Mesenchymal Stromal Cell-derived Extracellular Vesicles in Preclinical Animal Models of Tumor Growth: Systematic Review and Meta-analysis.

BACKGROUND: Mesenchymal stromal cell derived extracellular vesicles (MSC-EVs) have been implicated in the regulation of tumor growth. Studies remain preclinical with effects ranging from inhibition of tumor growth to cancer progression. A systematic review and meta-analysis is needed to clarify the effect of MSC-EVs on tumor growth to facilitate potential translation to clinical trials. METHODS: A systematic search of the literature (MEDLINE, Embase, and BIOSIS databases to June 1, 2019) identified all pre-clinical controlled studies investigating the effect of MSC-EVs on tumor growth. Study selection and data extraction were performed in duplicate. Potential risk of bias was assessed using the SYRCLE tool. A random effects meta-analysis of reduction in tumor weight/volume (primary outcome) was performed. RESULTS: We identified 29 articles and 22 reported data on tumor responses that were included for meta-analysis. Studies were associated with unclear risk of bias in a large proportion of domains in accordance with the SYRCLE tool for determining risk of bias in preclinical studies. A high risk of bias was not identified in any study. MSC-EVs had a mixed response on tumor progression with some studies reporting inhibition of tumor growth and others reporting tumor progression. Overall, MSC-EVs exerted a non-significant reduction in tumor growth compared to controls (standardized mean difference (SMD) -0.80, 95 % CI -1.64 to 0.03, p = 0.06, I2 = 87 %). Some studies reported increased tumor growth which aligned with their stated hypothesis and some interrogated mechanisms in cancer biology. EVs isolated from MSCs that overexpressed anti-tumor RNAs were associated with significant tumor reduction in meta-analysis (SMD - 2.40, 95 % CI -3.36 to -1.44, p < 0.001). Heterogeneity between studies was observed and included aspects of study design such as enrichment of MSC-EVs with specific anti-tumor molecules, tissue source of MSCs, method of EV isolation, characterization of MSCs and EVs, dosage and administration schedules, and tissue type and source of tumor cells studied. CONCLUSIONS: MSC-EVs are associated with mixed effects on tumor growth in animal models of cancer. In studies where anti-tumor RNAs are packaged in EVs, a significant reduction in tumor growth was observed. Reducing heterogeneity in study design may accelerate our understanding of the potential effects of MSC-EVs on cancer. [274 words] Forest plot of MSC-EV effect on tumor growth accordinggenetic modification of EVs in animal studies identified from a systematicreview of the literature. All cohorts from studies with multiple interventiongroups are presented separately with control groups divided equally among thegroups. M, modified; H, hypoxia.

MicroRNA in Human Acute Kidney Injury: A Systematic Review Protocol.

BACKGROUND: Acute kidney injury (AKI) is a common complication of hospitalization with high morbidity and mortality for which no effective treatments exist and for which current diagnostic tools have limitations for earlier identification. MicroRNAs (miRNAs) are small non-coding RNAs that have been implicated in the pathogenesis of AKI, and some miRNAs have shown promise as therapeutic tools in animal models of AKI. However, less is known about the role of miRNAs in human AKI. OBJECTIVE: To evaluate the role of miRNAs in human subjects with AKI. DESIGN: Systematic review and meta-analysis. MEASUREMENTS: Quantification of miRNA levels from human blood, urine, or kidney biopsy samples, and measures of renal function as defined in the study protocol. METHODS: A comprehensive search strategy for Ovid MEDLINE All, Embase, Web of Science, and CENTRAL will be developed to identify investigational studies that evaluated the relationship between miRNA levels and human AKI. Primary outcomes will include measurements of kidney function and miRNA levels. Study screening, review and data extraction will be performed independently by 2 reviewers. Study quality and certainty of evidence will be assessed with validated tools. A narrative synthesis will be included and the possibility for meta-analysis will be assessed according to characteristics of clinical and statistical heterogeneity between studies. LIMITATIONS: These include (1) lack of randomized trials of miRNAs for the prevention or treatment of human AKI, (2) quality of included studies, and (3) sources of clinical and statistical heterogeneity that may affect strength and reproducibility of results. CONCLUSION: Previous studies of miRNAs in different animal models of AKI have generated strong interest on their use for the prevention and treatment of human AKI. This systematic review will characterize the most promising miRNAs for human research and will identify methodological constraints from miRNA research in human AKI to help inform the design of future studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020201253.

