BACKGROUND: Blood for transfusion is stored for up to 42 days. Older blood develops lesions and accumulates potentially injurious substances. Some studies report increasing toxicity as blood ages. We ...assessed the safety of transfused older versus newer stored blood.
STUDY DESIGN AND METHODS: PubMed, Scopus, and Embase were searched using terms new and old and red blood cell and storage through May 6, 2011, for observational and randomized controlled studies comparing outcomes using transfused blood having longer and shorter storage times. Death was the outcome of interest.
RESULTS: Twenty‐one studies were identified, predominantly in cardiac surgery (n = 6) and trauma (n = 6) patients, including 409,966 patients. A test for heterogeneity of these studies' results was not significant for mortality (I2 = 3.7%, p = 0.41). Older blood was associated with a significantly increased risk of death (odds ratio, 1.16; 95% confidence interval CI, 1.07‐1.24). Using available mortality data, 97 (95% CI, 63‐199) patients need to be treated with only new blood to save one life. Subgroup analysis of these trials indicated that the increased risk was not restricted to a particular type of patient, size of trial, or amount of blood transfused.
CONCLUSION: Based on available data, use of older stored blood is associated with a significantly increased risk of death.
Two-year-old purpose-bred beagles (n = 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7- or 42-day-old canine universal ...donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P = .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P ≤ .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ∼ 10 hours afterward (all P ≤ .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P = .03) noted at the infection site postmortem. Plasma cell–free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P ≤ .03). The low haptoglobin (r = 0.61; P = .003) and high NO consumption levels at 24 hours (r = −0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P = .03) and not associated with survival (P = NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion.
•In canine S aureus pneumonia, first randomized blinded trial showing blood transfused at end of storage period increases mortality.•Increased in vivo hemolysis, cell-free hemoglobin, pulmonary hypertension, tissue damage, and gas exchange abnormalities each contributed.
Background Septic shock is associated with increases in end‐diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The ...mechanism is unknown. Methods and Results Purpose‐bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular‐arterial coupling, and circumferential strain. Early during sepsis, (0–24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. Conclusions The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.
Background High levels of catecholamines are cardiotoxic and associated with stress‐induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 ...days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. Methods and Results Purpose‐bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 μg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine‐stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High‐dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular‐aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800‐fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular‐aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. Conclusions Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion‐induced ischemia. However, epinephrine itself has potentially harmful long‐lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.
In a randomized controlled blinded trial, 2-year-old purpose-bred beagles (n = 24), with Staphylococcus aureus pneumonia, were exchanged-transfused with either 7- or 42-day-old washed or unwashed ...canine universal donor blood (80 mL/kg in 4 divided doses). Washing red cells (RBC) before transfusion had a significantly different effect on canine survival, multiple organ injury, plasma iron, and cell-free hemoglobin (CFH) levels depending on the age of stored blood (all, P < .05 for interactions). Washing older units of blood improved survival rates, shock score, lung injury, cardiac performance and liver function, and reduced levels of non-transferrin bound iron and plasma labile iron. In contrast, washing fresh blood worsened all these same clinical parameters and increased CFH levels. Our data indicate that transfusion of fresh blood, which results in less hemolysis, CFH, and iron release, is less toxic than transfusion of older blood in critically ill infected subjects. However, washing older blood prevented elevations in plasma circulating iron and improved survival and multiple organ injury in animals with an established pulmonary infection. Our data suggest that fresh blood should not be washed routinely because, in a setting of established infection, washed RBC are prone to release CFH and result in worsened clinical outcomes.
•Washing older blood before transfusion reduces plasma iron, improving outcomes from established infection in canines.•In contrast, washing fresh blood before transfusion increases in vivo plasma CFH release, worsening outcomes.
Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in preclinical models of pulmonary arterial ...hypertension (PAH). However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, eplerenone (EPL) and spironolactone (SPL), after the development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of
, before study treatment, confirmed features of established disease including reduced RV ejection fraction and RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared with placebo. Interventricular septal displacement was reduced by EPL whereas SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and proinflammatory gene induction in the RV. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in patients with PAH.
Determinants of left atrial (LA) reservoir function and its influence on left ventricular (LV) function have not been quantified.
