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Impact of red blood cell transfusion on oxygen transport and metabolism in patients with sepsis and septic shock: a systematic review and meta-analysis
Arango-Granados MC, Umaña M, Sánchez ÁI, García AF, Granados M, Ospina-Tascón GA
Revista Brasileira de terapia intensiva. 2021;33(1):154-166
Abstract
Red blood cell transfusion is thought to improve cell respiration during septic shock. Nevertheless, its acute impact on oxygen transport and metabolism in this condition remains highly debatable. The objective of this study was to evaluate the impact of red blood cell transfusion on microcirculation and oxygen metabolism in patients with sepsis and septic shock. We conducted a search in the MEDLINE®, Elsevier and Scopus databases. We included studies conducted in adult humans with sepsis and septic shock. A systematic review and meta-analysis were performed using the DerSimonian and Laird random-effects model. A p value < 0.05 was considered significant. Nineteen manuscripts with 428 patients were included in the analysis. Red blood cell transfusions were associated with an increase in the pooled mean venous oxygen saturation of 3.7% (p < 0.001), a decrease in oxygen extraction ratio of -6.98 (p < 0.001) and had no significant effect on the cardiac index (0.02L/minute; p = 0,96). Similar results were obtained in studies including simultaneous measurements of venous oxygen saturation, oxygen extraction ratio, and cardiac index. Red blood cell transfusions led to a significant increase in the proportion of perfused small vessels (2.85%; p = 0.553), while tissue oxygenation parameters revealed a significant increase in the tissue hemoglobin index (1.66; p = 0.018). Individual studies reported significant improvements in tissue oxygenation and sublingual microcirculatory parameters in patients with deranged microcirculation at baseline. Red blood cell transfusions seemed to improve systemic oxygen metabolism with apparent independence from cardiac index variations. Some beneficial effects have been observed for tissue oxygenation and microcirculation parameters, particularly in patients with more severe alterations at baseline. More studies are necessary to evaluate their clinical impact and to individualize transfusion decisions.
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Sepsis-related anemia in a pediatric intensive care unit: transfusion-associated outcomes
Elshinawy M, Kamal M, Nazir H, Khater D, Hassan R, Elkinany H, Wali Y
Transfusion. 2020;60 Suppl 1:S4-s9
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Editor's Choice
Abstract
BACKGROUND Pediatric patients with sepsis in intensive care units are at high risk of developing anemia, which might have adverse effects on their prognosis. This study aimed to evaluate the impact of red blood cell (RBC) transfusion on the outcomes of patients admitted to a pediatric intensive care unit (PICU) with sepsis. METHODS We conducted a prospective randomized clinical trial, enrolling 67 children, aged 2 to 144 months who were admitted to a PICU with a new episode of sepsis from November 2017 to April 2018. Patients were allocated randomly to two groups: Group 1, liberal transfusion strategy group, including 33 patients who had initial hemoglobin (Hb) between 7 or greater and less than 10 g/dL and received an RBC top-up transfusion to 12 g/dL; and Group 2, restrictive strategy group, including 34 patients who had the same Hb range and did not receive RBCs. Patients with Hb less than 7 or greater than 10 g/dL were excluded. RESULTS Of 33 patients who received liberal transfusions, 31 (93.94%) required ventilation, and 29 (87.88%) had multiorgan dysfunction. They had a significantly lengthier hospital stay and a higher incidence of acute respiratory distress syndrome and acute lung injury. Moreover, mortality was significantly higher in the liberal transfusion group (42.4% vs. 17.6%). CONCLUSIONS Compared to the restrictive transfusion strategy, liberal transfusion might be associated with a worse outcome. However, the possible role of other known and unknown confounding factors and minor protocol violations should be taken into consideration. We recommend minimizing factors worsening anemia in PICU patients to reduce the need for transfusion.
PICO Summary
Population
Children admitted to a pediatric intensive care unit (PICU) with new episode of sepsis (n= 67).