CONTEXTE: L'insuffisance rénale aiguë (IRA) est une complication fréquente des hospitalisations avec morbidité et mortalité élevées. Il n'existe aucun traitement efficace contre l'IRA et les outils diagnostiques actuels qui permettent son dépistage précoce comportent des limites. Les microARN (miARN) sont de petits ARN non codants ayant été impliqués dans la pathogenèse de l'IRA; certains d'entre eux se sont révélés prometteurs comme outils thérapeutiques dans les modèles animaux de l'IRA. Le rôle des miARN dans l'IRA chez l'humain est cependant moins connu. OBJECTIF: Évaluer le rôle des miARN chez les sujets humains atteints d'IRA. TYPE D'ÉTUDE: Examen systématique et méta-analyze. MESURES: La quantification des taux de miARN chez l'humain à partir d'échantillons de sang, d'urine ou de biopsie rénale, et mesure de la fonction rénale telle que définie dans le protocole de l'étude. MÉTHODOLOGIE: Une stratégie de recherche exhaustive des bases de données Ovid MEDLINE All, Embase, Web of Science et CENTRAL sera élaborée afin de répertorier les études expérimentales ayant évalué la relation entre les taux de miARN et l'IRA chez l'humain. Les principaux critères d'évaluation comprendront la mesure de la fonction rénale et des taux de miARN. Deux examinateurs procéderont de façon indépendante à la sélection des études, à leur examen et à l'extraction des données. La qualité des études et la robustesse des données seront évaluées à l'aide d'outils validés. Une synthèse descriptive sera incluse et la possibilité d'une méta-analyze sera évaluée en fonction des caractéristiques de l'hétérogénéité clinique et statistique entre les études. LIMITES: Les limites de l'étude concernent notamment (i) le manque d'essais randomisés examinant les miARN pour la prévention ou le traitement de l'IRA humaine; (ii) la qualité des études incluses; et (iii) les sources d'hétérogénéité clinique et statistique susceptibles d'affecter la robustesse et la reproductibilité des résultats. CONCLUSION: Des études antérieures sur les miARN dans différents modèles animaux de l'IRA ont suscité un vif intérêt pour leur utilization dans la prévention et le traitement de l'IRA chez l'humain. Cet examen systématique caractérisera les miARN les plus prometteurs pour la recherche sur l'IRA humaine et définira les contraintes méthodologiques de telles études, ce qui aidera à orienter la conception des études futures.

Effects of living kidney donation on arterial stiffness: a systematic review protocol.

INTRODUCTION: Kidney donors have been reported to have accelerated progression of aortic stiffness and decreased glomerular filtration compared with healthy non-donors. This is a concern because increased aortic stiffness is an independent predictor of overall cardiovascular disease and all-cause mortality in the general population. To confirm if arterial stiffness increases after donation, we will systematically review all studies that evaluated indices of arterial stiffness in healthy individuals who underwent unilateral nephrectomy for kidney donation compared with age-matched healthy non-nephrectomised controls. METHODS/ANALYSIS: We will comprehensively search for studies published between 1 January 1960 and 15 March 2021 in MEDLINE, EMBASE, Cochrane Central, OVID and EBM reviews. All prospective (cohort, case-control, case series and before-and-after studies) and retrospective non-randomised studies reporting indices of arterial stiffness in nephrectomised and non-nephrectomised healthy participants will be included. Primary outcome will be the difference in the functional metrics of arterial stiffness between donors and non-donors. Secondary outcomes will be the differences in systolic/diastolic blood pressures, serum creatinine, glomerular filtration, carotid artery intima-media thickness and vascular calcification. Study screening, selection and data extraction will be performed by two independent reviewers. Risk of bias will be independently assessed with the ROBINS-I tool and confidence in evidence by the Grading of Recommendations Assessment, Development and Evaluation recommendations. Qualitative and quantitative data syntheses as well as clinical and statistical heterogeneity (Forest plots, I2 and Cochran's Q statistics) will be evaluated. If clinical and statistical heterogeneity are acceptable, inverse variance-weighted effects will be analysed by random effect models. ETHICS AND DISSEMINATION: No ethical approval is necessary. Our results will be disseminated through peer-review publication and presentations to guide stakeholders on the evaluation and follow-up care of kidney donors. PROSPERO REGISTRATION NUMBER: CRD42020185551.

Therapeutic effects of micro-RNAs in preclinical studies of acute kidney injury: a systematic review and meta-analysis.

AKI has a high mortality rate, may lead to chronic kidney disease, and effective therapies are lacking. Micro-RNAs (miRNAs) regulate biologic processes by potently inhibiting protein expression, and pre-clinical studies have explored their roles in AKI. We conducted a systematic review and meta-analysis of miRNAs as therapeutics in pre-clinical AKI. Study screening, data extraction, and quality assessments were performed by 2 independent reviewers. Seventy studies involving 42 miRNA species were included in the analysis. All studies demonstrated significant effects of the miRNA intervention on kidney function and/or histology, with most implicating apoptosis and phosphatase and tensin homolog (PTEN) signaling. Fourteen studies (20.0%) examined the effect of miRNA-21 in AKI, and meta-analysis demonstrated significant increases in serum creatinine and kidney injury scores with miR-21 antagonism and pre-conditioning. No studies reported on adverse effects of miRNA therapy. Limitations also included lack of model diversity (100% rodents, 61.4% ischemia-reperfusion injury), and predominance of male sex (78.6%). Most studies had an unclear risk of bias, and the majority of miRNA-21 studies were conducted by a single team of investigators. In summary, several miRNAs target kidney function and apoptosis in pre-clinical AKI models, with data suggesting that miRNA-21 may mediate protection and kidney repair.Systematic review registration ID: CRD42019128854.

Patient tolerability of suprascapular and median nerve blocks for the management of pain in post-stroke shoulder-hand syndrome.

