Ceragenin-coated endotracheal tubes for the reduction of ventilator-associated pneumonia: a prospective, longitudinal, cross-over, interrupted time, implementation study protocol (CEASE VAP study).

BACKGROUND: Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes. METHODS: In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay. ETHICS AND DISSEMINATION: This study has been approved by the Health Sciences Research Ethics Board at Queen's University. The results of this study will be actively disseminated through manuscript publication and conference presentations. TRIAL REGISTRATION NUMBER: NCT05761613.

Non-ECG-gated cardiac CT angiography in acute stroke is feasible and detects sources of embolism.

BACKGROUND: A significant portion of cryptogenic stroke is hypothesized to be secondary to cardiac embolism. However, transthoracic echocardiogram is usually delayed after stroke, and more detailed cardiac imaging is not routinely done. AIMS: This study aimed to determine whether non-ECG-gated cardiac CT angiography (cCTA) during hyperacute stroke would provide diagnostic quality images and act as an adjunct modality of cardiac imaging to detect sources of emboli. METHODS: In this single-center prospective cohort study, modified Code Stroke imaging was implemented with a 64-slice CT scanner, where the longitudinal axis of CT angiography was extended from the carina to the diaphragm. The primary outcomes of image quality, recruitment feasibility, impact on hyperacute time metrics, and additional radiation dose were assessed. Secondary outcomes consisted of detection of high-risk cardiac sources of embolism, mediastinal or lung pathology, and impact on etiologic classification. RESULTS: One hundred and twenty eligible patients were enrolled, of which 105 (87.5%) had good/moderate quality images for motion artifact and 119 (99.2%) for contrast opacification. Total CT time, door-to-needle time, and door-to-groin puncture time were unchanged with the addition of cCTA. Eighty-nine patients received a final diagnosis of ischemic stroke, of which 12/89 (13.5%) had high-risk cardioembolic findings on cCTA. Incidental findings, such as pulmonary embolism (PE) (7/89, 7.9%) and malignancy (6/89, 6.7%), were observed. cCTA led to changes in management for 19/120 (15.8%) of all patients, and reclassification of stroke etiology for 8/89 (9%) of patients. CONCLUSIONS: Non-ECG-gated cCTA can be feasibly incorporated into Code Stroke and provide diagnostic quality images without delays in hyperacute time metrics. It can detect high-risk cardiac sources, and other findings impacting patient care. This may help reclassify a subset of cryptogenic stroke cases and improve secondary prevention.

Neurologic Physiology after Removal of Therapy (NeuPaRT) study: study protocol of a multicentre, prospective, observational, pilot feasibility study of neurophysiology after withdrawal of life-sustaining measures.

INTRODUCTION: In donation after circulatory determination of death, death is declared 5 min after circulatory arrest. This practice assumes, but does not explicitly confirm, permanent loss of brain activity. While this assumption is rooted a strong physiological rationale, paucity of direct human data regarding temporal relationship between cessation of brain activity and circulatory arrest during the dying process threatens public and healthcare provider trust in deceased organ donation. METHODS AND ANALYSIS: In this cohort study, we will prospectively record cerebral and brainstem electrical activity, cerebral blood flow velocity and arterial blood pressure using electroencephalography (EEG), brainstem evoked potentials, transcranial doppler and bedside haemodynamic monitors in adult patients undergoing planned withdrawal of life sustaining measures in the intensive care units at five hospital sites for 18 months. We will use MATLAB to synchronise waveform data and compute the time of cessation of each signal relative to circulatory arrest. Our primary outcome is the feasibility of patient accrual, while secondary outcomes are (a) proportion of patients with complete waveform recordings and data transfer to coordinating site and (b) time difference between cessation of neurophysiological signals and circulatory arrest. We expect to accrue 1 patient/site/month for a total of 90 patients. ETHICS AND DISSEMINATION: We have ethics approval from Clinical Trials Ontario (protocol #3862, version 1.0, date 19 January 2022.) and the relevant Research Ethics Board for each site. We will obtain written informed consent from legal substitute decision makers. We will present study results at research conferences including donor family partner forum and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05306327.

