Effects of simulated sample sizes on mortality estimates-Protocol for a study in 3 randomised ICU trials.

BACKGROUND: An increasing number of trials are stopped earlier than originally planned. It has been suggested that trials stopped pre-maturely overestimate the treatment effect. With the outlined observational study, we aim to simulate the results of stopping trials before they reach their planned sample size to assess the effects on mortality estimates. METHODS AND STATISTICS: Based on 3 international, randomised clinical trials (RCTs) in critical care: Scandinavian Starch for Severe Sepsis and Septic Shock (6S) trial, the Transfusion Requirements in Septic Shock (TRISS) trial and the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, we will estimate relative risks with 95% confidence intervals for the primary outcome 90-day mortality after the inclusion of each individual patient in each RCT. This will be presented graphically with the primary outcome as a function of the number of included patients. DISCUSSION: The outlined study will provide important knowledge about the effects of stopping critical care trials early. This may have important implications for patients, relatives, clinicians, researchers, guideline committee members and policy makers. ETHICS AND DISSEMINATION: We will use data from consenting patients enrolled in RCTs approved by the relevant ethical committees; this study requires no further permissions. We will report the results in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and submit the final approved manuscript to a peer-reviewed journal.

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

BACKGROUND: Intensive care unit (ICU) mortality prediction scores deteriorate over time, and their complexity decreases clinical applicability and commonly causes problems with missing data. We aimed to develop and internally validate a new and simple score that predicts 90-day mortality in adults upon acute admission to the ICU: the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU). METHODS: We used data from an international cohort of 2139 patients acutely admitted to the ICU and 1947 ICU patients with severe sepsis/septic shock from 2009 to 2016. We performed multiple imputations for missing data and used binary logistic regression analysis with variable selection by backward elimination, followed by conversion to a simple point-based score. We assessed the apparent performance and validated the score internally using bootstrapping to present optimism-corrected performance estimates. RESULTS: The SMS-ICU comprises seven variables available in 99.5% of the patients: two numeric variables: age and lowest systolic blood pressure, and five dichotomous variables: haematologic malignancy/metastatic cancer, acute surgical admission and use of vasopressors/inotropes, respiratory support and renal replacement therapy. Discrimination (area under the receiver operating characteristic curve) was 0.72 (95% CI: 0.71-0.74), overall performance (Nagelkerke's R2 ) was 0.19 and calibration (intercept and slope) was 0.00 and 0.99, respectively. Optimism-corrected performance was similar to apparent performance. CONCLUSIONS: The SMS-ICU predicted 90-day mortality with reasonable and stable performance. If performance remains adequate after external validation, the SMS-ICU could prove a valuable tool for ICU clinicians and researchers because of its simplicity and expected very low number of missing values.

Higher vs. lower haemoglobin threshold for transfusion in septic shock: subgroup analyses of the TRISS trial.

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.

Effects of red blood cell storage time on transfused patients in the ICU-protocol for a systematic review.

BACKGROUND: Patients in the intensive care unit (ICU) are often anaemic due to blood loss, impaired red blood cell (RBC) production and increased RBC destruction. In some studies, more than half of the patients were treated with RBC transfusion. During storage, the RBC and the storage medium undergo changes, which lead to impaired transportation and delivery of oxygen and may also promote an inflammatory response. Divergent results on the clinical consequences of storage have been reported in both observational studies and randomised trials. Therefore, we aim to gather and review the present evidence to assess the effects of shorter vs. longer storage time of transfused RBCs for ICU patients. METHODS: We will conduct a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials, and also include results of severe adverse events from large observational studies. Participants will be adult patients admitted to an ICU and treated with shorter vs. longer stored RBC units. We will systematically search the Cochrane Library, MEDLINE, Embase, BIOSIS, CINAHL and Science Citation Index for relevant literature, and we will follow the recommendation by the Cochrane Collaboration and the Preferred Reporting Items for Systemtic Review and Meta-Analysis (PRISMA)-statement. We will assess the risk of bias and random errors, and we will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to evaluate the overall quality of evidence. CONCLUSION: We need a high-quality systematic review to summarise the clinical consequences of RBC storage time among ICU patients.

Association between fluid balance and mortality in patients with septic shock: a post hoc analysis of the TRISS trial.

