Prevention of Nosocomial Infections in Critically Ill Patients With Lactoferrin: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: To obtain preliminary evidence for the efficacy of lactoferrin as a preventative measure for nosocomial infections and inform the conduct of a definitive study. DESIGN: Phase 2, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Medical-surgical ICUs. PATIENTS: Adult, critically ill patients receiving invasive mechanical ventilation. INTERVENTIONS: Randomized, eligible, consenting patients expected to require invasive mechanical ventilation more than 48 hours received lactoferrin both enterally and via an oral swab or a placebo of sterile water for up to 28 days. MEASUREMENTS AND MAIN RESULTS: Of the 214 patients who were randomized, 212 received at least one dose of the intervention and were analyzed (107 lactoferrin and 105 placebo). Protocol adherence was 87.5%. Patients receiving lactoferrin were older (mean [SD], 66.3 [13.5] vs 62.5 [16.2] yr), had a higher Acute Physiology and Chronic Health Evaluation II score (26.8 [7.8] vs 23.5 [7.9]), and need for vasopressors (79% vs 70%). Antibiotic-free days (17.3 [9.0] vs 18.5 [7.1]; p = 0.91) and nosocomial infections (0.3 [0.7] vs 0.4 [0.6] per patient; p = 0.48) did not differ between lactoferrin and placebo groups, respectively. Clinical outcomes for lactoferrin versus placebo were as follows: ICU length of stay (14.5 [18.0] vs 15.0 [37.3] d; p = 0.82), hospital length of stay (25.0 [25.9] vs 28.1 [44.6] d; p = 0.57), hospital mortality (41.1% vs 30.5%; p = 0.11), and 90-day mortality (44.9% vs 32.4%; p = 0.06). Biomarker levels did not differ between the groups. CONCLUSIONS: Lactoferrin did not improve the primary outcome of antibiotic-free days, nor any of the secondary outcomes. Our data do not support the conduct of a larger phase 3 trial.

Improving Access to Care, Patient Costs, and Environmental Impact Through a Community Outreach Lung Cancer Rapid Assessment Clinic.

PURPOSE: In Southeastern Ontario, increased patient distance from the regional lung cancer diagnostic assessment program (LDAP) is associated with a lower likelihood of patient care via LDAP while receiving care via LDAP is associated with improved survival. We implemented an LDAP outreach clinic to provide specialist assessment for patients with suspected lung cancer at a regional community hospital and assessed the impact on timeliness and accessibility of care. MATERIALS AND METHODS: The Kingston Health Sciences Centre LDAP team engaged with community hospital partners to develop and launch the LDAP outreach clinic. We performed a retrospective chart review of LDAP patients (N = 1,070) before (August-November 2021; n = 234) and after implementation of the outreach clinic (November 2021-October 2022; n = 836). Descriptive data are reported as No. (%). Unpaired t tests and statistical process control charts assess for significance. A cost analysis of out-of-pocket patient costs related to travel and parking is presented in 2022 Canadian dollars (CAD). RESULTS: Compared with a 3-month matched time period before (August-October 2021) and after outreach clinic (August-October 2022), the mean time from referral to assessment and time from referral to diagnosis decreased from 20.3 to 14.4 days (P = .0019) and 40.0 to 28.9 days (P = .0007), respectively. Over 12 months, the total patient travel was reduced by 8,856 km, which combined with parking cost-savings, resulted in patient out-of-pocket savings of CAD $5,755.60 (CAD $47.60/patient). Accounting for physician travel, the total travel saved was 5,688 km, corresponding to reduced CO2 emissions by 1.9 tCO2. CONCLUSION: Implementation of a lung cancer outreach clinic led to improved timeliness of care, patient cost-savings, and reduced carbon footprint while serving patients in their community.

HEART + score: integrating carotid ultrasound to chest pain assessment in the emergency department.

