A survey on perioperative red blood cell transfusion trigger strategies for pediatric patients in the Nordic countries.

BACKGROUND: Transfusion of red blood cells (RBC) to rapidly increase hemoglobin levels have been associated with increased risks and worse outcomes in critically ill children. The international TAXI consensus from 2018 (pediatric critical care transfusion and anemia expertise initiative) recommended restrictive RBC transfusion strategies in pediatric patients. OBJECTIVE: To elucidate physicians perioperative RBC transfusion trigger strategies for pediatric patients in the Nordic countries and to investigate what factors influence the decision to transfuse this group of patients. METHODS: An electronic web-based survey designed by the TransfUsion triggers in Pediatric perioperAtive Care (TUPAC) initiative including six different clinical scenarios was sent to anesthesiologist treating pediatric patients at university hospitals in the Nordic countries on February 1, 2023 and closed May 1, 2023. RESULTS: The study had a response rate of 67.7% (180 responders out of 266 contacted). Median hemoglobin thresholds triggering RBC transfusions were 7.0 [IQR, 7.0-7.3] g/dL in a stable young child (1-year-old), 7.0 [IQR, 7.0-7.0] g/dL in the stable older child (5-year-old), 8.5 [IQR, 8.0-9.0] g/dL in the older child with cardiac disease, 9.0 [IQR, 8.0-10.0] g/dL the older child with traumatic brain injury, 8.0 [IQR, 7.3-9.0] g/dL in stabilized older child with septic shock and 8.0 [IQR, 7.0-9.0] g/dL in the older child with active but non-life-threatening bleeding. Apart from specific hemoglobin level, RBC transfusions were mostly triggered by high lactate level (74.2%), increasing heart rate (68.0%), prolonged capillary refill time (48.3%), and lowered blood pressure (47.8%). No statistical difference was found between the Nordic countries, work experience, or enrollment in a pediatric anesthesia fellowship program regarding RBC transfusion strategies. CONCLUSIONS: Anesthesiologists in the Nordic countries report restrictive perioperative RBC transfusion strategies for children that are mostly in agreement with the international TAXI recommendations. However, RBC transfusions strategies were modified to be guided by more liberal trigger levels when pediatric patients presented with severe comorbidity such as severe sepsis, septic shock, and non-life-threatening bleeding.

Intravenous MELAtonin for prevention of Postoperative Agitation and Emergence Delirium in children (MELA-PAED): A protocol and statistical analysis plan for a randomized clinical trial.

BACKGROUND: Emergence agitation and delirium in children remain a common clinical challenge in the post-anesthetic care unit. Preoperative oral melatonin has been suggested as an effective preventive drug with a favorable safety profile. The oral bioavailability of melatonin, however, is low. Therefore, the MELA-PAED trial aims to investigate the efficacy and safety of intraoperative intravenous melatonin for the prevention of emergence agitation in pediatric surgical patients. METHODS: MELA-PAED is a randomized, double-blind, parallel two-arm, multi-center, superiority trial comparing intravenous melatonin with placebo. Four hundred participants aged 1-6 years will be randomized 1:1 to either the intervention or placebo. The intervention consists of intravenous melatonin 0.15 mg/kg administered approximately 30 min before the end of surgery. Participants will be monitored in the post-anesthetic care unit (PACU), and the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) will be performed on days 1, 7, and 14 after the intervention. Serious Adverse Events (SAE) will be assessed up to 30 days after the intervention. RESULTS: The primary outcome is the incidence of emergence agitation, assessed dichotomously as any Watcha score >2 during the participant's stay in the post-anesthetic care unit. Secondary outcomes are opioid consumption in the post-anesthetic care unit and adverse events. Exploratory outcomes include SAEs, postoperative pain, postoperative nausea and vomiting, and time to awakening, to first oral intake, and to discharge readiness. CONCLUSION: The MELA-PAED trial investigates the efficacy of intravenous intraoperative melatonin for the prevention of emergence agitation in pediatric surgical patients. Results may provide further knowledge concerning the use of melatonin in pediatric perioperative care.

Pre-procedural platelet transfusion thresholds in hospitalised children - Protocol for a scoping review.

BACKGROUND: Thrombocytopenia is a common condition in hospitalised critically ill children and most platelet transfusions are given as prophylaxis to non-bleeding children prior to invasive procedures such as central venous catheterisation and lumbar puncture. Platelet transfusion may reduce bleeding complications but have also been associated with potential adverse effects and variation in clinical practice exist. To direct future research, we aim to assess the current evidence regarding prophylactic platelet transfusion prior to procedures in hospitalised thrombocytopenic children. METHODS: We will conduct a scoping review of all study designs in accordance with the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) statement. We will include studies on hospitalised children undergoing invasive procedures where the prevalence of thrombocytopenia and the predefined outcome measures, including bleeding, transfusion-related adverse events and use of blood products and life support are reported. We will provide descriptive analyses of the included studies/trials and the quality of evidence will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. CONCLUSION: The outlined scoping review will provide an overview on the benefits and harms of prophylactic platelet transfusion prior to invasive procedures in thrombocytopenic hospitalised children.