Intervention
Liberal transfusion strategy group, (Group 1) received an red blood cell (RBC) top-up transfusion to 12 g/dL (n=33).
Comparison
Restrictive strategy group, (Group 2) did not receive RBCs. (n= 34).
Outcome
Of 33 patients who received liberal transfusions, 31 (93.94%) required ventilation, and 29 (87.88%) had multiorgan dysfunction. They had a significantly lengthier hospital stay and a higher incidence of acute respiratory distress syndrome and acute lung injury. Moreover, mortality was significantly higher in the liberal transfusion group (42.4% vs. 17.6%).
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Liberal versus restrictive red blood cell transfusion strategy in sepsis or septic shock: a systematic review and meta-analysis of randomized trials
Hirano Y, Miyoshi Y, Kondo Y, Okamoto K, Tanaka H
Critical care (London, England). 2019;23(1):262
Abstract
BACKGROUND We assessed the effect of liberal versus restrictive red blood cell transfusion strategy on survival outcome in sepsis or septic shock by systematically reviewing the literature and synthesizing evidence from randomized controlled trials (RCTs). METHODS We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science databases. We included RCTs that compared mortality between a liberal transfusion strategy with a hemoglobin threshold of 9 or 10 g/dL and a restrictive transfusion strategy with a hemoglobin threshold of 7 g/dL in adults with sepsis or septic shock. Two investigators independently screened citations and conducted data extraction. The primary outcome was 28- or 30-day mortality. Secondary outcomes were 60- and 90-day mortality, use of life support at 28 days of admission, and number of patients transfused during their intensive care unit stay. DerSimonian-Laird random-effects models were used to report pooled odds ratios (ORs). RESULTS A total of 1516 patients from three RCTs were included; 749 were randomly assigned to the liberal transfusion group and 767 to the restrictive strategy group. Within 28-30 days, 273 patients (36.4%) died in the liberal transfusion group, while 278 (36.2%) died in the restrictive transfusion group (pooled OR, 0.99; 95% confidence interval [CI], 0.67-1.46). For the primary outcome, heterogeneity was observed among the studies (I(2) = 61.0%, chi(2) = 5.13, p = 0.08). For secondary outcomes, only two RCTs were included. There were no significant differences in secondary outcomes between the two groups. CONCLUSIONS We could not show any difference in 28- or 30-day mortality between the liberal and restrictive transfusion strategies in sepsis or septic shock patients by meta-analysis of RCTs. Our results should be interpreted with caution due to the existence of heterogeneity. As sepsis complicates a potentially wide range of underlying diseases, further trials in carefully selected populations are anticipated. TRIAL REGISTRATION This present study was registered in the PROSPERO database (CRD42018108578).
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Heterogenous treatment effects of transfusion thresholds by patient age: post-hoc analysis of the TRISS trial
Jonsson AB, Granholm A, Rygard SL, Holst LB, Moller MH, Perner A
Acta anaesthesiologica Scandinavica. 2019
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Editor's Choice
Abstract
BACKGROUND Use of a lower haemoglobin (Hb) threshold to guide red blood cell (RBC) transfusion is now generally recommended in critically ill patients, but uncertainty remains regarding the optimal HB-threshold for RBC transfusion in patients of different ages. METHODS We conducted a post-hoc analysis of 998 patients with septic shock and anaemia randomised to RBC transfusion at a Hb-threshold of 7 g/dl [4.3 mmol/l] vs. 9 g/dl [5.6 mmol/l] in the Transfusion Requirements in Septic Shock (TRISS) trial. We assessed if there were heterogeneous effects between the allocated Hb-threshold and patient age categorised and on the continuous scale. The primary outcome was 1-year mortality; the secondary outcome was 90-day mortality. Both outcomes were analysed using logistic regression models and in sensitivity analyses with additional adjusting for site of enrolment, presence of haematological malignancy and the Sequential Organ Failure Assessment (SOFA) score. The secondary analyses were Kaplan-Meier curves with corresponding log-rank tests. RESULTS We found no heterogeneity between patient age and the allocated Hb-thresholds for RBC transfusion for 1-year mortality or 90-day mortality in the primary analyses. The sensitivity analyses suggested heterogeneity between age groups regarding 90-day mortality, however, this was not consistent for 1-year mortality or when assessing age on the continuous scale. CONCLUSION In this post-hoc study of ICU patients with septic shock, we found no reliable heterogeneous effects of transfusion at a Hb-threshold of 7 vs. 9 g/dl according to patient age on mortality. However, due to low power, this study should only be considered as hypothesis-generating.