OBJECTIVES: The HEART score is a clinical decision tool that stratifies patients into categories of low, moderate, and high-risk of major adverse cardiac events in the emergency department (ED) but cannot identify underlying cardiovascular disease in patients without prior history. The presence of atherosclerosis can easily be detected at the bedside using carotid ultrasound. Plaque quantification is well established, and plaque composition can be assessed using ultrasound grayscale pixel distribution analysis. This study aimed to determine whether carotid plaque burden and/or composition correlated with risk of events and could improve the sensitivity of the HEART score in risk stratifying ED patients with chest pain. METHODS: The HEART score was calculated based on history, electrocardiogram, age, risk factors, and initial troponin in patients presenting to the ED with chest pain (n = 321). Focused carotid ultrasound was performed, and maximum plaque height and total plaque area were used to determine plaque burden (quantity). Plaque composition (% blood, fat, muscle, fibrous, calcium-like tissue) was assessed by pixel distribution analysis. RESULTS: Carotid plaque height and area increased with HEART score (p < 0.0001). Carotid plaque % fibrous and % calcium also increased with HEART score. The HEART score had a higher area under the curve (AUC = 0.84) in predicting 30-day events compared to the plaque variables alone (AUCs < 0.70). Integrating plaque quantity into the HEART score slightly increased test sensitivity (62-69%) for 30-day events and reclassified 11 moderate-risk participants to high-risk (score 7-10). CONCLUSION: Plaque burden with advanced composition features (fibrous and calcium) was associated with increased HEART score. Integrating plaque assessment into the HEART score identified subclinical atherosclerosis in moderate-risk patients.

RéSUMé: OBJECTIFS: Le score HEART est un outil de décision clinique qui stratifie les patients en catégories de risque faible, modéré et élevé d'événements cardiaques indésirables majeurs à l'urgence (ED), mais ne peut pas identifier les maladies cardiovasculaires sous-jacentes chez les patients sans antécédents. La présence d'athérosclérose peut facilement être détectée au chevet du patient à l'aide de l'échographie carotide. La quantification de la plaque est bien établie et la composition de la plaque peut être évaluée à l'aide d'une analyse échographique de la distribution des pixels en niveaux de gris. Cette étude visait à déterminer si la charge et/ou la composition de la plaque carotidienne étaient corrélées avec le risque d'événements et pouvaient améliorer la sensibilité du score HEART chez les patients souffrant de douleurs thoraciques stratifiés. MéTHODES: Le score HEART a été calculé sur la base des antécédents, de l'électrocardiogramme, de l'âge, des facteurs de risque et de la troponine initiale chez les patients présentant une douleur thoracique à l'urgence (n = 321). L'échographie carotidienne focalisée a été effectuée, et la hauteur maximale de la plaque et la surface totale de la plaque ont été utilisées pour déterminer la charge de plaque (quantité). La composition de la plaque (% de sang, de graisse, de muscle, de tissu fibreux, de type calcique) a été évaluée par analyse de la distribution des pixels. RéSULTATS: La hauteur et la surface de la plaque carotide ont augmenté avec le score HEART (p<0,0001). Le pourcentage de plaque carotide fibreuse et le pourcentage de calcium ont également augmenté avec le score HEART. Le score HEART avait une zone plus élevée sous la courbe (ASC = 0,84) pour prédire les événements de 30 jours par rapport aux seules variables de la plaque (CCU < 0,70). L'intégration de la quantité de plaque dans le score HEART a légèrement augmenté la sensibilité au test (62 % à 69 %) pour les événements de 30 jours et a reclassé 11 participants à risque modéré à risque élevé (score de 7 à 10). CONCLUSION: La charge de plaque avec des caractéristiques de composition avancées (fibreuse et calcique) était associée à une augmentation du score HEART. Intégrer l'évaluation de la plaque dans le score HEART a identifié l'athérosclérose subclinique chez les patients à risque modéré.

Focused carotid ultrasound to predict major adverse cardiac events among emergency department patients with chest pain.

