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Benefits and harms of red blood cell transfusions in patients with septic shock in the intensive care unit
Holst LB
Danish Medical Journal. 2016;63((2)):B5209.
Abstract
BACKGROUND Transfusion of red blood cells (RBCs) is widely used for non-bleeding patients with septic shock in the intensive care unit (ICU). The evidence for effect and safety are limited showing conflicting results and transfused RBCs have the potential to harm subgroups of critically ill patients. Our aim was to assess the benefits and harms of RBC transfusion in patients with septic shock in a randomised clinical trial and to conduct an up-to-date systematic review with meta-analysis of all randomised clinical trials comparing different transfusion strategies. METHODS We planned and conducted a randomised, partly blinded, clinical trial assigning patients with septic shock in the ICU and a haemoglobin level of 9 g/dl (5.6 mM) or below to receive single units of pre-storage leukoreduced RBCs at a lower haemoglobin threshold level of 7 g/dl (4.3 mM) or below or a higher haemoglobin threshold level of 9 g/dl (5.6 mM) or below. The primary outcome was death by day 90 after randomisation. Secondary outcomes were need for life support, severe adverse reactions, ischaemic events in the ICU and days alive and out of hospital. Secondly, we conducted a systematic review of randomised controlled trials comparing benefits and harms of using restrictive (range of lower haemoglobin thresholds) versus liberal (range of higher haemoglobin threshold) transfusion trigger strategies to guide RBC transfusion and pooled results in meta-analyses and trial sequential analyses. RESULTS Of the 1005 patients that underwent randomisation 998 were included in analysis of the primary outcome of mortality. Ninety days after randomisation, 216 of 502 patients (43%) in the lower threshold group had died compared to 223 of 496 (45%) patients in the higher threshold group (relative risk (RR) 0.94, 95% confidence interval (CI) 0.78 to 1.09, p=0.44). The number of patients who required life support, who had ischaemic events, severe adverse reactions and number of days alive and out of hospital were similar in the two groups. Patients in the lower threshold group received 1588 units of RBCs compared to 3088 units in the higher group. A total of 176 (36%) patients in the lower threshold group never received RBCs in the ICU compared with six patients (1%) in the higher threshold group. The systematic review identified 31 trials with a total of 9813 patients in different clinical settings. In meta-analyses restrictive versus liberal transfusion strategies were not associated with the RR of death (0.89, 95% CI 0.76 to 1.05, 5607 patients in eight trials with lower risk of bias), overall morbidity (RR 0.98, 95% CI 0.85 to 1.12, 4517 patients in six trials with lower risk of bias), fatal or non-fatal myocardial infarction (RR 1.32, 95% CI 0.61 to 2.83, 4630 patients in six trials with lower risk of bias). Trial sequential analysis on mortality and myocardial infarction showed that required information sizes had not been reached but use of restrictive transfusion strategies was associated with reduced numbers of RBC units transfused (mean difference -1.43, 95% CI -2.01 to -0.86) and reduced proportion of patients transfused (RR 0.54, 95% CI 0.47 to 0.63). CONCLUSION The TRISS trial provided evidence for the safe use of 7 g/dl as transfusion trigger in patients with septic shock and reduced the number of units transfused with about half. In line with this, the updated systematic review including data from several recent trials showed no associations with mortality or other adverse events when comparing restrictive to liberal RBC transfusion strategies, however, restrictive transfusion strategies reduce the exposure of patients to RBC transfusions and reduce number of transfused RBC units. Given the fact that liberal transfusion strategies have not been proven beneficial, a more restrictive approach should be considered. Results from the TRISS trial together with other recent trials have the potential to alter the international guidelines for transfusing critically ill patients. Several guidelines have been updated the last years recommending the
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2.
Blood transfusions in septic shock: is 7.0 g/dL really the appropriate threshold?
Mazza BF, Freitas FG, Barros MM, Azevedo LC, Machado FR
Revista Brasileira de Terapia Intensiva. 2015;27((1)):36-43.