Lower vs higher transfusion threshold in septic shock patients of different ages: A study protocol.

BACKGROUND: Current evidence indicates that it is safe to use a lower haemoglobin (Hb) threshold for red blood cell (RBC) transfusion as compared to a higher Hb-threshold. However, the recent Transfusion Requirements in Cardiac Surgery (TRICS-3) trial reported a significant interaction between patient age and the effect of lower vs higher Hb-thresholds for RBC transfusion. The interaction between patient age and transfusion strategy appears to differ between trials. METHODS: This is the protocol and statistical analysis plan for a post hoc analysis of the Transfusion Requirements in Septic Shock (TRISS) trial. We will assess the effect of a lower vs a higher Hb-threshold for RBC transfusion in patients of different ages with septic shock. The primary and secondary outcomes are 1-year mortality and 90-day mortality respectively. We will assess age divided into six age groups and as a continuous variable and present baseline characteristics and odds ratios derived from both simple and adjusted (for the Sequential Organ Failure Assessment score, haematological malignancy, age and trial site) logistic regression models and P-values for the test-of-interaction. Furthermore, we will compare outcomes according to Hb-threshold in each age group using Kaplan-Meier curves and log-rank tests. DISCUSSION: The outlined study will make a detailed assessment of potential interaction of patient age with transfusion strategy in patients with septic shock. This may inform future trials on the benefits and harms of RBC transfusion.

External validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU).

BACKGROUND: The Simplified Mortality Score for the Intensive Care Unit (SMS-ICU) is a clinical prediction model, which estimates the risk of 90-day mortality in acutely ill adult ICU patients using 7 readily available variables. We aimed to externally validate the SMS-ICU and compare its discrimination with existing prediction models used with 90-day mortality as the outcome. METHODS: We externally validated the SMS-ICU using data from 3282 patients included in the Stress Ulcer Prophylaxis in the Intensive Care Unit trial, which randomised acutely ill adult ICU patients with risk factors for gastrointestinal bleeding to prophylactic pantoprazole or placebo in 33 ICUs in Europe. We assessed discrimination, calibration and overall performance of the SMS-ICU and compared discrimination with the commonly used and more complex SAPS II and SOFA scores. RESULTS: Mortality at day 90 was 30.7%. The discrimination (area under the receiver operating characteristic curve) for the SMS-ICU was 0.67 (95% CI: 0.65-0.69), as compared with 0.68 (95% CI: 0.66-0.70, P = 0.35) for SAPS II and 0.63 (95% CI: 0.61-0.65, P < 0.001) for the SOFA score. Calibration (intercept and slope) was 0.001 and 0.786, respectively, and Nagelkerke's R2 (overall performance) was 0.06. The proportions of missing data for the SMS-ICU, SAPS II and SOFA scores were 0.2%, 8.5% and 6.8%, respectively. CONCLUSIONS: Discrimination for 90-day mortality of the SMS-ICU in this cohort was poor, but similar to SAPS II and better than that of the SOFA score with markedly less missing data.

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.

Blood Product Administration in the Critical Care and Perioperative Settings.

The critical care and perioperative settings are high consumers of blood products, with multiple units and different products often given to an individual patient. The recommendation of this review is always to consider the risks and benefits for a specific blood product for a specific patient in a specific clinical setting. Optimize patient status by treating anemia and preventing the need for red blood cell transfusion. Consider other options for correction of anemia and coagulation disorders and use an imperative non-overtransfusion policy for all blood products.

Risks of bleeding and thrombosis in intensive care unit patients with haematological malignancies.