BACKGROUND: Current management options for pain in stroke patients with the shoulder-hand syndrome (SHS) are limited and often ineffective. The use of peripheral nerve blocking in SHS has been limited due to concerns of hyperalgesia and allodynia in these patients. This study assessed the tolerability of suprascapular nerve (SSN) and median nerve blocks for acute control of pain in patients with post-stroke SHS. METHODS: All SHS patients fulfilled diagnosis using the Budapest criteria. Patient tolerability was defined by a composite score that included a change on the visual analog scale (VAS) from baseline for shoulder and hand pain, presence of adverse events, and a self-reported patient satisfaction score. Pain assessment was performed 1 h before (baseline), and 1 h and 2 weeks after the procedure. RESULTS: Five patients (68.5 ± 9.5 years) with post-stroke SHS underwent SSN and median nerve blocks. Participant assessment 1 h after the procedure indicated that the 2 blocking procedures were well tolerated and that VAS scores for shoulder and hand pain decreased by 79% (- 62.6 mm ± 25.6; p = 0.043) and 48% (- 33 mm ± 40.2; p = 0.080), respectively from baseline. After 2 weeks, average VAS scores remained 56% and 37% below baseline, respectively. There were no adverse events and all patients were satisfied after the procedure. CONCLUSIONS: Suprascapular and median nerve blocks are safe and well-tolerated procedures for acute pain control in post-stroke SHS. Further studies should address the benefit of these procedures on overall pain reduction, functional recovery, and quality of life in SHS patients.

Variability Predictors of Vasospasm in Subarachnoid Hemorrhage: A Feasibility Study.

BACKGROUND: Mean cerebral blood flow velocity (mean-CBFV) obtained from Transcranial Doppler (TCD) poorly predicts cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). Variability descriptors of mean-CBFV obtained during extended TCD recordings may improve this prediction. We assessed the feasibility of generating reliable linear and non-linear descriptors of mean-CBFV variability using extended recordings in aSAH patients and in healthy controls. We also explored which of those metrics might have the ability to discriminate between aSAH patients and healthy controls, and among patients who would go on to develop vasospasm and those who would not. METHODS: Bilateral mean-CBFV, blood pressure, and heart rate were continuously recorded for 40 minutes in aSAH patients (n = 8) within the first 5 days after ictus, in age-matched healthy controls (n = 8) and in additional young controls (n = 8). We obtained linear [standard deviation, coefficient of variations, and the very-low (0.003-0.040 Hz), low (0.040-0.150 Hz), and high-frequency (0.15-0.4 Hz) power spectra] and non-linear (Fractality, deterministic Chaos analyses) variability metrics. RESULTS: We successfully obtained TCD recordings from patients and healthy controls and calculated the desired metrics of mean-CBFV variability. Differences were appreciable between aSAH patients and healthy controls, as well as between aSAH patients who later developed vasospasm and those who did not. CONCLUSIONS: A 40-minute TCD recording provides reliable variability metrics in aSAH patients and healthy controls. Future studies are required to determine if mean-CBFV variability metrics remain stable over time, and whether they may serve to identify patients who are at greatest risk of developing cerebral vasospasm after aSAH.

Pharmacologic Therapies for Aortic Stiffness in End-Stage Renal Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Increased carotid-femoral pulse wave velocity (cf-PWV), a surrogate of increased aortic stiffness, is a risk factor for cardiovascular events and all-cause mortality in end-stage renal disease (ESRD). To minimize the deleterious effects of an increased aortic stiffness in ESRD patients, several interventions have been developed and cf-PWV has been used to monitor responses. OBJECTIVE: The aim of this study was to determine the effects of pharmacologic interventions that target aortic stiffness on cf-PWV and systolic blood pressure (SBP) in adults with ESRD. STUDY DESIGN: This study implements a systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, Cochrane Central, Health Technology Assessment, and EBM databases were searched. STUDY ELIGIBILITY PARTICIPANTS AND INTERVENTIONS: Randomized and non-randomized studies involving adults (>18 years) with ESRD of any duration, receiving or not renal replacement therapy (hemodialysis, peritoneal dialysis) and exposed to a pharmacologic intervention whose effects were assessed by cf-PWV. METHODS: Study screening, selection, data extraction, and quality assessments were performed by 2 independent reviewers. Narrative synthesis and quantitative data analysis summarized the review. RESULTS: We included 1027 ESRD participants from 13 randomized and 5 non-randomized studies. Most pharmacologic interventions targeted bone mineral metabolism disorder or hypertension. Treatment with vitamin D analogues or cinacalcet did not decrease cf-PWV or SBP over placebo or matched controls (P > .05). Calcium-channel blockers (CCB) decreased cf-PWV and SBP compared with placebo or standard care (P < .05). Renin-angiotensin system inhibitors did not show any advantage over placebo in decreasing cf-PWV (P > .05). LIMITATIONS: Quality of evidence ranged from very low to moderate. Overall evidence was limited by the low number of studies, small sample sizes, and methodological inconsistencies. CONCLUSIONS: Pharmacologic interventions targeting aortic stiffness in ESRD have mixed effects on reducing cf-PWV, with some strategies suggesting potential benefit. The quality of evidence, however, is insufficient to draw definitive conclusions on their use to slow progression of aortic stiffness in ESRD. Further well-designed studies are needed to confirm these associations and their impact on cardiovascular outcomes in ESRD.Registered in PROSPERO (CRD42016033463).