PICO Summary
Population
Patients with septic shock and anaemia, (n=998) who had not previously been transfused in the intensive care unit (ICU).
Intervention
Lower threshold group: RBC transfusion at a lower Hb-threshold of 7 g/dl [4.3 mmol/l], (n=502).
Comparison
Higher threshold group: RBC transfusion at a higher Hb-threshold of 9 g/dl [5.6 mmol/l], (n=496).
Outcome
No heterogeneity between patient age and the allocated Hb-thresholds for RBC transfusion for 1-year mortality or 90-day mortality in the primary analyses. The sensitivity analyses suggested heterogeneity between age groups regarding 90-day mortality, however, this was not consistent for 1-year mortality or when assessing age on the continuous scale.
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Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial
Wei S, Rodriguez EG, Chang R, Holcomb JB, Kao LS, Wade CE
Journal of the American College of Surgeons. 2018;227((6):):587-595.
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Abstract
BACKGROUND Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. STUDY DESIGN We analyzed a subset of PROPPR patients that survived at least 72 hours after hospital admission and determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a p-value <0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. RESULTS We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (IQR 36 - 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL (IQR 67 - 336 ng/dL) in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, injury severity score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. CONCLUSIONS Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission is associated with subsequent sepsis.
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Effects of anemia and blood transfusion on clot formation and platelet function in patients with septic shock: a substudy of the randomized TRISS trial
Russell L, Holst LB, Lange T, Liang X, Ostrowski SR, Perner A
Transfusion. 2018;58((12):):2807-2818.
Abstract
BACKGROUND The effects of anemia and red blood cell (RBC) transfusion on markers of clot formation and platelet function in patients with septic shock are unknown. We assessed these effects in a randomized transfusion trial of patients with septic shock. STUDY DESIGN AND METHODS We performed a prospective substudy of the Transfusion Requirements in Septic Shock (TRISS) trial, randomly assigning patients in the intensive care unit with septic shock and hemoglobin concentration of 9.0 g/dL or less to transfusion with one unit of RBCs at a hemoglobin level of 9.0 g/dL or a level of 7.0 g/dL. We assessed thromboelastography (TEG), multiple electrode aggregometry (MEA), platelet count, and international normalized ratio (INR) immediately before and after the first blood transfusion and again 3 hours after. The effects of hemoglobin level were analyzed using multiple linear regression and the association between markers of hemostasis and subsequent bleeding by Cox regression models. RESULTS We included 58 patients in this substudy. We observed no differences in whole blood clot formation, platelet count or function, or INR between patients with hemoglobin levels of 7.0 and 9.0 g/dL, and we found no effect of RBC transfusion on these markers. Platelet function, assessed by MEA, but not whole blood clot formation, was associated with subsequent bleeding. CONCLUSIONS In patients with septic shock, the level of anemia and the transfusion of RBCs did not appear to influence clot formation or platelet function. Low platelet function, as evaluated by MEA, was associated with increased risk of subsequent bleeding.