Haemoglobin transfusion threshold in traumatic brain injury optimisation (HEMOTION): a multicentre, randomised, clinical trial protocol.

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability in young adults. Despite the high prevalence of anaemia and red blood cell transfusion in patients with TBI, the optimal haemoglobin (Hb) transfusion threshold is unknown. We undertook a randomised trial to evaluate whether a liberal transfusion strategy improves clinical outcomes compared with a restrictive strategy. METHODS AND ANALYSIS: HEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatiON is an international pragmatic randomised open label blinded-endpoint clinical trial. We will include 742 adult patients admitted to an intensive care unit (ICU) with an acute moderate or severe blunt TBI (Glasgow Coma Scale ≤12) and a Hb level ≤100 g/L. Patients are randomly allocated using a 1:1 ratio, stratified by site, to a liberal (triggered by Hb ≤100 g/L) or a restrictive (triggered by Hb ≤70 g/L) transfusion strategy applied from the time of randomisation to the decision to withdraw life-sustaining therapies, ICU discharge or death. Primary and secondary outcomes are assessed centrally by trained research personnel blinded to the intervention. The primary outcome is the Glasgow Outcome Scale extended at 6 months. Secondary outcomes include overall functional independence measure, overall quality of life (EuroQoL 5-Dimension 5-Level; EQ-5D-5L), TBI-specific quality of life (Quality of Life after Brain Injury; QOLIBRI), depression (Patient Health Questionnaire; PHQ-9) and mortality. ETHICS AND DISSEMINATION: This trial is approved by the CHU de Québec-Université Laval research ethics board (MP-20-2018-3706) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT03260478.

Identifying neurocognitive outcomes and cerebral oxygenation in critically ill adults on acute kidney replacement therapy in the intensive care unit: the INCOGNITO-AKI study protocol.

INTRODUCTION: Initiation of acute kidney replacement therapy (KRT) is common in critically ill adults admitted to the intensive care unit (ICU), and associated with increased morbidity and mortality. KRT has been linked to poor neurocognitive outcomes, leading to reduced quality of life and increased utilisation of healthcare resources. Adults on dialysis in the ICU may be particularly at risk of neurocognitive impairment, as survivors of critical illness are already predisposed to developing cerebrovascular disease and cognitive dysfunction long-term relative to healthy controls. Regional cerebral oxygen saturation may provide a critical early marker of long-term neurocognitive impairment in this population. This study aims to understand cerebral oxygenation in patients undergoing KRT (continuous or intermittent) in the ICU. These findings will be correlated with long-term cognitive and functional outcomes, and structural brain pathology. METHODS AND ANALYSIS: 108 patients scheduled to undergo treatment for acute kidney injury with KRT in the Kingston Health Sciences Centre ICU will be recruited into this prospective observational study. Enrolled patients will be assessed with intradialytic cerebral oximetry using near infrared spectroscopy. Delirium will be assessed daily with the Confusion Assessment Method-ICU (CAM-ICU) and severity quantified as cumulative CAM-ICU-7 scores. Neurocognitive impairment will be assessed at 3 and 12 months after hospital discharge using the Kinarm and Repeatable Battery for the Assessment of Neuropsychological Status. Structural brain pathology on MRI will also be measured at the same timepoints. Driving safety, adverse events and medication adherence will be assessed at 12 months to evaluate the impact of neurocognitive impairment on functional outcomes. ETHICS AND DISSEMINATION: This study is approved by the Queen's University Health Sciences/Affiliated Teaching Hospitals Research Ethics Board (DMED-2424-20). Results will be presented at critical care conferences, and a lay summary will be provided to patients in their preferred format. TRIAL REGISTRATION NUMBER: NCT04722939.

Cerebral Perfusion in Hemodialysis Patients: A Feasibility Study.

