r = 0.47 and r = 0.35, respectively; P < 0.05) were significant univariate correlates, and mitral deceleration time was the only significant correlate of MPI. However the index did not correlate with aortic valve area, peak and mean valve gradients, left ventricular mass, or age. CONCLUSIONS: Doppler-derived MPI reflects severity of global left ventricular dysfunction in patients with aortic stenosis and may be of clinical value in this patient population.

Naturally occurring variation in cardiovascular traits among inbred mouse strains.

The objective of this study was to characterize genetic variation in complex cardiovascular traits in two commonly used inbred mouse strains. We performed echocardiography, graded treadmill exercise, tail cuff plethysmography, and telemetry (heart rate, activity, temperature) in age- ( approximately 9 weeks) and sex-matched A/J and C57BL/6J (B6) inbred mice. B6 mice had significantly larger end-diastolic dimension (3.31+/-0.42 mm versus 2.83+/-0.31 mm) and left ventricle mass (46.2+/-14.1 versus 32.7+/-11.5 g) than A/J mice. This relative hypertrophy was eccentric (relative wall thickness ratios: 0.30+/-0.01 versus 0.32+/-0.01) and was not associated with a difference in systolic blood pressure (122.0+/-13.2 versus 123.1+/-20.8 mmHg). Left ventricle fractional shortening (39.1+/-6.2 versus 47.1+/-6.9%) and heart rate (433+/-55 versus 524+/-45 beats per minute) were significantly lower in B6 versus A/J, respectively, resulting in similar resting echocardiographic cardiac indices (0.58+/-0.19 versus 0.50+/-0.17 ml/min/g). Maximum exercise time on a treadmill was significantly greater in B6 than in A/J mice (9.6+/-3.4 versus 4.4+/-1.9 minutes). Telemetry showed that body temperature was generally greater and heart rate lower in B6 than A/J; the relation with activity was more complex. These data suggest that relative to A/J, B6 mice have a phenotype characteristic of the "athlete's heart," that is, eccentric, physiologic hypertrophy, slower heart rates, and increased exercise endurance. This systematic characterization of functionally related cardiovascular traits in A/J and C57BL/6J mice revealed numerous differences whose genetic bases can be dissected with recombinant inbred, recombinant congenic, and chromosome substitution strains.

The essential role of Cited2, a negative regulator for HIF-1alpha, in heart development and neurulation.

Cited2 is a cAMP-responsive element-binding protein (CBP)/p300 interacting transcriptional modulator and a proposed negative regulator for hypoxia-inducible factor (HIF)-1alpha through its competitive binding with HIF-1alpha to CBP/p300. Disruption of the gene encoding Cited2 is embryonic lethal because of defects in the development of heart and neural tube. Morphological and Doppler echocardiographic analyses of Cited2(-/-) embryos reveal severe cardiovascular abnormalities, including pulmonic arterial stenosis and ventricular septal defects accompanied by high peak outflow velocities, features of the human congenital cardiac defect termed tetralogy of Fallot. The mRNA levels of several HIF-1alpha-responsive genes, such as vascular endothelial growth factor (VEGF), Glut1, and phosphoglycerate kinase 1, increased in the Cited2(-/-) hearts. The increase of VEGF levels is significant, because defects in the Cited2(-/-) embryos closely resemble the major defects observed in the VEGF transgenic embryos. Finally, compared with wild-type, cultured fibroblasts from Cited2(-/-) embryos demonstrate an enhanced expression of HIF-1alpha-responsive genes under hypoxic conditions. These observations suggest that functional loss of Cited2 is responsible for defects in heart and neural tube development, in part because of the modulation of HIF-1 transcriptional activities in the absence of Cited2. These findings demonstrate that Cited2 is an indispensable regulatory gene during prenatal development.