BACKGROUND: Several studies have shown an association between a positive fluid balance and increased mortality in patients with septic shock. This may have led to a more restrictive use of intravenous fluids. The association between fluid accumulation and mortality in the setting of a more restrictive use of intravenous fluids, however, is uncertain. We therefore aimed to investigate the association between a cumulative fluid balance 3 days after randomization and 90-day mortality in a recent Nordic multicentre cohort of patients with septic shock. METHODS: A post hoc analysis of patients from the Transfusion Requirements in Septic Shock (TRISS) trial treated for 3 days or more in the ICU after randomization. The patients were categorized into four groups depending on their weight-adjusted cumulative fluid balance after 3 days. We performed multivariable Cox regression analysis, adjusting for important prognostics (study site, age, chronic cardiovascular and chronic lung disease, haematologic malignancy, chronic dialysis, source of infection, baseline SOFA score and plasma lactate). RESULTS: The median cumulative fluid balance of the 841 included patients was 2480 ml (IQR 47-5045). The median time from ICU admission to inclusion in the trial was 22 h. The overall 90-day mortality was 52%. There was no statistically significant association between fluid balance 3 days from inclusion and 90-day mortality after the adjustment for the prognostics (P = 0.37). CONCLUSION: In our cohort of patients with septic shock and a comparably low cumulative fluid balance, there was no association between fluid balance and mortality. However, the study design and the limited power preclude strong conclusions. There is an urgent need for high-quality trials assessing the benefit and harm of different fluid volume strategies in patients with septic shock.

Variability in targeted arterial oxygenation levels in patients with severe sepsis or septic shock.

BACKGROUND: Supplemental oxygen therapy is used for intensive care (ICU) patients with severe sepsis, but with no general guidelines and few safety data. The aim of this observational study was to describe the variability in oxygen administration as well as the association between partial pressure of arterial oxygen (PaO2 ) and mortality. METHODS: We extracted data from two Scandinavian clinical trials of ICU patients with severe sepsis or septic shock. We calculated average PaO2 and fraction of inspired oxygen (FiO2 ) from trial inclusion and the following 5 days, and assessed the association between PaO2 and 90-day mortality. RESULTS: The median PaO2 was 9.8 kPa [5-95% range 6.4-19.9] and FiO2 was 0.51 [5-95% range 0.27-1.00], respectively. Eight hundred and five of 1,770 patients (45%) died. The relative risk of mortality was 1.43 [95% CI: 1.19-1.65] in patients with average PaO2 < 8 kPa and 1.29 [95% CI: 0.84-1.68] in patients with average PaO2 ≥ 16 kPa, as compared to patients with average PaO2 10-12 kPa. The relative risk of mortality was 1.38 [95% CI: 1.17-1.58] in patients with an average FiO2 0.60-0.80 and 2.10 [95% CI: 1.88-2.23] in patients with an average FiO2  ≥ 0.80 as compared to patients with an average FiO2  ≤ 0.40. CONCLUSION: Administration of oxygen in patients with severe sepsis resulted in a wide range of PaO2 . Significantly higher mortality was observed in patients with an average PaO2 < 8 kPa and FiO2 ≥ 0.60. The results do not imply causation and the associations between average PaO2 and adverse outcomes have to be assessed further.

Red blood cell transfusion during septic shock in the ICU.

BACKGROUND: Transfusion of red blood cells (RBCs) remains controversial in patients with septic shock, but current practice is unknown. Our aim was to evaluate RBC transfusion practice in septic shock in the intensive care unit (ICU), and patient characteristics and outcome associated with RBC transfusion. METHODS: Prospective cohort study of all adult patients with septic shock (n = 164) in six general ICUs during a 3-month period. Characteristics, other treatments, monitoring and outcome were compared in RBC-transfused and -non-transfused patients. RESULTS: Ninety-nine patients (95% confidence interval 87-111) received a median 900 ml (interquartile range 490-1405) of RBC during septic shock in ICU. Among transfused patients, there were more females [49/99 (49%) vs. 22/65 (34%), P = 0.048] and surgical patients [39/99 (39%) vs. 14/65 (22%), P = 0.02] than among patients not transfused. Also, admission simplified acute physiology score II was higher and minimal haemoglobin levels (days 1-3) were lower in transfused patients compared with those not transfused. In contrast, age, markers of shock and severity organ failure assessment score on day 1 and 90-day mortality did not differ between RBC-transfused and -non-transfused patients. CONCLUSIONS: Most patients with septic shock received RBCs during shock, and these patients had higher disease severity and lower haemoglobin levels than those not transfused. In spite of this, mortality did not differ between groups neither in the unadjusted or adjusted analyses. However, neither the design nor the sample size allows us to make inferences about treatment effects, which underlines the need for large randomised, clinical trials on transfusion in septic shock.