Pearl Toy

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.

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.

Acute severe isovolemic anemia impairs cognitive function and memory in humans.

Background Erythrocytes are transfused to prevent or treat inadequate oxygen delivery resulting from insufficient hemoglobin concentration. Previous studies failed to find evidence of inadequate systemic oxygen delivery at a hemoglobin concentration of 5 g/dl. However, in those studies, sensitive, specific measures of critical organ function were not used. This study tested the hypothesis that acute severe decreases of hemoglobin concentration alters human cognitive function. Methods Nine healthy volunteers, age 29 ± 5 yr (mean ± SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and after acute isovolemic reduction of their hemoglobin to 7, 6, and 5 g/dl and again after transfusion of their autologous erythrocytes to return their hemoglobin concentration to 7 g/dl. To control for duration of the experiment, each volunteer also completed the same tests on a separate day, without alteration of hemoglobin, at times of the day approximately equivalent to those on the experimental day. Results No test showed any change in reaction time or error rate at hemoglobin concentration of 7 g/dl compared with the data at the baseline hemoglobin concentration of 14 g/dl. Reaction time, but not error rate, for horizontal addition and digit–symbol substitution test (DSST) increased at hemoglobin 6 g/dl (mean horizontal addition, 19%; 95% confidence interval [CI], 4–34%; mean DSST, 10%; 95% CI, 4–17%) and further at 5 g/dl (mean horizontal addition, 43%; 95% CI, 6–79%; mean DSST, 18%; 95% CI, 4–31%). Immediate and delayed memory was degraded at hemoglobin 5 g/dl but not at 6 g/dl. Return of hemoglobin to 7 g/dl returned all tests to baseline, except for the DSST, which significantly improved, and returned to baseline the following morning after transfusion of all autologous erythrocytes. Conclusion Acute reduction of hemoglobin concentration to 7 g/dl does not produce detectable changes in human cognitive function. Further reduction of hemoglobin level to 6 and 5 g/dl produces subtle, reversible increases in reaction time and impaired immediate and delayed memory. These are the first prospective data to demonstrate subtle degraded human function with acute anemia of hemoglobin concentrations of 6 and 5 g/dl. This reversibility of these decrements with erythrocyte transfusion suggests that our model can be used to test the efficacy of erythrocytes, oxygen therapeutics, or other treatments for acute anemia.

Lack of increased bleeding after paracentesis and thoracentesis in patients with mild coagulation abnormalities

To determine whether untreated mild coagulopathy in patients with no evidence of clinical bleeding is associated with an increased risk of hemorrhage after paracentesis or thoracentesis, retrospective examination was conducted of 608 consecutive procedures for which prothrombin time (PT), partial thromboplastin time (PTT), platelet (Plt) counts, and preprocedure and postprocedure hemoglobin concentrations were available. There was no increased bleeding in patients with mild to moderate coagulopathy (defined as PT or PTT up to twice the midpoint normal range or pit count of 50 to 99 × 10(3) per microL [50–99 × 109/L]). However, patients with markedly elevated serum creatinine levels (6.0 to 14.0 mg/dL [530–1240 mumol/L]) had a significantly greater average hemoglobin loss (−0.82 ± 1.3 g/dL [−8 +/− 13 g/L], n = 11) than patients with normal serum creatinine levels (−0.12 ± 0.88 g/dL [−1 ± 9 g/L], n = 450) (p = 0.011). Overall, the frequency of bleeding complications requiring red cell transfusions was very low: 0.2 percent of events. The most common diagnosis for patients who had paracentesis was alcoholic liver disease (72%); for those having thoracentesis, it was infection (37%). It can be concluded that, for these patients, prophylactic plasma or platelet transfusions are not necessary. Patients with markedly elevated serum creatinine deserve close postprocedure observation.

The variability of transfusion practice in coronary artery bypass surgery. Transfusion Medicine Academic Award Group.

We audited 540 patients undergoing elective first-time coronary artery bypass grafts at 18 institutions. The purposes of the study were to describe the variability in transfusions among institutions and to determine factors that may account for variability. Mean homologous red blood cell use per patient was 2.9(+/- 0.1) U (institutional range, 0.4 to 6.3 U). One hundred seventy-seven patients (32%) received plasma (institutional range, 0% to 97%), and 119 (22%) received platelets (institutional range, 0% to 80%). After controlling for patient and surgical practice variables, transfusion practice factors still accounted for variation in red blood cell transfusions. Variation in patients receiving plasma and platelet transfusions among institutions was determined in part by prophylactic transfusions. We conclude that blood component usage for coronary artery bypass grafts differs widely among institutions. The variability in use of these components is accounted for in part by unnecessary transfusions in otherwise routine, uncomplicated coronary artery bypass graft procedures.