BACKGROUND: Patients on hemodialysis (HD) are known to exhibit low values of regional cerebral oxygenation (rSO2) and impaired cognitive functioning. The etiology of both is currently unknown. OBJECTIVE: To determine the feasibility of serially monitoring rSO2 in patients initiating HD. In addition, we sought to investigate how rSO2 is related to hemodynamic and dialysis parameters. DESIGN: Prospective observational study. SETTING: Single-center tertiary academic teaching hospital in Ontario, Canada. PARTICIPANTS: Six patients initiating HD were enrolled in the study. METHODS: Feasibility was defined as successful study enrollment (>1 patient/month), successful consent rate (>70%), high data capture rates (>90%), and assessment tolerability. Regional cerebral oxygenation monitoring was performed 1 time/wk for the first year of dialysis. A neuropsychological battery was performed 3 times during the study: before dialysis initiation, 3 months, and 1 year after dialysis initiation. The neuropsychological battery included a traditional screening tool: the Repeatable Battery for the Assessment of Neuropsychological Status, and a robot-based assessment: Kinarm. RESULTS: Our overall consent rate was 33%, and our enrollment rate was 0.4 patients/mo. In total 243 rSO2 sessions were recorded, with a data capture rate of 91.4% (222/243) across the 6 patients. Throughout the study, no adverse interactions were reported. Correlations between rSO2 with hemodynamic and dialysis parameters showed individual patient variability. However, at the individual level, all patients demonstrated positive correlations between mean arterial pressure and rSO2. Patients who had more than 3 liters of fluid showed significant negative correlations with rSO2. Less cognitive impairment was detected after initiating dialysis. LIMITATION: This small cohort limits conclusions that can be made between rSO2 and hemodynamic and dialysis parameters. CONCLUSIONS: Prospectively monitoring rSO2 in patients was unfeasible in a single dialysis unit, due to low consent and enrollment rates. However, rSO2 monitoring may provide unique insights into the effects of HD on cerebral oxygenation that should be further investigated. TRIAL REGISTRATION: Due to the feasibility nature of this study, no trial registration was performed.

CONTEXTE: Les patients sous hémodialyse (HD) sont connus pour présenter de faibles valeurs de saturation cérébrale régionale (rSO2) et des fonctions cognitives altérées. L'étiologie de ces deux affections est actuellement inconnue. OBJECTIFS: Vérifier la faisabilité d'un suivi en série de la rSO2 chez des patients ayant amorcé des traitements d'HD. Nous souhaitions également étudier la façon dont la rSO2 est liée aux paramètres hémodynamiques et de dialyse. TYPE D'ÉTUDE: Étude observationnelle prospective. CADRE: Un centre hospitalier universitaire de soins tertiaires situé en Ontario, au Canada. SUJETS: L'étude porte sur six patients ayant amorcé des traitements d'HD. MÉTHODOLOGIE: La faisabilité a été définie par un recrutement efficace à l'étude (plus d'un patient/mois), un taux de consentement élevé (au-delà de 70 %), des taux de saisie de données élevés (au-delà de 90 %) et la tolérance de l'évaluation. La rSO2 a été mesurée une fois par semaine pendant la première année de dialyse. Une batterie neuropsychologique a été réalisée trois fois au cours de l'étude: avant l'initiation de la dialyse, puis trois mois et un an après l'initiation de la dialyse. La batterie de tests neuropsychologiques comprenait un outil de dépistage traditionnel: le Repeatable Battery for the Assessment of Neuropsychological Status, et une évaluation robotisée: Kinarm. RÉSULTATS: Le pourcentage global de consentement était de 33 % et le taux de recrutement était de 0,4 patient/mois. En tout, 243 mesures de la rSO2 ont été enregistrées, avec un taux de saisie des données de 91,4 % (222/243), chez les 6 patients inclus à l'étude. Aucune interaction indésirable n'a été signalée en cours d'étude. Les corrélations entre la rSO2 et les paramètres hémodynamiques et de dialyse étaient variables d'un patient à l'autre. Tous les patients ont cependant montré une corrélation positive entre la pression artérielle moyenne et la rSO2 d'un point de vue individuel. Des corrélations négatives significatives avec la rSO2 ont été observées chez les patients ayant plus de trois litres de liquides. Moins de troubles cognitifs ont été détectés après l'amorce de la dialyse. LIMITES: La faible taille de la cohorte limite les conclusions pouvant être tirées sur les liens entre la rSO2 et les paramètres hémodynamiques et de dialyse. CONCLUSION: Le suivi prospectif de la rSO2 chez les patients s'est avéré irréalisable dans cette unité de dialyse en raison des faibles taux de consentement et de recrutement. Le suivi de la rSO2 pourrait cependant fournir une perspective unique sur les effets de l'HD sur la saturation cérébrale, laquelle devrait être examinée plus attentivement.