CONTEXTE: L'accroissement de la vitesse de l'onde de pouls carotido-fémorale (VOPcf), un substitut à l'accroissement de la rigidité aortique, constitue un facteur de risque d'événements cardiovasculaires et de mortalité toutes causes confondues en contexte d'insuffisance rénale terminale (IRT). Plusieurs interventions pharmacologiques ont été développées pour minimiser les effets délétères de l'accroissement de la rigidité aortique chez les patients atteints d'IRT, et la VOPcf a été employée pour en mesurer la réponse. OBJECTIF: Mesurer les effets d'interventions pharmacologiques ciblant la rigidité aortique sur la VOPcf et la pression systolique (PS) d'adultes atteints d'IRT. TYPE D'ÉTUDE: Revue systématique et méta-analyse. SOURCES: Les bases de données MEDLINE, EMBASE, Cochrane Central, EMB et du Service d'évaluation des technologies de la santé ont été consultées. ADMISSIBILITÉ PARTICIPANTS ET INTERVENTIONS: Ont été sélectionnées les études réparties aléatoirement ou non, peu importe leur durée, qui portaient sur des adultes atteints d'IRT, recevant ou non une thérapie de remplacement rénal (hémodialyse, dialyse péritonéale), qui avaient été exposés à une intervention pharmacologique dont les effets avaient été mesurés avec la VOPcf. MÉTHODOLOGIE: Deux réviseurs indépendants ont procédé à la recherche et à la sélection des études, à l'extraction des données et à l'évaluation de leur qualité. Une synthèse narrative et une analyse quantitative des données ont synthétisé les résultats de la revue. RÉSULTATS: L'étude porte sur un total de 1 027 sujets atteints d'IRT issus de 13 études à répartition aléatoire et de 5 études non réparties aléatoirement. La plupart des interventions pharmacologiques ciblaient l'hypertension ou un trouble du métabolisme de la densité osseuse. Lorsque comparés à un placebo ou à un témoin, les traitements impliquant un analogue de la vitamine D ou le cinacalcet n'ont eu aucun effet réducteur sur la VOPcf ou la PS (p>0,05). Les bloqueurs des canaux calciques ont montré un effet réducteur sur la VOPcf et la PS en comparaison du placebo ou du traitement standard (p<0,05). Les inhibiteurs du système rénine-angiotensine n'ont présenté aucun avantage pour réduire la VOPcf par rapport au placebo (p>0,05). LIMITES: La qualité des données recueillies variait de très pauvre à modérée. L'ensemble des données recueillies est limité par le faible nombre d'études, la petite taille des échantillons et par des divergences méthodologiques. CONCLUSION: Les interventions pharmacologiques ciblant la rigidité aortique en contexte d'IRT ont eu des résultats mitigés sur la réduction de la VOPcf, quoique certaines stratégies suggèrent de potentiels avantages. La qualité des données recueillies est toutefois insuffisante pour conclure de façon définitive que ces interventions ralentissent la progression de la rigidité aortique chez les patients atteints d'IRT. Des études bien conçues sont nécessaires pour confirmer ces associations et leur incidence sur les issues cardiovasculaires en contexte d'IRT.

The therapeutic effects of microRNAs in preclinical studies of acute kidney injury: a systematic review protocol.

BACKGROUND: Acute kidney injury (AKI) causes significant morbidity and mortality in humans, and there are currently no effective treatments to enhance renal recovery. MicroRNAs (miRNAs) are short chain nucleotides that regulate protein expression and have been implicated in the pathogenesis of AKI. Recently, preclinical studies in vivo have uncovered a therapeutic role for administration of specific miRNAs in AKI. However, the overall benefits of this strategy in preclinical studies have not been systematically reviewed, and the potential for translation to human studies is unclear. AIM: The primary aim is to conduct a systematic review of the therapeutic properties of miRNAs in preclinical studies of AKI. The secondary aim is to determine potential adverse effects of miRNA administration in these studies. METHODS: A comprehensive search strategy will identify relevant studies in AKI in vivo models, using the MEDLINE, EMBASE, OVID, PUBMED, and Web of Science databases. The search strategy will include terms for mammalian (non-human) AKI models, including injury related to ischemia/reperfusion, nephrotoxicity, sepsis, contrast agents, cardio-pulmonary bypass, and hemorrhagic shock. Interventions will be defined as direct administration of exogenous miRNAs or antagonists of miRNAs, as well as maneuvers that alter expression of miRNAs that are mechanistically linked to AKI outcomes. The primary outcomes will be indices of kidney function and structure, and there will be no restriction on comparator interventions. Two independent investigators will initially screen abstracts, and selected articles that meet eligibility criteria will be reviewed for data abstraction and analysis. The SYRCLE RoB tool for animal studies will determine risk of bias, and meta-analysis will be performed as appropriate. The GRADE methodology will assess the quality of evidence. DISCUSSION: The administration of selective miRNA mimics or antagonists exerts beneficial effects in mammalian models of AKI, although multiple obstacles must be addressed prior to translation to human clinical trials. The proposed systematic review will document key miRNA candidates, and determine effect size estimates and sources of outcome bias. The review will also identify gaps in knowledge and guide future directions in AKI research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128854.

A Systematic Review and Meta-analysis of Nonpharmacologic-based Interventions for Aortic Stiffness in End-Stage Renal Disease.

INTRODUCTION: Increased carotid-femoral pulse wave velocity (cf-PWV) in end-stage renal disease (ESRD) indicates enhanced aortic stiffness and mortality risk. We conducted a systematic review and meta-analysis of nonpharmacologic interventions in adults with ESRD to determine their effects on cf-PWV, systolic blood pressure (SBP), and intervention-associated adverse events. METHODS: MEDLINE, EMBASE, and EBM databases were searched. Study screening, selection, data collection, and methodological quality assessments were performed by 2 independent reviewers. Pooled-effect estimates from mean differences and 95% confidence intervals (CIs) were calculated using random effect models. RESULTS: A total of 2166 subjects with ESRD from 33 studies (17 randomized; 16 nonrandomized) were included. Four intervention-comparator pairs were meta-analyzed. Quality of evidence ranged from very low to moderate. Kidney transplantation decreased cf-PWV (-0.70 m/s; CI: -1.3 to -0.11; P = 0.02) and SBP (-8.3 mm Hg; CI: -13.2 to -3.3; P < 0.001) over pretransplantation. In randomized trials, control of fluid overload by bio-impedance reduced cf-PWV (-1.90 m/s; CI: -3.3 to -0.5); P = 0.02) and SBP (-4.3 mm Hg; CI: -7.7 to -0.93); P = 0.01) compared with clinical assessment alone. Cross-sectional studies also demonstrated significantly lower cf-PWV and SBP in normovolemia compared with hypervolemia (P ≤ 0.01). Low calcium dialysate decreased cf-PWV (-1.70 m/s; CI: -2.4 to -1.0; P < 0.00001) without affecting SBP (-1.6 mm Hg; CI: -8.9 to 5.8; P = 0.61). Intradialytic exercise compared with no exercise reduced cf-PWV (-1.13 m/s; CI: -2.2 to -0.03; P = 0.04), but not SBP (+0.5 mm Hg; CI: -9.5 to 10.4); P = 0.93). CONCLUSIONS: Several nonpharmacologic interventions effectively decrease aortic stiffness in ESRD. The impact of these interventions on cardiovascular outcomes and mortality risk reduction in ESRD requires further study.

The impact of intervention strategies that target arterial stiffness in end-stage renal disease: a systematic review protocol.

BACKGROUND/OBJECTIVES: Vascular damage contributes to the high cardiovascular morbidity and mortality in end-stage renal disease (ESRD). Increased aortic stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) is a strong and independent predictor of the cardiovascular risk in ESRD patients. Recently, there has been considerable interest in developing strategies to lessen the progression of arterial stiffness in ESRD patients using cf-PWV as a tool to monitor therapeutic responses, but their benefit on the long-term cardiovascular risk is not known. Appraisal of the effects of existing stiffness-based interventions on the cf-PWV would facilitate selecting optimal therapies to be tested in randomized clinical trials. The aim of this systematic review will be to evaluate the impact of arterial stiffness-based interventions on the cf-PWV in ESRD patients. Secondarily, for each intervention, we will determine the minimal duration needed to achieve a significant reduction of cf-PWV, the minimal cf-PWV reduction threshold or effect size, and adverse events. METHODS/DESIGN: This review will be conducted using MEDLINE, EMBASE, and EBM Reviews. We will select clinical trials and observational studies (cohort, case-control, and before/after studies and case series) that evaluated pharmacologic or non-pharmacologic interventions in which the primary effect is to improve structural and/or dynamic components of arterial stiffness in adults with stage 5 chronic kidney disease. The primary outcome of interest will be cf-PWV. Study selection and data collection will be performed by two reviewers. Validated tools will be used to assess the methodological quality and risk of bias among different study designs. We will describe all included citations according to study characteristics, methodological quality, and outcomes. Suitability for meta-analysis will be determined by the degree of clinical and statistical heterogeneity between studies. If appropriate, we will calculate effect estimates by obtaining the relative risks with 95 % confidence intervals pooled according to study design using a random effects model. DISCUSSION: This review will summarize evidence regarding effects of interventions targeting arterial stiffness in ESRD patients. Our results will inform clinicians and researchers on the type of existing arterial stiffness-based interventions for ESRD patients and their potential efficacy and safety, with a goal to guide future clinical trials aimed at reducing adverse cardiovascular events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033463.

Reproducibility of carotid-femoral pulse wave velocity in end-stage renal disease patients: methodological considerations.