Critical Oxygen Delivery in Conscious Humans Is Less Than 7.3 ml O2· kg−1· min−1

Background The “critical” level of oxygen delivery (DO2) is the value below which DO2 fails to satisfy the metabolic need for oxygen. No prospective data in healthy, conscious humans define this value. The authors reduced DO2 in healthy volunteers in an attempt to determine the critical DO2. Methods With Institutional Review Board approval and informed consent, the authors studied eight healthy, conscious volunteers, aged 19–25 yr. Hemodynamic measurements were obtained at steady state before and after profound acute isovolemic hemodilution with 5% albumin and autologous plasma, and again at the reduced hemoglobin concentration after additional reduction of DO2 by an infusion of a &bgr;-adrenergic antagonist, esmolol. Results Reduction of hemoglobin from 12.5 ± 0.8 g/dl to 4.8 ± 0.2 g/dl (mean ± SD) increased heart rate, stroke volume index, and cardiac index, and reduced DO2 (14.0 ± 2.9 to 9.9 ± 2.0 ml O2 · kg−1 · min−1; all P < 0.001). Oxygen consumption (VO2; 3.0 ± 0.5 to 3.4 ± 0.6 ml O2 · kg−1 · min−1;P < 0.05) and plasma lactate concentration (0.50 ± 0.10 to 0.62 ± 0.16 mM;P < 0.05; n = 7) increased slightly. Esmolol decreased heart rate, stroke volume index, and cardiac index, and further decreased DO2 (to 7.3 ± 1.4 ml O2 · kg−1 · min−1; all P < 0.01 vs. before esmolol). VO2 (3.2 ± 0.6 ml O2 · kg−1 · min−1;P > 0.05) and plasma lactate (0.66 ± 0.14 mM;P > 0.05) did not change further. No value of plasma lactate exceeded the normal range. Conclusions A decrease in DO2 to 7.3 ± 1.4 ml O2 · kg−1 · min−1 in resting, healthy, conscious humans does not produce evidence of inadequate systemic oxygenation. The critical DO2 in healthy, resting, conscious humans appears to be less than this value.

Fresh Blood and Aged Stored Blood Are Equally Efficacious in Immediately Reversing Anemia-induced Brain Oxygenation Deficits in Humans

Background:Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h. Methods:Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit–symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h (“fresh”) or 3 weeks (“stored”) to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion. Results:Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion–induced DSST improvement did not differ between groups (P = 0.96). Conclusion:Erythrocytes stored for 3 weeks are as efficacious as are erythrocytes stored for 3.5 h in reversing the neurocognitive deficit of acute anemia. Requiring fresh rather than stored erythrocytes for augmentation of oxygen delivery does not seem warranted.

Oxygen Reverses Deficits of Cognitive Function and Memory and Increased Heart Rate Induced by Acute Severe Isovolemic Anemia

Background Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2–3 g/dl and thus reverse the effects of acute anemia. Methods Thirty-one healthy volunteers, aged 28 ± 4 yr (mean ± SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 ± 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test. Results Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 ± 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 ± 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia. Conclusion The authors confirmed that acute isovolemic anemia subtly slows human reaction time, degrades memory, increases heart rate, and decreases energy level. The findings of this study support the hypothesis that increasing Pao2 to 350 mmHg or greater by breathing oxygen reverses all of these effects of acute anemia except for decreased energy.

Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans.

BackgroundControversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia. MethodsFifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 ± 1.2 to 5.2 ± 0.5 g/dl (mean ± SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia. ResultsDuring hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5–7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values. ConclusionWith acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.

Fresh frozen plasma and platelet transfusion for nonbleeding patients in the intensive care unit: benefit or harm?

Objective:Whereas restrictive red cell transfusion has become a standard of care for the critically ill, evidenced-based indications for use of other blood components such as fresh frozen plasma (FFP) and platelet transfusions are limited. We searched the National Library of Medicine PubMed database as well as references of retrieved articles and summarized the current evidence for the use of FFP and platelet transfusions in critically ill patients. Results:Routine coagulation tests are poor determinants of bleeding risk in critically ill patients with coagulopathy. FFP transfusion has limited efficacy and is associated with significant morbidity in critically ill patients, in particular, pulmonary edema and acute lung injury. Routine minimally invasive critical care procedures can be safely performed by experienced clinicians in the setting of mildly abnormal coagulation test results, and there is no evidence that FFP transfusion alters the risk of bleeding. For platelet transfusion, the American Society of Clinical Oncology has developed practice guidelines designed for oncology patients. However, because the pathophysiology of thrombocytopenia in critically ill patients often differs from that of thrombocytopenia in oncology patients, published guidelines for oncology patients may not be applicable. Conclusion:Because the risk-benefit ratio of a liberal FFP or platelet transfusion strategy for critically ill patients may not be favorable, randomized controlled trials are warranted for evaluating a restrictive vs. liberal FFP or platelet transfusion strategy for nonbleeding patients in the intensive care unit.