Robotic technology quantifies novel perceptual-motor impairments in patients with chronic kidney disease.

BACKGROUND: Neurocognitive impairment is commonly reported in patients with chronic kidney disease (CKD). The precise nature of this impairment is unclear, due to the lack of objective and quantitative assessment tools used. The feasibility of using robotic technology to precisely quantify neurocognitive impairment in patients with CKD is unknown. METHODS: Patients with stage 4 and 5 CKD with no previous history of stroke or neurodegenerative disease were eligible for study enrollment. Feasibility was defined as successful study enrollment, high data capture rates (> 90%), and assessment tolerability. Our assessment included a traditional assessment: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and a robot-based assessment: Kinarm. RESULTS: Our enrollment rate was 1.6 patients/month. All patients completed the RBANS portion of the assessment, with a 97.8% (range 92-100%) completion rate on Kinarm. Missing data on Kinarm were mainly due to time constraints. Data from 49 CKD patients were analyzed. Kinarm defined more individuals as impaired, compared to RBANS, particularly in the domains of perceptual-motor function (17-49% impairment), complex attention (22-49% impairment), and executive function (29-37.5% impairment). Demographic features (sex and education) predicted performance on some, but not all neurocognitive tasks. CONCLUSIONS: It is feasible to quantify neurocognitive impairments in patients with CKD using robotic technology. Kinarm characterized more patients with CKD as impaired, and importantly identified novel perceptual-motor impairments in these patients, when compared to traditional assessments.

Variability in deceased donor care in Canada: a report of the Canada-DONATE cohort study.

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.

RéSUMé: OBJECTIF: Les pratiques canadiennes de prise en charge des donneurs n'ont pas été rapportées. Notre objectif était d'informer les cliniciens et autres parties intéressées quant à l'éventail des pratiques actuelles. MéTHODE: Cette étude de cohorte observationnelle et prospective a recruté des donneurs d'organes consécutifs ayant récemment consenti au don entre le 1er août 2015 et le 31 juillet 2018 dans 27 unités de soins intensifs universitaires et cinq unités de soins intensifs pour adultes en milieu communautaire en Colombie-Britannique, en Alberta, en Ontario et au Québec. Le personnel de recherche a enregistré de manière prospective les données de prise en charge des donneurs. Les organismes de dons d'organes provinciaux ont vérifié les organes donnés. Nous avons formellement comparé les pratiques d'une province à l'autre. RéSULTATS: Sur une période médiane de collecte de huit mois, 622 donneurs potentiels ont été catégorisés au départ comme ayant un diagnostic de décès neurologique (donneurs DDN; n = 403) ou un décès cardiocirculatoire (donneurs DDC; n = 219). Parmi les donneurs DDN, 85,6 % ont subi un test d'apnée (rarement avec insufflation de dioxyde de carbone), 33,2 % ont subi des tests complémentaires, et une hypothermie thérapeutique subséquente (34-35°C) était rare. Les donneurs par diagnostic de décès neurologique étaient plus instables hémodynamiquement, la plupart ayant reçu des perfusions de vasopressine et de norépinéphrine, et une vaste majorité de ces donneurs ont reçu des corticostéroïdes à forte dose ainsi que de la thyroxine intraveineuse. Parmi les donneurs par DDC, 61,6 % avaient reçu des corticostéroïdes, et 8,9 % de la thyroxine. La plupart des donneurs n'avaient pas bénéficié de stratégies de ventilation protectrice des poumons. Les interventions invasives réalisées après le consentement au don comprenaient la bronchoscopie (71,7 %), le cathétérisme cardiaque (donneurs DDN seulement; 21,3 %) et les transfusions sanguines (19,3 %). Les médecins ont prescrit de l'héparine intraveineuse ante mortem chez 94,8 % des donneurs DDC. La cohorte a donné 1629 organes, résultant en 1532 greffes. La sélection de cas, la détermination de décès et les pratiques hormonales, nutritionnelles et hépariniques variaient toutes d'une province à l'autre. CONCLUSION: Ces résultats soulignent des domaines propices à la transmission de connaissances et aux recherches cliniques plus poussées. Les différences interprovinciales poseront probablement des défis uniques pour les études randomisées nationales. Enregistrement de l'étude : www.clinicaltrials.gov (NCT03114436); enregistrée le 10 avril 2017.

