Neurologically deceased organ donors (NDDs) generally display an immune response involving an intense production of pro-inflammatory cytokines referred to as the cytokine storm. The sudden surge of ...inflammatory mediators in circulation promotes tissue and organ damages and ultimately leads to poor transplant outcome. As microRNAs (miRNAs) are frequently proposed as key regulators of inflammation and are relatively stable in circulation, changes in their profiles could play a role in the onset of the cytokine storm in NDDs. In this proof-of-concept study, we sought to investigate differentially abundant circulating miRNAs in a temporal manner between neurological death and organ recovery and to assess the association between specific miRNAs and levels of inflammatory cytokines in blood. Plasma samples from five NDDs were obtained at multiple time points between organ donation consent and organ recovery. Using a time-course analysis and miRNA sequencing, we identified 32 plasma miRNAs fluctuating between consent and organ recovery (false discovery rate; q-value < 0.1). Eleven miRNAs relatively abundant (>100 reads) and detected in all samples were selected for further biological pathway analysis (miR-486-3p, miR-103a-3p, miR-106b-3p, miR-182-5p, miR-101-3p, miR-10a-5p, miR-125a-5p, miR-146b-5p, miR-26a-5p, miR-423-5p, miR-92b-3p). These miRNAs targeted genes such as c-JUN (TNF signalling pathway) and eEF2 (AMPK pathway), suggesting a potential role in regulation of inflammation. Our results contribute to a better understanding of the miRNAs dynamic after neurological death in organ donors and could potentially be used to predict the related early cytokine storm.Trial registration: ClinicalTrials.gov ID NCT03786991. Registered December 2018
Purpose
Canadian donor management practices have not been reported. Our aim was to inform clinicians and other stakeholders about the range of current practices.
Methods
This prospective ...observational cohort study enrolled consecutive, newly consented organ donors from August 1 2015 to July 31 2018 at 27 academic and five community adult intensive care units in British Columbia, Alberta, Ontario, and Quebec. Research staff prospectively recorded donor management data. Provincial organ donation organizations verified the organs donated. We formally compared practices across provinces.
Results
Over a median collection period of eight months, 622 potential donors were classified at baseline as having neurologic determination of death (NDD donors;
n
= 403) or circulatory death (DCD donors;
n
= 219). Among NDD donors, 85.6% underwent apnea testing (rarely with carbon dioxide insufflation), 33.2% underwent ancillary testing, and subsequent therapeutic hypothermia (34–35°C) was rare. Neurologic determination of death donors were more hemodynamically unstable with most having received vasopressin and norepinephrine infusions, with a large majority having received high-dose corticosteroids and intravenous thyroxine. Among DCD donors, 61.6% received corticosteroids, and 8.9% received thyroxine. Most donors did not receive lung-protective ventilation strategies. Invasive procedures after donation consent included bronchoscopy (71.7%), cardiac catheterization (NDD donors only; 21.3%), and blood transfusions (19.3%). Physicians ordered intravenous antemortem heparin for 94.8% of DCD donors. The cohort donated 1,629 organs resulting in 1,532 transplants. Case selection, death determinations, and hormone, nutrition and heparin practices all varied across provinces.
Conclusion
These study findings highlight areas for knowledge translation and further clinical research. Interprovincial discrepancies will likely pose unique challenges to national randomized trials.
Trial registration
: www.clinicaltrials.gov (NCT03114436); registered 10 April, 2017.
The aim of this review is to describe the use of usual care arms in randomized trials.
Randomization of patients to an experimental or a control arm remains paramount for the estimation of average ...causal effects. Selection of the control arm is as important as the definition of the intervention, and it might include a placebo control, specific standards of care, protocolized usual care, or unrestricted clinical practice. Usual care control arms may enhance generalizability, clinician acceptability of the protocol, patient recruitment, and ensure community equipoise, while at the same time introducing significant variability in the care delivered in the control group. This effect may reduce the difference in treatments delivered between the two groups and lead to a negative result or the requirement for a larger sample size. Moreover, usual care control groups can be subject to changes in clinician behavior induced by the trial itself, or by secular trends in time.
Usual care control arms may enhance generalizability while introducing significant limitations. Potential solutions include the use of pretrial surveys to evaluate the extent to which a protocolized control arm reflects the current standard of care and the implementation of adaptive trials.
High-dose vitamin C is increasingly used for sepsis and more recently for coronavirus disease 2019 (COVID-19) infections. Proponents argue that the low cost and near perfect safety profile of vitamin ...C support its early adoption. Yet, adverse events might be underreported and underappreciated.
We report a 73-year-old non-diabetic white man with end-stage renal disease on peritoneal dialysis admitted to the intensive care unit with septic shock that was suspected to be due to peritonitis. The patient was enrolled in LOVIT (Lessening Organ Dysfunction with VITamin C; ClinicalTrials.gov identifier: NCT03680274), a randomized placebo-controlled trial of high-dose intravenous vitamin C. He developed factitious hyperglycemia, as measured with a point-of-care glucometer, that persisted for 6 days after discontinuation of the study drug, confirmed to be vitamin C after unblinding. He also had short-lived iatrogenic coma because of hypoglycemia secondary to insulin administration. These events triggered a protocol amendment.
Although factitious hyperglycemia has been reported before using certain glucometers in patients treated with high-dose vitamin C, the persistence of this phenomenon for 6 days after the discontinuation of the therapy is a distinguishing feature. This case highlights the importance of monitoring glucose with a core laboratory assay for up to a week in specific populations, such as patients on peritoneal dialysis.
To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing ...probiotics for critically ill patients.
In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety.
Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 32%) and the informed consent process (133/566 23%). Most observations were missing operational records (438/566 77%) rather than errors in process (128/566 23%). Of 75 findings, 13 (62/566 observations 11%) posed a potential threat to data integrity, 1 (1/566 observation 0.18%) to patient privacy, and 9 (49/566 observations 8.7%) to patient safety.
Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety.
Trial Registration: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.
•We analyzed monitoring and auditing visits for a randomized trial in the ICU•Visit findings mostly concerned missing documentation rather than errors•There were minimal threats to data integrity, patient privacy or safety
In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. ...However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old.
For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: 1 at least 1 month before the trial started, and 2 during the trial period and randomized to usual care, or not enrolled in the trial.
We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 63.0% vs. n = 153 66.8%; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76).
The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.
The burden of sepsis is high in India and is associated with substantial morbidity and mortality. Vitamin C, an endogenous antioxidant, may improve patient outcomes.
This was a parallel-group pilot ...feasibility randomized controlled trial conducted at 2 intensive care units in India. Adult patients (≥18 years) with proven or suspected infection as the main diagnosis and needing a continuous intravenous vasopressor infusion were randomized to intravenous vitamin C (50 mg/kg every 6 hours for a maximum of 16 doses) or matching placebo. Primary outcomes were related to protocol adherence and feasibility (enrollment per month). The key secondary outcome was the composite of mortality or persistent organ dysfunction (POD) at day 28 after randomization.
60 patients were screened, 51 were eligible, 32 were randomized, and 30 were included in the analysis (randomized/eligible ratio: 0.63). The overall rate of enrollment was 1.5 patients per month. The median (IQR) age was 63.5 (51.0, 70.0) and 70.0% of the patients were male. In both arms, all patients received ≥90% of scheduled doses of the study drug. No patient received open-label vitamin C and there were no deviations from the glucose monitoring protocol. The composite outcome of mortality or POD at day 28 occurred in 56.3% (9/16) in the vitamin C arm as compared to 42.9% (6/14) in the placebo arm RR: 1.31 (95% CI: 0.62, 2.76),
= 0.47.
In this pilot feasibility randomized controlled trial of vitamin C for adult patients with sepsis, protocol adherence was excellent and feasibility endpoints were met.
CTRI/2020/03/024371.
Vijayaraghavan BKT, Venkataraman R, Ramanathan Y, Margabandhu S, Jayakumar D, Ramachandran P,
. A Pilot Feasibility Randomized Controlled Trial of Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit: The Lessening Organ Dysfunction with Vitamin C-India (LOVIT-India) Trial. Indian J Crit Care Med 2023;27(12):910-916.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Introduction
The aim of this study was to assess the efficacy and safety of fluocinolone acetonide implant (FAci) injected 1 month after the last dexamethasone intravitreal implant (DEXi) in chronic ...diabetic macular oedema (DME) patients.
Methods
Retrospective multicentric study conducted in pseudophakic patients with chronic DME frequently treated with dexamethasone intravitreal implant (DEXi; time to DME recurrence ≤ 6 months), receiving FAci 1 month after the last DEXi, with at least a 6-month follow-up. Best-corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography, intraocular pressure (IOP) and additional treatments were assessed on the day of FAci injection (M0), 1 (M1) and 3 months (M3) later and then every 3 months.
Results
A total of 41 eyes from 34 patients were included. At M0, patients’ mean age was 68.7 ± 9.8 years, the mean DME duration was 63.9 ± 22.9 months, the mean interval between two DEXi was 14.2 ± 3.3 weeks. M12 data were available for 71% of patients. At baseline, the mean BCVA, CMT and IOP were 63.2 ± 16.6 letters, 299.4 ± 103.3 µm, and 16.2 ± 4.5 mmHg, respectively, and remained stable during the follow-up. At M12, 14% of patients required additional intravitreal treatments.
Conclusion
In pseudophakic patients with chronic DME showing good response to DEXi but requiring repeated injections every < 6 months, switching to FAci 1 month after the last DEXi was effective and safe. Further prospective randomized controlled studies are needed to confirm these findings, and to determine the best interval between the last DEXi and the first FAci.
IntroductionObservational evidence suggests physiological benefits and lower mortality with lower chloride solutions; however, 0.9% saline remains the most widely used fluid worldwide. Given ...uncertainty regarding the association of lower chloride on mortality, it is unlikely that practice will change without direct randomised clinical trial (RCT) evidence. This pilot RCT will investigate the feasibility of a large-scale trial directly comparing low chloride with high chloride fluids in patients with septic shock.Methods and analysisThis is a randomised, concealed, blinded parallel-group multicentre pilot trial. We will include adult critically ill patients with septic shock, defined as ongoing hypotension despite 1 L of fluid, or a serum lactate >4 mmol/L, who are within 6 hours of hospital presentation or rapid response team activation. We will exclude patients if they have an aetiology of shock other than sepsis, if they have acute burn injury, elevated intracranial pressure, intent to withdraw life support or previous enrolment in this or a competing trial. Following informed consent, patients will be randomised to a low chloride fluid strategy or a high chloride fluid strategy for the duration of their ICU stay or until 30 days postrandomisation. Clinicians, patients, families and research staff will be blinded. The primary outcome for this trial will be feasibility, assessed by consent rate, recruitment success and protocol adherence. Patient-important clinical outcomes include mortality, receipt of renal replacement therapy, intensive care unit and hospital lengths of stay and surrogate outcomes of incidence of acidosis, hyperkalaemia and acute kidney injury.Ethics and disseminationThis pilot trial will test the feasibility of conducting the main trial, which will examine the effect of high versus low chloride fluids in patients with septic shock on patient-important outcomes.Trial registration numberNCT02748382, registered 8 April 2016.Protocol date1 July 2016.
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