BACKGROUND AND OBJECTIVE: Point-of-care focused vascular ultrasound (FOVUS), an assessment of carotid artery plaque, predicts coronary artery disease in outpatients referred for coronary angiography. Our primary objective was to determine the diagnostic accuracy of sonographer-performed FOVUS to predict major adverse cardiac events (MACE) within 30 days among patients with suspected cardiac ischemia in the emergency department (ED). METHODS: We conducted a prospective cohort study of patients with chest pain presenting to a tertiary care ED who had an electrocardiogram and cardiac troponin testing. The primary outcome was a composite of death, acute myocardial infarction, or re-vascularization at 30 days. A sonographer performed FOVUS scans in consenting eligible subjects. Emergency physicians, blinded to the sonographer FOVUS result, performed a second FOVUS on some subjects. RESULTS: We recruited 326 subjects (age 62.1 ± 13.5 years; 166 (52%) men), 319 of whom completed an FOVUS scan by the sonographer. Of these, 198 (62%) had a positive FOVUS scan and 41 (13%) had a 30-day MACE. The sensitivity was 83% (95% CI 71-94%), specificity 41% (95% CI 36-47%), positive-likelihood ratio 1.41 (95% CI 1.19-1.68), and negative-likelihood ratio 0.41 (95% CI 0.23-0.75). Among 71 subjects also scanned by an emergency physician, the Kappa was 0.50 (95% CI 0.31-0.70), suggesting moderate agreement between sonographer and emergency physician on the determination of significant carotid plaque. CONCLUSIONS: The presence of carotid plaque on sonographer-performed FOVUS is associated with 30-day MACE in ED patients presenting with chest pain. The prognostic performance of FOVUS is not sufficient to support its use as a stand-alone risk stratification tool in the ED. Future work should investigate FOVUS in conjunction with validated clinical decision rules for chest pain and the impact of enhanced training and quality improvement in the conduct of FOVUS by emergency physicians. REGISTRATION: This study was registered at clinicaltrials.gov (NCT02947360).

RéSUMé: CONTEXTE ET OBJECTIF: L'échographie vasculaire focalisée au point de service (FOVUS), une évaluation de la plaque de l'artère carotide, prédit la maladie coronarienne chez les patients externes référés pour une coronarographie. Notre objectif principal était de déterminer la précision diagnostique du FOVUS réalisé par un échographiste pour prédire les événements cardiaques indésirables majeurs (MACE) dans les 30 jours chez les patients présentant une suspicion d'ischémie cardiaque aux urgences. MéTHODES: Nous avons mené une étude de cohorte prospective de patients souffrant de douleurs thoraciques se présentant à un service d'urgence de soins tertiaires et ayant subi un électrocardiogramme et un test de troponine cardiaque. L'issue primaire était un critère composite de décès, d'infarctus aigu du myocarde ou de revascularisation à 30 jours. Un échographiste a effectué des scans FOVUS chez les sujets éligibles consentants. Les médecins urgentistes, aveuglés par le résultat FOVUS de l'échographiste, ont effectué un deuxième FOVUS sur certains sujets. RéSULTATS: Nous avons recruté 326 sujets (âge 62,1 ± 13,5 ans; 166 (52%) hommes), dont 319 ont effectué un examen FOVUS par l'échographiste. Parmi ceux-ci, 198 (62%) avaient un scan FOVUS positif et 41 (13%) avaient un MACE de 30 jours. La sensibilité était de 83% (IC à 95% 71%-94%), la spécificité de 41% (IC à 95% 36%-47%), le rapport de vraisemblance positif de 1,41 (IC à 95% 1,19­1,68) et le rapport de vraisemblance négatif de 0,41 (IC à 95% 0,23­0,75). Parmi les 71 sujets également examinés par un médecin urgentiste, le Kappa était de 0,50 (IC à 95%: 0,31­0,70), ce qui suggère une concordance modérée entre l'échographiste et le médecin urgentiste pour la détermination de la plaque carotide significative. CONCLUSIONS: La présence d'une plaque carotidienne sur un FOVUS effectué par un échographiste est associée à la MACE à 30 jours chez les patients des urgences présentant des douleurs thoraciques. La performance pronostique du FOVUS n'est pas suffisante pour justifier son utilisation comme outil autonome de stratification du risque dans les urgences. Des travaux futurs devraient étudier le FOVUS en conjonction avec des règles de décision clinique validées pour la douleur thoracique et l'impact d'une formation renforcée et d'une amélioration de la qualité dans la conduite du FOVUS par les médecins urgentistes. ENREGISTREMENT: Cette étude a été enregistrée sur clinicaltrials.gov (NCT02947360).

The relationship between immune status as measured by stimulated ex-vivo tumour necrosis factor alpha levels and the acquisition of nosocomial infections in critically ill mechanically ventilated patients.