BACKGROUND: In end-stage renal disease (ESRD) patients, increased arterial stiffness detected by carotid-femoral pulse wave velocity (cf-PWV) is associated with fatal cardiovascular events and all-cause mortality. Since cf-PWV is an operator-dependent technique, poor reproducibility may be a source of bias in the estimation of arterial stiffness. OBJECTIVES: We assessed the week-to-week reproducibility of cf-PWV and radial artery pulse wave analysis in healthy subjects and ESRD patients. We also determined the extent of patient eligibility, enrollment, acceptance, and comfort. METHODS: In a cohort study design, independent tonometric examinations of carotid, femoral, and radial arteries were conducted in 20 healthy subjects and 15 ESRD patients attending chronic hemodialysis treatments according to a randomized sequence by two operators on 2 days scheduled 1-week apart. cf-PWV, augmentation index (AIx@HR75) and central pulse pressure (CPP) were the outcome measures. Patients were tested at mid-week and prior to dialysis treatment. The variability on the distance measured between the suprasternal notch and femoral site using two different methods (standard vs direct) was compared. A post-examination survey assessed acceptance and comfort associated with examinations. Reproducibility was evaluated by intra-class correlations (ICCs). RESULTS: The mean age for healthy subjects and ESRD patients was 45 ± 12 and 63 ± 16 years, respectively. ESRD patients had higher cf-PWV (p = 0.0002), elevated AIx@HR75 (p = 0.003), and increased CPP (p = 0.001) compared to healthy subjects. The mean inter-visit differences for all stiffness indices were non-significant (p > 0.05), but the mean inter-operator differences for the cf-PWV were significant only in the healthy subject group (-0.7 m/s; p = 0.02). The ICCs between operators and visits were higher for the ESRD group compared to the healthy subjects (between operators, 0.870 vs 0.461; between visits, 0.830 vs 0.570). Distances were longer (p < 0.001), but less variable with the standard method compared to the direct method (healthy subjects, p = 0.036; ESRD, p = 0.39). There was a high rate of patient acceptance and minimal discomfort. CONCLUSIONS: Week-to-week measurements of cf-PWV and pulse wave analysis are highly reproducible in ESRD patients prior to hemodialysis treatment. The high reproducibility and minimal test-to-test variations encourage use of cf-PWV to monitor changes in arterial stiffness and the efficacy of interventions in ESRD patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02196610.

MISE EN CONTEXTE: L'accroissement de la rigidité des artères présente un risque élevé d'accidents cardiovasculaires ou de mortalité toutes causes confondues chez les patients souffrant d'insuffisance rénale terminale (IRT). La rigidité des artères est décelée par la mesure de la vitesse de l'onde de pouls carotido-fémorale (VOPcf). La technique impliquant l'intervention d'un opérateur, des préoccupations en matière de reproductibilité sont soulevées du fait que celle-ci peut représenter une source de biais dans l'évaluation de cette mesure. OBJECTIFS DE L'ÉTUDE: L'étude visait à évaluer la reproductibilité semaine après semaine des mesures de la VOPcf et de la VOP au niveau de l'artère radiale chez des sujets sains et des patients atteints d'IRT. On cherchait également à déterminer l'influence de facteurs tels l'admissibilité des patients, leur recrutement ainsi que leur tolérance et leur niveau de confort à l'égard de ces examens. MÉTHODOLOGIE: Lors de cette étude de cohorte, des examens tonométriques indépendants de la carotide et des artères fémorale et radiale ont été pratiqués sur un groupe de sujets sains (n = 20) et un groupe de patients atteints d'IRT (n = 15) sous hémodialyse chronique. Les examens ont été réalisés selon une séquence aléatoire, par deux opérateurs différents, à raison de deux séances prévues à une semaine d'intervalle. La VOPcf, l'indice d'augmentation ajusté sur une fréquence cardiaque de 75 bpm (AIx@HR75) et la pression centrale (CPP) ont été employés à titre d'indicateurs de résultats. Les patients ont été testés tout juste avant leur séance d'hémodialyse prévue en milieu de semaine. La variabilité dans la distance mesurée entre l'espace suprasternal et l'emplacement au niveau fémoral a été évaluée en utilisant deux méthodes différentes (méthode régulière et méthode directe) puis comparée. Un sondage remis aux participants à la suite de chaque test a permis de jauger l'acceptation et le niveau d'inconfort lié à l'examen. La reproductibilité du test a été évaluée par coefficient de corrélation inter-classes (ICC). RÉSULTATS: L'âge médian des participants se situait à 45 ± 12 ans pour les sujets sains et à 63 ± 16 chez les patients atteints d'IRT. Ces derniers présentaient des valeurs de VOPcf (p = 0,0002) et des AIx@HR75 supérieurs (p = 0,003) en plus d'une CCP plus élevée (p = 0,001) en comparaison aux valeurs obtenues chez les sujets sains. Dans l'ensemble, aucun des indices de la rigidité des artères n'a démontré de différence significative d'une séance à l'autre (p > 0,05) bien qu'une différence significative ait été notée dans la mesure de la VOPcf d'un opérateur à l'autre chez les sujets sains. Les valeurs d'ICC d'un opérateur à l'autre et inter-séance se sont avérées supérieures chez les patients atteints d'IRT lorsque comparées aux valeurs obtenues chez les sujets sains (entre opérateurs : 0,870 vs 0,461; inter-séances : 0,830 vs 0,570). Les distances mesurées entre l'espace suprasternal et l'emplacement fémoral se sont révélées plus longues (p < 0,001), mais moins variables lorsqu'évaluées par la méthode normalisée que par la méthode directe (sujets sains : p = 0,036; patients en IRT: p = 0,39). Finalement, les sondages post-examens ont indiqué un taux élevé d'acceptation et un inconfort minimal pour les participants. RÉSULTATS: Il apparait que les mesures de la VOPcf et l'analyse de l'onde de pouls sont très reproductibles d'une semaine à l'autre chez les patients atteints d'IRT lorsque mesurées tout juste avant la séance d'hémodialyse. Forte d'une reproductibilité élevée et doublée d'une variabilité minimale d'essai en essai, la mesure de la VOPcf s'avère une technique recommandée pour suivre les changements dans la rigidité artérielle chez les patients atteints d'IRT et assurer l'efficacité des interventions auprès de cette clientèle.

Auditory-evoked potentials during coma: do they improve our prediction of awakening in comatose patients?

OBJECTIVE: The mismatch negativity (MMN), an auditory event-related potential, has been identified as a good indicator of recovery of consciousness during coma. We explored the predictive value of the MMN and other auditory-evoked potentials including brainstem and middle-latency potentials for predicting awakening in comatose patients after cardiac arrest or cardiogenic shock. MATERIALS AND METHODS: Auditory brainstem, middle-latency (Pa wave), and event-related potentials (N100 and MMN waves) were recorded in 17 comatose patients and 9 surgical patients matched by age and coronary artery disease. Comatose patients were followed up daily to determine recovery of consciousness and classified as awakened and nonawakened. RESULTS: Among the auditory-evoked potentials, the presence or absence of MMN best discriminated between patients who awakened or those who did not. Mismatch negativity was present during coma in all patients who awakened (7/7) and in 2 of those (2/10) who did not awaken. In patients who awakened and in whom MMN was detected, 3 of those awakened between 2 and 3 days and 4 between 9 and 21 days after evoked potential examination. All awakened patients had intact N100 waves and identifiable brainstem and middle-latency waves. In nonawakened patients, N100 and Pa waves were detected in 5 cases (50%) and brainstem waves in 9 (90%). CONCLUSIONS: The MMN is a good predictor of awakening in comatose patients after cardiac arrest and cardiogenic shock and can be measured days before awakening encouraging ongoing life support.

Effect of 200µG/day of vitamin K1 on the variability of anticoagulation control in patients on warfarin: a randomized controlled trial.

BACKGROUND: Controversy exists whether low-dose vitamin K supplementation can improve anticoagulation control in patients with unstable anticoagulation under warfarin. In a single- centre randomized, double-blind, placebo-controlled study, we evaluated the effectiveness of 200 µg/day of vitamin K1 in patients with unstable control under warfarin. METHODS: Effectiveness of Vitamin K1 supplementation was primarily assessed by the percentage (%) of Time-in-Therapeutic-Range (TTR) and secondarily by the standard deviation (SD) of the patient's INR values; the proportion of out-of-range INRs; and the number of dose changes on warfarin. Their change scores were obtained by subtracting the mean value in the 6 months pre-randomization from the mean value in the 6 months post-randomization. Multivariable linear-regressions identified factors associated with anticoagulation instability. RESULTS: Fifty out of 54 patients were analyzed (intervention: n=26; placebo: n=24). Most indications (87%) for anticoagulation were venous thromboembolism (VTE). The intervention was associated with a greater reduction in the change scores for the SD of INRs between the pre and post-randomization periods compared with placebo. The mean change score was -0.259±0.307 with the intervention and -0.046±0.345 with placebo (p=0.026). There was no effect on the change scores of the (%) TTR (p=0.98), the number of INRs out-of-range (p=0.58) and the number of dose changes (p=0.604). Factors independently associated with increased variability in the SD of INRs were increased alcoholic drinks/week (p=0.017), dosing errors (p=0.0009) and missed INR appointments (p=0.035). CONCLUSION: Vitamin K1 supplementation reduces the SD of INRs as an indicator of the variability in anticoagulation control in patients treated with warfarin for VTE.

Long-lasting functional disabilities in patients who recover from coma after cardiac operations.

BACKGROUND: Uncertainty regarding the long-term functional outcome of patients who awaken from coma after cardiac operations is difficult for families and physicians and may delay rehabilitation. We studied the long-term functional status of these patients to determine if duration of coma predicted outcome. METHODS: We followed 71 patients who underwent cardiac operations; recovered their ability to respond to verbal commands after coma associated with postoperative stroke, encephalopathy, and/or seizures; and were discharged from the hospital. The Glasgow Outcome Scale Extended (GOSE) was used to assess functional disability 2 to 4 years after discharge. Outcomes were classified as favorable (GOSE scores 7 and 8) and unfavorable (GOSE scores 1-6). RESULTS: Of 71 patients identified, 39 were interviewed, 15 died, 1 refused to be interviewed, and 16 were lost to follow-up. Of the 54 patients with completed GOSE evaluations, only 15 (28%) had favorable outcomes. Among patients with unfavorable outcomes, 15 (28%) died, 14 (26%) survived with moderate disabilities, and 10 (18%) had severe disabilities. Factors associated with unfavorable outcomes were increases in duration of coma (p = 0.007), time in intensive care (p = 0.006), length of hospitalization (p = 0.004), and postoperative serum creatine kinase levels (p = 0.006). Only duration of coma was an independent predictor of unfavorable outcome (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.008-1.537; p = 0.042). Patients with durations of coma greater than 4 days were more likely to have unfavorable outcomes (OR, 5.1; 95% CI, 1.3-21.3; p = 0.02). CONCLUSIONS: Two thirds of comatose patients who survived to discharge after cardiac operations had unfavorable long-term functional outcomes. A longer duration of unconsciousness is a predictor of unfavorable outcome.

Predictors of duration of unconsciousness in patients with coma after cardiac surgery.

