Second intravenous immunoglobulin dose in patients with Guillain-Barré syndrome with poor prognosis (SID-GBS): a double-blind, randomised, placebo-controlled trial
Walgaard C, Jacobs BC, Lingsma HF, Steyerberg EW, van den Berg B, Doets AY, Leonhard SE, Verboon C, Huizinga R, Drenthen J, et al
The Lancet. Neurology. 2021;20(4):275-283
BACKGROUND Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barré syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barré syndrome with a predicted poor outcome. METHODS In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barré syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barré syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7-9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barré syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. FINDINGS Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barré syndrome disability score at 4 weeks was 1·4 (95% CI 0·6-3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13-24 weeks after randomisation). INTERPRETATION Our study does not provide evidence that patients with Guillain-Barré syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barré syndrome. FUNDING Prinses Beatrix Spierfonds and Sanquin Plasma Products.
Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death
Fustolo-Gunnink SF, Fijnvandraat K, van Klaveren D, Stanworth S, Curley AE, Onland W, Steyerberg EW, de Kort E, d'Haens E, Hulzebos C, et al
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25x109/L compared to 50x109/L for major bleeding and/or mortality in preterm neonates (7% absolute risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25x109/L threshold. We aimed to assess this heterogeneity of treatment effect in the PlaNet-2 trial, in order to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariable logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into four risk quartiles. Within these quartiles we assessed absolute risk difference between the 50x109/L and 25x109/L threshold group. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval 0.58 - 0.68). The 25x109/L threshold was associated with absolute risk reduction in all risk groups, varying from 4.9% in the lowest to 12.3% in the highest risk group. These results suggest that a 25x109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. Current Controlled Trials number ISRCTN87736839.
Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository
Dijkland SA, Jaja BNR, van der Jagt M, Roozenbeek B, Vergouwen MDI, Suarez JI, Torner JC, Todd MM, van den Bergh WM, Saposnik G, et al
Journal of neurosurgery. 2019;:1-9
OBJECTIVE Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1-3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4-6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country. RESULTS The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16-1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11-1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00-1.40). CONCLUSIONS Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.
Early identification of patients requiring massive transfusion, embolization or hemostatic surgery for traumatic hemorrhage: a systematic review and meta-analysis
Tran A, Matar M, Lampron J, Steyerberg EW, Taljaard M, Vaillancourt C
The Journal of Trauma and Acute Care Surgery. 2017;84((3):):505-516
BACKGROUND Delays in appropriate triage of bleeding trauma patients result in poor outcomes. Clinical gestalt is fallible and objective measures of risk stratification are needed. The objective of this review is to identify and assess prediction models and predictors for the early identification of traumatic hemorrhage patients requiring massive transfusion, surgery or embolization. METHODS We searched electronic databases through to September 31st, 2016 for studies describing clinical, laboratory and imaging predictors available within the first hour of resuscitation for identifying patients requiring major intervention for hemorrhage within the first 24 hours. RESULTS We included 84 studies describing any predictor-outcome association, including 47 multivariable models; of these, 26 (55%) were specifically designed for prediction. We identified 35 distinct predictors of which systolic blood pressure, age, heart rate and mechanism of injury were most frequently studied. Quality of multivariable models was generally poor with only 21 (45%) meeting a commonly recommended sample size threshold of 10 events per predictor. From 21 models meeting this threshold, we identified 7 predictors that were examined in at least two models: mechanism of injury, systolic blood pressure, heart rate, hemoglobin, lactate and FAST. Pooled odds ratios were obtained from random-effects meta-analyses. CONCLUSION The majority of traumatic hemorrhagic prediction studies are of poor quality, as assessed by the PROGRESS recommendations and CHARMS checklist. There exists a need for a well-designed clinical prediction model for early identification of patients requiring intervention. The variables of clinical importance identified in this review are consistent with recent expert guideline recommendations and may serve as candidates for future derivation studies. LEVEL OF EVIDENCE Systematic review, Level III.