Abstract
OBJECTIVE To evaluate the immediate effects of red blood cell transfusion on central venous oxygen saturation and lactate levels in septic shock patients with different transfusion triggers. METHODS We included patients with a diagnosis of septic shock within the last 48 hours and hemoglobin levels below 9.0 g/dL Patients were randomized for immediate transfusion with hemoglobin concentrations maintained above 9.0 g/dL (Group Hb9) or to withhold transfusion unless hemoglobin felt bellow 7.0 g/dL (Group Hb7). Hemoglobin, lactate, central venous oxygen saturation levels were determined before and one hour after each transfusion. RESULTS We included 46 patients and 74 transfusions. Patients in Group Hb7 had a significant reduction in median lactate from 2.44 (2.00 - 3.22) mMol/L to 2.21 (1.80 - 2.79) mMol/L, p = 0.005, which was not observed in Group Hb9 [1.90 (1.80 - 2.65) mMol/L to 2.00 (1.70 - 2.41) mMol/L, p = 0.23]. Central venous oxygen saturation levels increased in Group Hb7 [68.0 (64.0 - 72.0)% to 72.0 (69.0 - 75.0)%, p < 0.0001] but not in Group Hb9 [72.0 (69.0 - 74.0)% to 72.0 (71.0 - 73.0)%, p = 0.98]. Patients with elevated lactate or central venous oxygen saturation < 70% at baseline had a significant increase in these variables, regardless of baseline hemoglobin levels. Patients with normal values did not show a decrease in either group. CONCLUSION Red blood cell transfusion increased central venous oxygen saturation and decreased lactate levels in patients with hypoperfusion regardless of their baseline hemoglobin levels. Transfusion did not appear to impair these variables in patients without hypoperfusion. ClinicalTrials.gov NCT01611753.
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Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis
Damiani E, Adrario E, Luchetti MM, Scorcella C, Carsetti A, Mininno N, Pierantozzi S, Principi T, Strovegli D, Bencivenga R, et al
PLoS ONE. 2015;10((5)):e0122655.
Abstract
BACKGROUND Free hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected. METHODS This is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed. RESULTS Similar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098-0.219] mg/mL to 0.238 [0.163-0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003). CONCLUSIONS Old RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density. TRIAL REGISTRATION ClinicalTrials.gov NCT01584999.
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Lower versus higher hemoglobin threshold for transfusion in septic shock
Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, et al
New England Journal of Medicine. 2014;371((15):):1381-91.
Abstract
BACKGROUND Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. RESULTS We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).
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Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study
Donati A, Damiani E, Luchetti M, Domizi R, Scorcella C, Carsetti A, Gabbanelli V, Carletti P, Bencivenga R, Vink H, et al
Critical Care. 2014;18((2):):R33.
Abstract
INTRODUCTION Microvascular alterations impair tissue oxygenation during sepsis. A red blood cell (RBC) transfusion increases oxygen (O2) delivery but rarely improves tissue O2 uptake in patients with sepsis. Possible causes include RBC alterations due to prolonged storage or residual leukocyte-derived inflammatory mediators. The aim of this study was to compare the effects of two types of transfused RBCs on microcirculation in patients with sepsis. METHODS In a prospective randomized trial, 20 patients with sepsis were divided into two separate groups and received either non-leukodepleted (n=10) or leukodepleted (n=10) RBC transfusions. Microvascular density and perfusion were assessed with sidestream dark field (SDF) imaging sublingually, before and 1 hour after transfusions. Thenar tissue O2 saturation (StO2) and tissue hemoglobin index (THI) were determined with near-infrared spectroscopy, and a vascular occlusion test was performed. The microcirculatory perfused boundary region was assessed in SDF images as an index of glycocalyx damage, and glycocalyx compounds (syndecan-1, hyaluronan, and heparan sulfate) were measured in the serum. RESULTS No differences were observed in microvascular parameters at baseline and after transfusion between the groups, except for the proportion of perfused vessels (PPV) and blood flow velocity, which were higher after transfusion in the leukodepleted group. Microvascular flow index in small vessels (MFI) and blood flow velocity exhibited different responses to transfusion between the two groups (P=0.03 and P=0.04, respectively), with a positive effect of leukodepleted RBCs. When within-group changes were examined, microcirculatory improvement was observed only in patients who received leukodepleted RBC transfusion as suggested by the increase in De Backer score (P=0.02), perfused vessel density (P=0.04), PPV (P=0.01), and MFI (P=0.04). Blood flow velocity decreased in the non-leukodepleted group (P=0.03). THI and StO2 upslope increased in both groups. StO2 and StO2 downslope increased in patients who received non-leukodepleted RBC transfusions. Syndecan-1 increased after the transfusion of non-leukodepleted RBCs (P=0.03). CONCLUSIONS This study does not show a clear superiority of leukodepleted over non-leukodepleted RBC transfusions on microvascular perfusion in patients with sepsis, although it suggests a more favorable effect of leukodepleted RBCs on microcirculatory convective flow. Further studies are needed to confirm these findings. TRIAL REGISTRATION ClinicalTrials.gov, NCT01584999.
