Factors associated with non-response at health-related quality of life follow-up in a septic shock trial.

BACKGROUND: Follow-up of intensive care unit (ICU) patients often includes health-related quality of life (HRQoL) surveying, but non-responders hamper the interpretation. Our aim was to assess factors for non-response to HRQoL survey in ICU patients with septic shock at follow-up in a clinical trial. METHODS: In a post hoc follow-up registry study, we assessed all the Danish survivors in the Transfusion-Requirements in Septic Shock trial patients, who were mailed the Short Form 36-item Survey (SF-36) 1-year after randomization. We used covariates from the trial database merged with covariates from nation-wide registries using the unique national identification number to explore possible factors for not responding. Five covariates were pre-specified to be included in the primary multivariate analysis: age, number of days in hospital from randomization to follow-up, level of education, cohabitation and employment status at follow-up. We compared the mortality from 1-year survival (2012-2014) till end of final follow-up (January 2016) between non-responders and responders. RESULTS: We assessed 308 survivors of whom 108 (35%) were non-responders. In the primary analysis lower age (odds ratio 1.03, 95% CI [1.01-1.05]), more admission days in hospital (1.006 [1.001-1.011]) and living alone (4.33 [2.46-7.63]) were associated with non-responding, whereas the level of education and employment status were not. Non-responders had a hazard ratio of 1.63 [0.97-2.72] for mortality from 1-year follow-up to final follow-up as compared to the responders. CONCLUSION: Being younger, spending more days in hospital and living alone were all associated with non-response at 1-year HRQoL follow-up among ICU patients with septic shock.

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.

Lower vs. higher fluid volumes in sepsis-protocol for a systematic review with meta-analysis.

BACKGROUND: Intravenous fluid administration with crystalloids is recommended in the initial management of sepsis. However, the quality of evidence supporting the recommendation on fluid volumes is low, and clinical equipoise exists. Potential benefits of restricting fluid volumes has been suggested, but the overall benefit or harm in patients with sepsis is unknown. Accordingly, we aim to assess patient-important benefits and harms of lower vs. higher fluid volumes in resuscitation of adult patients with sepsis. METHODS/DESIGN: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials comparing different strategies to obtain separation in fluid volumes or balances during resuscitation of adult patients with sepsis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: The outlined systematic review will provide important data on how patient-important outcomes are affected by higher vs. lower resuscitation fluid volumes in adults with sepsis. Using trial sequential analysis to assess the risk of random errors will increase the validity of the summary estimates calculated and help estimate the required information size for future trials.

Effects of hydroxyethyl starch 130/0.42 vs. Ringer's acetate on cytokine levels in severe sepsis.

BACKGROUND: The Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial showed increased 90-day mortality with hydroxyethyl starch (HES) 130/0.42 vs. Ringer's acetate. To explore the underlying pathophysiology, we compared early changes in plasma cytokine concentrations between patients resuscitated with HES vs. Ringer's acetate. METHODS: In a subgroup of 226 patients from the 6S trial, we calculated delta plasma concentrations of tumour necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-10 from randomization to day 2. We used multiple linear and logistic regression analyses to assess differences between the groups and associations between delta cytokine concentrations and 90-day mortality, respectively. RESULTS: Baseline characteristics and day 2 mortality were comparable between the groups. We observed similar delta cytokine concentrations in the HES vs. Ringer's group (mean difference in delta TNF-α: -1.5 pg/ml (95% CI, -4.9 to 1.9), P = 0.39; IL-6: 36.0 pg/ml (-24.1 to 96.1), P = 0.24; IL-10: -3.9 pg/ml (-21.1 to 28.9), P = 0.76). In all included patients, we observed a linear relationship between increases in TNF-α and 90-day mortality (P = 0.005). CONCLUSION: Resuscitation with HES 130/0.42 vs. Ringer's acetate did not appear to affect plasma concentrations of TNF-α, IL-6 or IL-10 differently during the first days after randomization into the 6S trial. In the overall cohort, increases in TNF-α were associated with increased 90-day mortality. Although interpretation should be done with caution, it seems unlikely that the increased mortality observed with the use HES in the 6S trial is signalled by early changes in three biomarkers of systemic inflammation.

Use of life support in acutely admitted ICU patients. An international cohort study.