BACKGROUND: Patients with malignant haematological disease and especially those who require intensive care have an increased risk of bleeding and thrombosis, but none of these data were obtained in ICU patients only. We assessed the incidence of bleeding and thrombotic complications, use of blood products and risk factors for bleeding in an adult population of ICU patients with haematological malignancies. METHODS: We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008-2012. Bleeding in ICU was scored according to the WHO grading system, and risk factors were evaluated using unadjusted and adjusted analyses. RESULTS: In total, 116 of 129 ICU patients were included; their median length of stay was 7 (IQR 2-16) days. Of these, 66 patients (57%) had at least one bleeding episode in ICU; they bled for 3 (2-6) days and most often from lower and upper airways and upper GI tract. Thirty-nine (59%) of the 66 patients had severe or debilitating (WHO grade 3 or 4) bleeding. The median platelet count on the day of grade 3 or 4 bleeding was 23 × 109 per litre (IQR 13-39). Nine patients (8%) died in ICU following a bleeding episode; five of these had intra-cerebral haemorrhage. Platelet count on admission was associated with subsequent bleeding (adjusted odds ratio 1.18 (95% CI 1.03-1.35) for every 10 × 109 per litre drop in platelet count, p = 0.016). Eleven of the 116 patients (9%) developed a clinically significant thrombosis in ICU, which was the cause of death in four patients. The median platelet count was 20 × 109 per litre (15-48) at the time of thrombosis. The patients received a median of 6 units of red blood cells, 1 unit of fresh frozen plasma and 8 units of platelet concentrates in ICU. CONCLUSIONS: Severe and debilitating bleeding complications were frequent in our ICU patients with haematological malignancies, but thrombosis also occurred in spite of low platelet counts. Platelet count on ICU admission was associated with subsequent bleeding.

Simplified Mortality Score for the Intensive Care Unit (SMS-ICU): protocol for the development and validation of a bedside clinical prediction rule.

INTRODUCTION: Mortality prediction scores are widely used in intensive care units (ICUs) and in research, but their predictive value deteriorates as scores age. Existing mortality prediction scores are imprecise and complex, which increases the risk of missing data and decreases the applicability bedside in daily clinical practice. We propose the development and validation of a new, simple and updated clinical prediction rule: the Simplified Mortality Score for use in the Intensive Care Unit (SMS-ICU). METHODS AND ANALYSIS: During the first phase of the study, we will develop and internally validate a clinical prediction rule that predicts 90-day mortality on ICU admission. The development sample will comprise 4247 adult critically ill patients acutely admitted to the ICU, enrolled in 5 contemporary high-quality ICU studies/trials. The score will be developed using binary logistic regression analysis with backward stepwise elimination of candidate variables, and subsequently be converted into a point-based clinical prediction rule. The general performance, discrimination and calibration of the score will be evaluated, and the score will be internally validated using bootstrapping. During the second phase of the study, the score will be externally validated in a fully independent sample consisting of 3350 patients included in the ongoing Stress Ulcer Prophylaxis in the Intensive Care Unit trial. We will compare the performance of the SMS-ICU to that of existing scores. ETHICS AND DISSEMINATION: We will use data from patients enrolled in studies/trials already approved by the relevant ethical committees and this study requires no further permissions. The results will be reported in accordance with the Transparent Reporting of multivariate prediction models for Individual Prognosis Or Diagnosis (TRIPOD) statement, and submitted to a peer-reviewed journal.

Benefits and harms of red blood cell transfusions in patients with septic shock in the intensive care unit.

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 use of 7-8 g/dl as the ''universal'' trigger level. Patients with acute myocardial ischaemia and patients with acute brain injury may need special considerations.

[The evidence for blood cell transfusions to non-bleeding, critically ill patients is sparse]. / Der er kun sparsom evidens for blodtransfusion til ikkeblødende kritisk syge patienter.

Critically ill non-bleeding patients often receive red blood cell transfusions in the intensive care unit because of anaemia. The evidence that transfusion leads to improved outcome is limited and the treatment may be harmful to some of these patients. Current recommendations support a restrictive transfusion strategy. Additional randomised clinical trials are needed to elucidate the association between specific haemoglobin levels, transfusion and morbidity and mortality in critically ill patients including those with severe sepsis and acute coronary syndrome.

Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial.

BACKGROUND: By tradition colloid solutions have been used to obtain fast circulatory stabilisation in shock, but high molecular weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis. Now lower molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICUs) and 1st choice fluid for patients with severe sepsis. However, HES 130/0.4 is largely unstudied in patients with severe sepsis. METHODS/DESIGN: The 6S trial will randomize 800 patients with severe sepsis in 30 Scandinavian ICUs to masked fluid resuscitation using either 6% HES 130/0.4 in Ringer's acetate or Ringer's acetate alone. The composite endpoint of 90-day mortality or end-stage kidney failure is the primary outcome measure. The secondary outcome measures are severe bleeding or allergic reactions, organ failure, acute kidney failure, days alive without renal replacement therapy or ventilator support and 28-day and 1/2- and one-year mortality. The sample size will allow the detection of a 10% absolute difference between the two groups in the composite endpoint with a power of 80%. DISCUSSION: The 6S trial will provide important safety and efficacy data on the use of HES 130/0.4 in patients with severe sepsis. The effects on mortality, dialysis-dependency, time on ventilator, bleeding and markers of resuscitation, metabolism, kidney failure, and coagulation will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00962156.