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Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial
Holst LB, Haase N, Wetterslev J, Wernerman J, Aneman A, Guttormsen AB, Johansson PI, Karlsson S, Klemenzson G, Winding R, et al
Trials [Electronic Resource]. 2013;14:150
Abstract
BACKGROUND Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P <=0.001 is present at this point. DISCUSSION The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated. TRIAL REGISTRATION ClinicalTrials.gov: NCT01485315. Registration date 30 November 2011. First patient was randomised 3 December 2011.
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Red blood cell transfusion does not increase oxygen consumption in critically ill septic patients
Fernandes CJ Jr, Akamine N, De Marco FV, De Souza JA, Lagudis S, Knobel E
Critical Care (London, England). 2001;5((6):):362-7.
Abstract
BACKGROUND Red blood cell (RBC) transfusion is commonly used to increase oxygen transport in patients with sepsis. However it does not consistently increase oxygen uptake at either the whole-body level, as calculated by the Fick method, or within individual organs, as assessed by gastric intra-mucosal pH. AIM: This study evaluates the hemodynamic and oxygen utilization effects of hemoglobin infusion on critically ill septic patients. METHODS Fifteen septic patients undergoing mechanical ventilation whose hemoglobin was <10 g% were eligible. Ten patients (APACHE II 25.5 +/- 7.6) received an infusion of 1 unit of packed RBC over 1 h while sedated and paralyzed. The remaining five control patients (APACHE II 24.3 +/- 6.0) received a 5% albumin solution (500 ml) over 1 h. Hemodynamic data, gastric tonometry and calorimetry were obtained prior to and immediately after RBC transfusion or 5% albumin infusion. RESULTS Transfusion of RBC was associated with an improvement in left ventricular systolic work index (38.6 +/- 12.6 to 41.1 +/- 13.0 g/min/m2; P = 0.04). In the control group there was no significant change in the left ventricular systolic work index (37.2 +/- 14.3 to 42.2 +/- 18.9 g/min/m2). An increase in pulmonary vascular resistance index (203 +/- 58 to 238 +/- 49 dyne/cm5/m2; P = 0.04) was also observed, while no change was produced by colloid infusion (237 +/- 87.8 to 226.4 +/- 57.8 dyne/cm5/m2). Oxygen utilization did not increase either by Fick equation or by indirect calorimetry in either group. Gastric intramucosal pH increased only in the control group but did not reach statistical significance. CONCLUSION Hemoglobin increase does not improve either global or regional oxygen utilization in anemic septic patients. Furthermore, RBC transfusion may hamper right ventricular ejection by increasing the pulmonary vascular resistance index.
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Early goal-directed therapy in the treatment of severe sepsis and septic shock
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed TherapyCollaborative Group
New England Journal of Medicine. 2001;345((19)):1368-77.
Abstract
BACKGROUND Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. METHODS We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. RESULTS Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P = 0.009). During the interval from 7 to 72 hours, the patients assigned to early goal-directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P < or = 0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P < 0.001). CONCLUSIONS Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.