INTRODUCTION: Immunological dysfunction is common in critically ill patients but its clinical significance and the optimal method to measure it are unknown. The level of tumor necrosis factor alpha (TNF-α) after ex-vivo whole blood stimulation with lipopolysaccharide (LPS) has been proposed as a possible method to quantify immunological function. We hypothesized that in a cohort of critically ill patients, those with a lower post-stimulation TNF-α level would have increased rates of nosocomial infections (NIs) and worse clinical outcomes. METHODS: A secondary analysis of a phase 2 randomized, multi-centre, double-blinded placebo-controlled trial. As there was no difference between treatment and control arms in outcomes and NI rate, all the patients were analyzed as one cohort. On enrolment, day 4, 7, and weekly until day 28, whole blood was incubated with LPS ex-vivo and subsequent TNF-α level was measured. Patients were grouped in tertiles according to delta and peak TNF-α level. The primary outcome was the association between NIs and tertiles of TNF-α level post LPS stimulation; secondary outcomes included ICU and 90-day mortality, and ICU and hospital length of stay. RESULTS: Data was available for 201 patients. Neither the post LPS stimulation delta TNF-α group nor the peak TNF-α post-stimulation group were associated with the development of NIs or clinical outcomes. Patients in the highest tertile for post LPS stimulation delta TNF-α compared to the lowest tertile were younger [61.1 years ± 15.7 vs. 68.6 years ± 12.8 standard deviations (SD) in the lowest tertile], had lower acuity of illness (APACHE II 25.0 ± 9.7 vs. 26.7 ± 6.1) and had lower baseline TNF-α (9.9 pg/mL ± 19.0 vs. 31.0 pg/mL ± 68.5). When grouped according to peak post-stimulation TNF-α levels, patients in the highest tertile had higher serum TNF-α at baseline (21.3 pg/mL ± 66.7 compared to 6.5 pg/mL ± 9.0 in the lowest tertile). CONCLUSION: In this prospective multicenter study, ex-vivo stimulated TNF-α level was not associated with the occurrence of NIs or clinical outcomes. Further study is required to better ascertain whether TNF levels and ex-vivo stimulation can be used to characterize immune function in critical illness and if other assays might be better suited to this task.

Improving Timeliness of Lung Cancer Diagnosis and Staging Investigations Through Implementation of Standardized Triage Pathways.

PURPOSE: Timely care for patients with lung cancer (LC) is associated with improved clinical outcomes. In Southeastern Ontario, Canada, we identified delays in the diagnostic process for patients undergoing evaluation for suspected LC through a rapid assessment clinic. We developed improvement initiatives with an aim of reducing the time from referral to diagnosis. METHODS: A Standardized Triage Process (STP) was implemented for patients referred with suspected LC, including routine interdisciplinary triage, standardized pathways with preordered staging tests, and a new Small Nodule Clinic. We retrospectively analyzed all patients referred pre-STP (January to April 2018) and prospectively for improvement (May 2018 to March 2019). Process measures included STP compliance and time to completion of staging investigations (positron emission tomography [PET] and computed tomography/magnetic resonance imaging of brain). Data are reported as means; significance was determined by special-cause variation using Statistical Process Control charts; unpaired t tests were compared between groups. RESULTS: We reviewed 833 referrals (207 baseline and 626 post-STP). STP compliance improved monthly to 99.4%. Post-STP, time from referral to PET decreased (from 38.5 to 15.7 days), time from referral to brain imaging decreased (from 33.4 to 13.1 days), and time from referral to diagnosis decreased (from 38.0 to 22.7 days), all demonstrating special-cause variation. Patients completing preordered staging tests experienced significantly faster care than those without preordered tests, including time to PET (23.0 v 35.9 days), computed tomography/magnetic resonance imaging of brain (16.2 v 29.9 days), and diagnosis (39.9 v 28.1 days), all P < .001. CONCLUSION: An STP significantly improved timeliness of diagnosis and staging for patients with suspected LC undergoing evaluation in a rapid assessment clinic.

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 .

Rates and determinants of informed consent: a case study of an international thromboprophylaxis trial.

BACKGROUND: Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials. OBJECTIVE: The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143). DESIGN: Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily. SETTING: The trial was conducted in 67 centers in 6 countries. MEASUREMENTS AND MAIN RESULTS: A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P < .001 for those with >10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs, <0.5; P < .001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P < .001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P < .001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P < .001). CONCLUSIONS: Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial.