Impact of red blood cell transfusion on oxygen transport and metabolism in patients with sepsis and septic shock: a systematic review and meta-analysis
Revista Brasileira de terapia intensiva. 2021;33(1):154-166
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.
Sepsis-related anemia in a pediatric intensive care unit: transfusion-associated outcomes
Transfusion. 2020;60 Suppl 1:S4-s9
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.
Children admitted to a pediatric intensive care unit (PICU) with new episode of sepsis (n= 67).
Liberal transfusion strategy group, (Group 1) received an red blood cell (RBC) top-up transfusion to 12 g/dL (n=33).
Restrictive strategy group, (Group 2) did not receive RBCs. (n= 34).
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%).
Heterogenous treatment effects of transfusion thresholds by patient age: post-hoc analysis of the TRISS trial
Acta anaesthesiologica Scandinavica. 2019
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.
Patients with septic shock and anaemia, (n=998) who had not previously been transfused in the intensive care unit (ICU).
Lower threshold group: RBC transfusion at a lower Hb-threshold of 7 g/dl [4.3 mmol/l], (n=502).
Higher threshold group: RBC transfusion at a higher Hb-threshold of 9 g/dl [5.6 mmol/l], (n=496).
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.
Liberal versus restrictive red blood cell transfusion strategy in sepsis or septic shock: a systematic review and meta-analysis of randomized trials
Critical care (London, England). 2019;23(1):262
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).
Effects of anemia and blood transfusion on clot formation and platelet function in patients with septic shock: a substudy of the randomized TRISS trial
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.
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
Journal of the American College of Surgeons. 2018;227((6):):587-595.
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.
Impact of transfusion on patients with sepsis admitted in intensive care unit: a systematic review and meta-analysis
Annals of Intensive Care. 2017;7((1)):5.
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.
Liberal versus restrictive transfusion strategy in critically ill oncologic patients: the Transfusion Requirements in Critically Ill Oncologic Patients randomized controlled trial
Critical Care Medicine. 2017;45((5):):766-773
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.
Benefits and harms of red blood cell transfusions in patients with septic shock in the intensive care unit
Danish Medical Journal. 2016;63((2)):B5209.
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
Higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial
Acta Anaesthesiologica Scandinavica. 2016;61((2):):166-175
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.