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Liberal versus restrictive transfusion strategy in critically ill oncologic patients: the Transfusion Requirements in Critically Ill Oncologic Patients randomized controlled trial
Bergamin FS, Almeida JP, Landoni G, Galas FR, Fukushima JT, Fominskiy E, Park CH, Osawa EA, Diz MP, Oliveira GQ, et al
Critical Care Medicine. 2017;45((5):):766-773
Abstract
OBJECTIVE To assess whether a restrictive strategy of RBC transfusion reduces 28-day mortality when compared with a liberal strategy in cancer patients with septic shock. DESIGN Single center, randomized, double-blind controlled trial. SETTING Teaching hospital. PATIENTS Adult cancer patients with septic shock in the first 6 hours of ICU admission. INTERVENTIONS Patients were randomized to the liberal (hemoglobin threshold, < 9g/dL) or to the restrictive strategy (hemoglobin threshold, < 7g/dL) of RBC transfusion during ICU stay. MEASUREMENTS AND MAIN RESULTS Patients were randomized to the liberal (n = 149) or to the restrictive transfusion strategy (n = 151) group. Patients in the liberal group received more RBC units than patients in the restrictive group (1 [0-3] vs 0 [0-2] unit; p < 0.001). At 28 days after randomization, mortality rate in the liberal group (primary endpoint of the study) was 45% (67 patients) versus 56% (84 patients) in the restrictive group (hazard ratio, 0.74; 95% CI, 0.53-1.04; p = 0.08) with no differences in ICU and hospital length of stay. At 90 days after randomization, mortality rate in the liberal group was lower (59% vs 70%) than in the restrictive group (hazard ratio, 0.72; 95% CI, 0.53-0.97; p = 0.03). CONCLUSIONS We observed a survival trend favoring a liberal transfusion strategy in patients with septic shock when compared with the restrictive strategy. These results went in the opposite direction of the a priori hypothesis and of other trials in the field and need to be confirmed.
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Impact of transfusion on patients with sepsis admitted in intensive care unit: a systematic review and meta-analysis
Dupuis C, Sonneville R, Adrie C, Gros A, Darmon M, Bouadma L, Timsit JF
Annals of Intensive Care. 2017;7((1)):5.
Abstract
Red blood cell transfusion (RBCT) threshold in patients with sepsis remains a matter of controversy. A threshold of 7 g/dL for stabilized patients with sepsis is commonly proposed, although debated. The aim of the study was to compare the benefit and harm of restrictive versus liberal RBCT strategies in order to guide physicians on RBCT strategies in patients with severe sepsis or septic shock. Four outcomes were assessed: death, nosocomial infection (NI), acute lung injury (ALI) and acute kidney injury (AKI). Studies assessing RBCT strategies or RBCT impact on outcome and including intensive care unit (ICU) patients with sepsis were assessed. Two systematic reviews were achieved: first for the randomized controlled studies (RCTs) and second for the observational studies. MEDLINE, EMBASE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Clinical Trials.gov were analyzed up to March 01, 2015. Der Simonian and Laird random-effects models were used to report pooled odds ratios (ORs). Subgroup analyses and meta-regressions were performed to explore studies heterogeneity. One RCT was finally included. The restrictive RBCT strategy was not associated with harm or benefit compared to liberal strategy. Twelve cohort studies were included, of which nine focused on mortality rate. RBCT was not associated with increased mortality rate (overall pooled OR was 1.10 [0.75, 1.60]; I 2 = 57%, p = 0.03), but was associated with the occurrence of NI (2 studies: pooled OR 1.25 [1.04-1.50]; I 2 = 0%, p = 0.97), the occurrence of ALI (1 study: OR 2.75 [1.22-6.37]; p = 0.016) and the occurrence of AKI (1 study: OR 5.22 [2.1-15.8]; p = 0.001). Because there was only one RCT, the final meta-analyses were only based on the cohort studies. As a result, the safety of a RBCT restrictive strategy was confirmed, although only one study specifically focused on ICU patients with sepsis. Then, RBCT was not associated with increased mortality rate, but was associated with increased in occurrence of NI, ALI and AKI. Nevertheless, the data on RBCT in patients with sepsis are sparse and the high heterogeneity between studies prevents from drawing any definitive conclusions.