In an open-pericardium, paced (70 and 90 bpm) pig model of LV ...regional ischemia (left anterior descending coronary constriction), with high-fidelity LV, LA, and RV pressure recordings, we obtained the LA area with 2D automated border detection echocardiography, LA pressure-area loops, and Doppler transmitral flow. We calculated LV tau, LA relaxation (a-x pressure difference divided by time, normalized by a pressure), and stiffness (slope between x and v pressure points of v loop). Determinants of total LA reservoir (maximum-minimum area, cm(2)) were identified by multiple regression analysis. Different mean rates of LA area increase identified 2 consecutive (early rapid and late slow) reservoir phases. During ischemia, LV long-axis shortening (LAS, LV base systolic descent) and LA reservoir area change decreased (7.3+/-0.3 SEM versus 5.6+/-0.3 cm(2), P<0.001) and LA stiffness increased (1.6+/-0.3 versus 3.1+/-0.3 mm Hg/cm(2), P=0.009). Early reservoir area change depended on LA mean ejection rate (LA area at ECG P wave minus minimum area divided by time; multiple regression coefficient=0.9; P<0.001) and relaxation (coefficient=4.9 cm(2)xms/s; P<0.001). Late reservoir area change depended on LAS (coefficient=8 cm/s; P<0.001). Total reservoir filling depended on LA stiffness (coefficient=-0.31 cm(4)/mm Hg; P=0. 001) and cardiac output (coefficient=0.001 cm(2)xmin/L; P=0.002). The strongest predictor of cardiac output was LA reservoir filling (coefficient=301 L/minxcm(2); P<0.001). The v loop area was determined by cardiac output, LV ejection time, tau, and early transmitral flow.
Two (early and late) reservoir phases are determined by LA contraction and relaxation and LV base descent. Acute LV regional ischemia increases LA stiffness and impairs LA reservoir function by reducing LV base descent.
The purpose of this study was to identify risk factors associated with local tumor progression-free survival (LTPFS) and complications after colorectal liver metastases (CLM) thermal ablation (TA).
...This retrospective analysis included 286 patients with 415 CLM undergoing TA (radiofrequency and microwave ablation) in 378 procedures from January 2003 to July 2017. Prior hepatic artery infusion (HAI), bevacizumab, pre-existing biliary dilatation, ablation modality, minimal ablation margin (MM), prior hepatectomy, CLM number, and size were analyzed as factors influencing complications and LTPFS. Statistical analysis included the Kaplan-Meier method, Cox proportional hazards model, competing risk analysis, univariate/multivariate logistic/exact logistic regressions, and the Fisher exact test. Complications were reported according to modified Society of Interventional Radiology guidelines.
The median follow-up was 31 months. There was no LTP for MM > 10 mm. Smaller tumor size, increased MM, and prior hepatectomy correlated with longer LTPFS. The major complications occurred following 28 (7%) of 378 procedures. There were no biliary complications in HAI-naive patients, versus 11% in HAI patients (P < .001), of which 7% were major. Biliary complications predictors in HAI patients included biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, ablation with 6 to 10 mm and > 10 mm MM resulted in major biliary complication rates of 4% and 21% (P = .0011), with corresponding LTP rates of 24% and 0% (P = .0033). In HAI-naive patients, the LTP rates for 6 to 10 mm and > 10 mm MM were 27% and 0%, respectively.
No LTP was seen for MM > 10 mm. Biliary complications occurred only in HAI patients, especially in those with biliary dilatation, bevacizumab, and MM > 10 mm. In HAI patients, MM of 6 to 10 mm resulted in 76% local tumor control and 4% major biliary complications incidence.
Thermal ablation of colorectal cancer liver metastases with minimum margin > 10 mm offers the best local tumor control. Biliary complications occurred only in patients that received hepatic artery infusion especially in the face of pre-existing biliary dilatation, exposure to bevacizumab, and ablation with minimum margin > 10 mm. For patients at risk, such as those in the hepatic artery infusion group, a margin of 6 to 10 mm offers 76% local tumor control rate and 4% major biliary complications incidence.
During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced ...acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water-induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.
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