BACKGROUND: Use of life support in intensive care unit (ICU) patients has been associated with increased risk of poor outcome. The prognostic importance of the duration of support is less studied. We assessed the use of life support and the association between its duration and 90-day mortality in a contemporary cohort of acutely admitted adult ICU patients. METHODS: We performed a post-hoc analysis of the SUP-ICU 7-day inception cohort study (n = 1034), which was conducted in 97 ICUs in 11 countries. We included patients with an ICU stay of 3 days or more. We assessed the use of life support during the first 3 days in ICU and the crude and adjusted association between its duration and 90-day mortality using logistic regression analyses. RESULTS: We included 690 patients; their 90-day mortality was 23%. During the first 3 days in ICU mechanical ventilation was used in 65%, vasopressors/inotropes in 57% and renal replacement therapy in 13%. Renal replacement therapy for 3 days or more was associated with a higher 90-day mortality as compared with 1 day of renal replacement therapy [odds ratio 6.5 (95% confidence interval 1.3 to 32.8)]. For mechanical ventilation and vasopressors/inotropes the odds ratios were 2.2 [0.9 to 5.3] and 1.2 [0.5 to 2.6], respectively. CONCLUSIONS: Among acutely admitted adult ICU patients, a higher number of days of renal replacement therapy in the initial ICU stay were associated with increased risk of death within 90 days. We did not observe such an association for mechanical ventilation or vasopressor/inotropic therapy.

Effects of fluid restriction on measures of circulatory efficacy in adults with septic shock.

BACKGROUND: The haemodynamic consequences of fluid resuscitation in septic shock have not been fully elucidated. Therefore, we assessed circulatory effects in the first 24 h of restriction of resuscitation fluid as compared to standard care in intensive care unit (ICU) patients with septic shock. METHODS: This was a post-hoc analysis of the multicentre CLASSIC randomised trial in which patients with septic shock, who had received the initial fluid resuscitation, were randomised to a protocol restricting resuscitation fluid or a standard care protocol in nine ICUs. The highest plasma lactate, highest dose of noradrenaline, and the urinary output were recorded in five time frames in the first 24 h after randomisation. We used multiple linear mixed effects models to compare the two groups. RESULTS: We included all 151 randomised patients; the cumulated fluid resuscitation volume in the first 24 h after randomisation was median 500 ml (Interquartile range (IQR) 0-1500) and 1250 ml (500-2500) in the fluid restriction group and standard care group, respectively. The estimated differences in the fluid restriction group vs. the standard care group were 0.1 mM (95% confidence interval -0.7 to 0.9; P = 0.86) for lactate, 0.01 µg/kg/min (-0.02 to 0.05; P = 0.48) for dose of noradrenaline, and -0.1 ml/kg/h (-0.3 to 0.2; P = 0.70) for urinary output during the first 24 h after randomisation. CONCLUSIONS: We observed no indications of worsening of measures of circulatory efficacy in the first 24 h of restriction of resuscitation fluid as compared with standard care in adults with septic shock who had received initial resuscitation.

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.

Predictive value of NGAL for use of renal replacement therapy in patients with severe sepsis.

BACKGROUND: The predictive value of plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) for use of renal replacement therapy (RRT) and acute kidney injury (AKI) is not established in patients with severe sepsis. METHODS: This was a prospective observational study in three general intensive care units (ICUs) in adult ICU patients with severe sepsis needing fluid resuscitation and a sub-study of the 6S trial. Plasma and urine were sampled at baseline and NGAL was measured using particle-enhanced turbidimetric immunoassay (The NGAL Test). Outcome measures were use of RRT in ICU, development of AKI according to the Kidney Disease: Improving Global Outcomes plasma creatinine criteria within 48 h and 90-day mortality. RESULTS: Two-hundred- twenty-two patients had samples taken (211 had plasma and 162 urine sampled); simplified acute physiology score II was 54 (39-66). Forty patients (18%) had RRT in the ICU, 91 patients had AKI at enrollment; of the remaining 131 patients 24% developed AKI during the first 48 h, and 55% had died at 90 days. Areas under receiver-operating characteristics curve (AuROC) for predicting use of RRT in ICU were 0.70 (95% confidence interval 0.61-0.78) and 0.62 (0.51-0.73) for plasma and urine NGAL, respectively. AuROC of plasma and urine NGAL for AKI were 0.66 (0.54-0.77) and 0.71 (0.59-0.82), respectively, and for 90-day mortality 0.55 (0.47-0.63) and 0.61 (0.53-0.70), respectively. Combining NGAL values with plasma creatinine did not improve AuROCs. CONCLUSION: In ICU patients with severe sepsis, plasma and urine NGAL had low predictive power for use of RRT, AKI and 90-day mortality. These results were supported by sensitivity and exploratory analyses.