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Long-term outcomes in patients with septic shock transfused at a lower versus a higher haemoglobin threshold: the TRISS randomised, multicentre clinical trial
Rygard SL, Holst LB, Wetterslev J, Winkel P, Johansson PI, Wernerman J, Guttormsen AB, Karlsson S, Perner A
Intensive Care Medicine. 2016;42((11):):1685-1694
Abstract
PURPOSE We assessed the predefined long-term outcomes in patients randomised in the Transfusion Requirements in Septic Shock (TRISS) trial. METHODS In 32 Scandinavian ICUs, we randomised 1005 patients with septic shock and haemoglobin of 9 g/dl or less to receive single units of leuko-reduced red cells when haemoglobin level was 7 g/dl or less (lower threshold) or 9 g/dl or less (higher threshold) during ICU stay. We assessed mortality rates 1 year after randomisation and again in all patients at time of longest follow-up in the intention-to-treat population (n = 998) and health-related quality of life (HRQoL) 1 year after randomisation in the Danish patients only (n = 777). RESULTS Mortality rates in the lower- versus higher-threshold group at 1 year were 53.5 % (268/501 patients) versus 54.6 % (271/496) [relative risk 0.97; 95 % confidence interval (CI) 0.85-1.09; P = 0.62]; at longest follow-up (median 21 months), they were 56.7 % (284/501) versus 61.0 % (302/495) (hazard ratio 0.88; 95 % CI 0.75-1.03; P = 0.12). We obtained HRQoL data at 1 year in 629 of the 777 (81 %) Danish patients, and mean differences between the lower- and higher-threshold group in scores of physical HRQoL were 0.4 (95 % CI -2.4 to 3.1; P = 0.79) and in mental HRQoL 0.5 (95 % CI -3.1 to 4.0; P = 0.79). CONCLUSIONS Long-term mortality rates and HRQoL did not differ in patients with septic shock and anaemia who were transfused at a haemoglobin threshold of 7 g/dl versus a threshold of 9 g/dl. We may reject a more than 3 % increased hazard of death in the lower- versus higher-threshold group at the time of longest follow-up.
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Higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial
Rygard SL, Holst LB, Wetterslev J, Johansson PI, Perner A
Acta Anaesthesiologica Scandinavica. 2016;61((2):):166-175
Abstract
BACKGROUND Using a restrictive transfusion strategy appears to be safe in sepsis, but there may be subgroups of patients who benefit from transfusion at a higher haemoglobin level. We explored if subgroups of patients with septic shock and anaemia had better outcome when transfused at a higher vs. a lower haemoglobin threshold. METHODS In post-hoc analyses of the full trial population of 998 patients from the Transfusion Requirements in Septic Shock (TRISS) trial, we investigated the intervention effect on 90-day mortality in patients with severe comorbidity (chronic lung disease, haematological malignancy or metastatic cancer), in patients who had undergone surgery (elective or acute) and in patients with septic shock as defined by the new consensus definition: lactate above 2 mmol/l and the need for vasopressors to maintain a mean arterial pressure above 65 mmHg. RESULTS The baseline characteristics were mostly similar between the two intervention groups in the different subgroups. There were no differences in the intervention effect on 90-day mortality in patients with chronic lung disease (test of interaction P = 0.31), haematological malignancy (P = 0.47), metastatic cancer (P = 0.51), in those who had undergone surgery (P = 0.99) or in patients with septic shock by the new definition (P = 0.20). CONCLUSION In exploratory analyses of a randomized trial in patients with septic shock and anaemia, we observed no survival benefit in any subgroups of transfusion at a haemoglobin threshold of 90 g/l vs. 70 g/l.
