Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan.

BACKGROUND: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor. OBJECTIVE: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database. METHODS: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses. RESULTS: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status. CONCLUSIONS: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36261.

Renoprotection by remote ischemic conditioning during elective coronary revascularization: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Remote ischemic conditioning (RIC) has been recognized an emerging non-invasive approach for preventing acute kidney injury (AKI) in patients undergoing either elective coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). On the other hand, accumulating evidence has indicated the involving role of pre-CABG contrast usage for coronary angiography in post-surgery AKI risk. Along with the shortening time delay of CABG after coronary angiography, and the prevalent hybrid coronary revascularization (HCR), the AKI prevention by RIC has faced challenges following coronary revascuralization. METHODS: Randomized controlled trials (RCTs) were searched from Pubmed, EMBase, and Cochrane library (until May 2016). The primary outcome was postoperative AKI. The second outcomes were included the requirement for renal replacement therapy (RRT), and in-hospital or 30-day mortality. RESULTS: Twenty eligible RCTs (CABG, 3357 patients; PCI, 1501 patients) were selected. RIC significantly halved the incidence of AKI following PCI when compared with controls [n=1501; odds ratio (OR)=0.51; 95% CI, 0.32 to 0.82; P=0.006; I(2)=29.6%]. However, RIC did not affect the incidence of AKI following CABG (n=1850; OR=0.94; 95% CI, 0.73 to 1.19; P=0.586; I(2)=12.4%). The requirement for RRT and in-hospital mortality was not affected by RIC in CABG (n=2049, OR=1.04, P=0.87; n=1920, OR=0.89, P=0.7; respectively). CONCLUSIONS: Our meta-analysis suggests that RIC for preventing AKI following CABG has faced with challenges in terms of AKI, the requirement for RRT, and mortality. However, RIC shows a renoprotective benefit for PCI. Hence, our findings may infer the preserved renal effects of RIC in CABG with preconditioning before the coronary angiography, or in HCR.

A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol.

The efficacy of remote ischemic preconditioning (RIPC) in high-risk cardiac surgery is uncertain. In this study, 96 adults undergoing high-risk cardiac surgery were randomised to RIPC (3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion) or control. Main endpoints were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 h, worst post-operative acute kidney injury (AKI) based on RIFLE criteria, and noradrenaline duration. hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [810 ng/ml (IQR 527-1,724) vs. 634 ng/ml (429-1,012); ratio of means 1.41 (99.17% CI 0.92-2.17); P=0.04] and 12 h [742 ng/ml (IQR 427-1,700) vs. 514 ng/ml (IQR 356-833); ratio of means 1.56 (99.17% CI 0.97-2.53); P=0.01]. After adjustment for baseline confounders, the ratio of means of hsTNT at 6 h was 1.23 (99.17% CI 0.88-1.72; P=0.10) and at 12 h was 1.30 (99.17% CI 0.92-1.84; P=0.05). In the RIPC group, 35/48 (72.9%) had no AKI, 5/48 (10.4%) had AKI risk, and 8/48 (16.7%) had either renal injury or failure compared to the control group where 34/48 (70.8%) had no AKI, 7/48 (14.6%) had AKI risk, and 7/48 (14.6%) had renal injury or failure (Chi-squared 0.41; two degrees of freedom; P = 0.82). RIPC increased post-operative duration of noradrenaline support [21 h (IQR 7-45) vs. 9 h (IQR 3-19); ratio of means 1.70 (99.17% CI 0.86-3.34); P=0.04]. RIPC does not reduce hsTNT, AKI, or ICU-support requirements in high-risk cardiac surgery.

Early peak temperature and mortality in critically ill patients with or without infection.

PURPOSE: To determine whether fever is associated with an increased or decreased risk of death in patients admitted to an intensive care unit (ICU) with infection. METHODS: We evaluated the independent association between peak temperature in the first 24 h after ICU admission and in-hospital mortality according to whether there was an admission diagnosis of infection using a database of admissions to 129 ICUs in Australia and New Zealand (ANZ) (n = 269,078). Subsequently, we sought to confirm or refute the ANZ database findings using a validation cohort of admissions to 201 ICUs in the UK (n = 366,973). RESULTS: A total of 29,083/269,078 (10.8%) ANZ patients and 103,191/366,973 (28.1%) of UK patients were categorised as having an infection. In the ANZ cohort, adjusted in-hospital mortality risk progressively decreased with increasing peak temperature in patients with infection. Relative to the risk at 36.5-36.9°C, the lowest risk was at 39-39.4°C (adjusted OR 0.56; 95% CI 0.48-0.66). In patients without infection, the adjusted mortality risk progressively increased above 39.0°C (adjusted OR 2.07 at 40.0°C or above; 95% CI 1.68-2.55). In the UK cohort, findings were similar with adjusted odds ratios at corresponding temperatures of 0.77 (95% CI 0.71-0.85) and 1.94 (95% CI 1.60-2.34) for infection and non-infection groups, respectively. CONCLUSIONS: Elevated peak temperature in the first 24 h in ICU is associated with decreased in-hospital mortality in critically ill patients with an infection; randomised trials are needed to determine whether controlling fever increases mortality in such patients.