Road to recovery: a study protocol quantifying neurological outcome in cardiac surgery patients and the role of cerebral oximetry.

INTRODUCTION: Patients undergoing cardiac surgery may experience both short-term and long-term postoperative neurological problems. However, the underlying cause of this impairment is unclear. Regional cerebral oxygen saturation (rSO2) levels may play a role in the development of acute dysfunction, known as postoperative delirium, in addition to longer term outcomes after cardiac surgery. Yet the degree of impairment has been difficult to define, partly due to subjective methods of assessments. This study aims to fill this knowledge gap by determining the relationship between rSO2, postoperative delirium and long-term neurological outcome after cardiac surgery using quantitative robotic technology. METHODS AND ANALYSIS: 95 patients scheduled for elective cardiac surgery will be recruited for this single-centre prospective observational study. Patients will be assessed before as well as 3 and 12 months after their surgery using the Kinarm End-Point Lab and standardised tasks. Intraoperatively, rSO2 and other haemodynamic data will be collected for the duration of the procedure. Following their operation, patients will also be screened daily for delirium during their hospital stay. ETHICS AND DISSEMINATION: This study has been approved by the Health Sciences Research Ethics Board at Queen's University (DMED-1672-14). The results of this study will be published in a peer-review journal and presented at international and/or national conferences as poster or oral presentations. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: NCT04081649.

Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL study): study protocol for a randomized controlled trial.

BACKGROUND: Nosocomial infections remain an important source of morbidity, mortality, and increased health care costs in hospitalized patients. This is particularly problematic in intensive care units (ICUs) because of increased patient vulnerability due to the underlying severity of illness and increased susceptibility from utilization of invasive therapeutic and monitoring devices. Lactoferrin (LF) and the products of its breakdown have multiple biological effects, which make its utilization of interest for the prevention of nosocomial infections in the critically ill. METHODS/DESIGN: This is a phase II randomized, multicenter, double-blinded trial to determine the effect of LF on antibiotic-free days in mechanically ventilated, critically ill, adult patients in the ICU. Eligible, consenting patients will be randomized to receive either LF or placebo. The treating clinician will remain blinded to allocation during the study; blinding will be maintained by using opaque syringes and containers. The primary outcome will be antibiotic-free days, defined as the number of days alive and free of antibiotics 28 days after randomization. Secondary outcomes will include: antibiotic utilization, adjudicated diagnosis of nosocomial infection (longer than 72 h of admission to ICU), hospital and ICU length of stay, change in organ function after randomization, hospital and 90-day mortality, incidence of tracheal colonization, changes in gastrointestinal permeability, and immune function. Outcomes to inform the conduct of a larger definitive trial will also be evaluated, including feasibility as determined by recruitment rates and protocol adherence. DISCUSSION: The results from this study are expected to provide insight into a potential novel therapeutic use for LF in critically ill adult patients. Further, analysis of study outcomes will inform a future, large-scale phase III randomized controlled trial powered on clinically important outcomes related to the use of LF. TRIAL REGISTRATION: The trial was registered at www.ClinicalTrials.gov on 18 November 2013. TRIAL REGISTRATION NUMBER: NCT01996579 .