Effects of restrictive fluid therapy on the time to resolution of hyperlactatemia in ICU patients with septic shock. A secondary post hoc analysis of the CLASSIC randomized trial.

PURPOSE: The aim of this study was to examine the effects of intravenous (IV) fluid restriction on time to resolution of hyperlactatemia in septic shock. Hyperlactatemia in sepsis is associated with worse outcome. Sepsis guidelines suggest targeting lactate clearance to guide fluid therapy despite the complexity of hyperlactatemia and the potential harm of fluid overload. METHODS: We conducted a post hoc analysis of serial plasma lactate concentrations in a sub-cohort of 777 patients from the international multicenter clinical CLASSIC trial (restriction of intravenous fluids in intensive care unit (ICU) patients with septic shock). Adult ICU patients with septic shock had been randomized to restrictive (n = 385) or standard (n = 392) intravenous fluid therapy. The primary outcome, time to resolution of hyperlactatemia, was analyzed with a competing-risks regression model. Death and discharge were competing outcomes, and administrative censoring was imposed 72 h after randomization if hyperlactatemia persisted. The regression analysis was adjusted for the same stratification variables and covariates as in the original CLASSIC trial analysis. RESULTS: The hazard ratios (HRs) for the cumulative probability of resolution of hyperlactatemia, in the restrictive vs the standard group, in the unadjusted analysis, with time split, were 0.94 (confidence interval (CI) 0.78-1.14) at day 1 and 1.21 (0.89-1.65) at day 2-3. The adjusted analyses were consistent with the unadjusted results. CONCLUSION: In this post hoc retrospective analysis of a multicenter randomized controlled trial (RCT), a restrictive intravenous fluid strategy did not seem to affect the time to resolution of hyperlactatemia in adult ICU patients with septic shock.

A survey of preferences for respiratory support in the intensive care unit for patients with acute hypoxaemic respiratory failure.

BACKGROUND: When caring for mechanically ventilated adults with acute hypoxaemic respiratory failure (AHRF), clinicians are faced with an uncertain choice between ventilator modes allowing for spontaneous breaths or ventilation fully controlled by the ventilator. The preferences of clinicians managing such patients, and what motivates their choice of ventilator mode, are largely unknown. To better understand how clinicians' preferences may impact the choice of ventilatory support for patients with AHRF, we issued a survey to an international network of intensive care unit (ICU) researchers. METHODS: We distributed an online survey with 32 broadly similar and interlinked questions on how clinicians prioritise spontaneous or controlled ventilation in invasively ventilated patients with AHRF of different severity, and which factors determine their choice. RESULTS: The survey was distributed to 1337 recipients in 12 countries. Of these, 415 (31%) completed the survey either fully (52%) or partially (48%). Most respondents were identified as medical specialists (87%) or physicians in training (11%). Modes allowing for spontaneous ventilation were considered preferable in mild AHRF, with controlled ventilation considered as progressively more important in moderate and severe AHRF. Among respondents there was strong support (90%) for a randomised clinical trial comparing spontaneous with controlled ventilation in patients with moderate AHRF. CONCLUSIONS: The responses from this international survey suggest that there is clinical equipoise for the preferred ventilator mode in patients with AHRF of moderate severity. We found strong support for a randomised trial comparing modes of ventilation in patients with moderate AHRF.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

BACKGROUND: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan.

INTRODUCTION: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. METHODS: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.

The effect of perioperative glucose control on postoperative insulin resistance.

BACKGROUND & AIMS: Postoperative insulin resistance and the consequent hyperglycemia affects clinical outcome. Insulin sensitivity may be modulated by preoperative nutrition, adequate pain management and minimal invasive surgery. This study aims to disclose the impact of perioperative glucose control on postoperative insulin resistance. METHODS: Twenty patients scheduled for elective open hepatectomy were enrolled in this prospective, randomized study. In the treatment group (n = 9) insulin was administered intravenously to keep blood glucose between 6 and 8 mmol/l during surgery. The control group (n = 8) received insulin if blood glucose >14 mmol/l. Insulin sensitivity was measured by a hyperinsulinemic normoglycemic clamp (0.8 mU/kg/min), performed on all patients both on the day before surgery and immediately postoperatively. Plasma cortisol, insulin and C-peptide were measured. RESULTS: There was a significant difference in mean glucose value during surgery. In the control group 8.8 mmol/l (SD 1.5) vs. 6.9 mmol/l (SD 0.4) in the treated group, p = 0.003. In the control group insulin sensitivity decreased to 21.9% ± 16.2% of the preoperative value and in the insulin treated group to 46.8 ± 15.5%, p < 0.005. Insulin levels were significantly higher in the treatment group as well as consequently lower C-peptide levels. CONCLUSIONS: This trial revealed a significant difference in postoperative insulin resistance in the group treated with insulin during surgery.