OBJECTIVES: To describe clinical and brain imaging characteristics of patients who recovered and did not recover consciousness from a coma after cardiac surgery and to investigate predictors of the duration of unconsciousness in those patients who ultimately recovered consciousness. DESIGN: A retrospective analysis from a cohort of patients who developed coma after cardiac surgery. SETTING: A single university hospital. PARTICIPANTS: One hundred twelve patients with postoperative stroke, encephalopathy, and/or seizures who remained in coma longer than 24 hours after cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors analyzed the patients' perioperative and intraoperative characteristics, laboratory values, noncontrast head computed tomography (CT) scans, and outcomes. Patients who did not recover consciousness (n = 16) were more likely to have been classified preoperatively as New York Heart Association class III/IV (p = 0.037). In patients who recovered consciousness (n = 96), only increased preoperative serum creatinine was an independent predictor of a longer duration of unconsciousness (p = 0.011). In patients who eventually recovered consciousness and had no acute findings on brain imaging, preoperative creatinine (p = 0.014), the lowest postoperative hemoglobin (p = 0.039), and surgical emergency (p = 0.045) were independent predictors of the duration of unconsciousness (p = 0.002). In patients who regained consciousness but had acute findings on brain imaging, cardiogenic shock (p = 0.012) and the insertion of an intra-aortic balloon pump before or during surgery (p = 0.025) predicted longer durations of unconsciousness (p < 0.001). CONCLUSIONS: In patients who ultimately recovered consciousness after being in a coma for at least 24 hours after cardiac surgery and have no abnormality on a brain CT scan, elevated preoperative serum creatinine, urgent cardiac surgery, and lower postoperative hemoglobin were correlated with an increased duration of unconsciousness.

Cerebral emboli detected by transcranial Doppler during cardiopulmonary bypass are not correlated with postoperative cognitive deficits.

BACKGROUND AND PURPOSE: High-intensity transient signals (HITS) are the transcranial Doppler representation of both air and solid cerebral emboli. We studied the frequency of HITS associated with different surgical maneuvers during cardiopulmonary bypass for coronary artery bypass graft surgery and their association with postoperative cognitive dysfunction (POCD). METHODS: We combined 356 patients undergoing coronary artery bypass graft from 2 clinical trials who had both neuropsychological testing (before, 1 week and 3 months after surgery) and transcranial Doppler during cardiopulmonary bypass. HITS were grouped into periods that included: cannulation, cardiopulmonary bypass onset, aortic crossclamp-on, aortic crossclamp-off, side clamp-on, side clamp-off, and decannulation. POCD was defined by a decreased combined Z-score of at least 2.0 or reduction in Z-scores of at least 2.0 in 20% of the individual tests. RESULTS: Incidence of POCD was 47.3% and 6.3% at 1 week and 3 months after surgery. There was no association between cardiopulmonary bypass counts of HITS and POCD at 1 week (P=0.617) and 3 months (P=0.110). No differences in HITS counts were identified at any of the surgical periods between patients with and without POCD. Factors affecting HITS counts were surgical period (P<0.0001), blood flow velocity (P=0.012), cardiopulmonary bypass duration (P=0.040), and clinical study (P=0.048). CONCLUSIONS: Although cerebral microemboli have been implicated in the pathogenesis of POCD, in this study that included low-risk patients undergoing coronary artery bypass surgery, there was no demonstrable correlation between the counts of HITS and POCD.

A method to distinguish between gaseous and solid cerebral emboli in patients with prosthetic heart valves.

BACKGROUND: The difficulty of distinguishing solid from air emboli using transcranial Doppler has limited its use in situations where both types of emboli can occur, such as in mechanical heart valve patients. To make transcranial Doppler clinically useful, a method must be found to distinguish benign air bubbles from the more damaging solid particulates. Since inhalation of 100% oxygen reduces the amount of air bubbles in mechanical heart valve patients, the ultrasonic features of the remaining emboli would be characteristic of solid particulates. OBJECTIVE: We determined the accuracy of the signal relative intensity measured with transcranial Doppler to distinguish between gaseous and non-gaseous emboli in mechanical heart valve patients examined during room air and 100% oxygen. Embolic signals detected in patients with bioprosthetic valves examined during 100% oxygen comprised the source of solid particulates. METHODS: Embolic signals were detected during room air (n=141) and 100% oxygen (n=45) from 17 mechanical valve patients at two Doppler examinations (4h and 4 days after surgery). Solid embolic signals (n=31) from seven patients with bioprosthetic valves were identified with 100% oxygen within the first 4h after surgery. Frequency plots and receiver operating characteristic curves assessed signal intensity differences between mechanical and bioprosthetic valve groups during 100% oxygen and the efficacy of the relative intensity for differentiating gaseous from solid emboli. RESULTS: Administration of 100% oxygen during transcranial Doppler examination in mechanical heart valve patients decreased the count of embolic signals compared with room air (p=0.006). The embolic signals of mechanical heart valve patients breathing 100% oxygen showed lower relative intensities compared with those during room air. The distribution of the signal relative intensity between mechanical and bioprosthetic valve groups during 100% oxygen was similar. A 16dB cut-off threshold achieved the best accuracy for differentiating non-gaseous from gaseous emboli (sensitivity: 60%; specificity: 82%; area: 0.721; p<0.0001). CONCLUSIONS: The use of a signal intensity cut-off offers adequate discrimination of the embolic composition in mechanical heart valve patients. Future studies evaluating prophylactic treatments of thrombosis in these patients should assess the predictive value of this intensity threshold and their potential association with outcome indicators and procoagulant markers.