Clinical effectiveness of therapy with continuous-flow left ventricular assist devices in nonischemic versus ischemic cardiomyopathy: a systematic review and meta-analysis.

Background: Clinicians may be less inclined to consider long-term left ventricular assist device (LVAD) therapy in end-stage heart failure (ESHF) as a result of nonischemic cardiomyopathy (NICM) versus ischemic cardiomyopathy (ICM) owing to potentially greater right ventricular involvement in the former; however, it is unknown whether the cause of heart failure has a clinically meaningful effect on outcomes following LVAD implantation. In this systematic review, we aimed to determine whether ischemic versus nonischemic etiology has any impact on patient-relevant outcomes. Methods: We searched MEDLINE, Embase, PubMed and the Cochrane Library for studies published in English between Jan. 1, 2000, and Nov. 22, 2018, that examined survival and transplantation rates following LVAD implantation in patients with NICM or ICM. Randomized clinical trials, cohort studies, case-control studies, cross-sectional studies and case series with a sample size of at least 8 patients were eligible for inclusion. To be included in the meta-analysis, outcomes had to include at least death reported at 30 days or 1 year after LVAD implantation. Quality of included studies was assessed by 2 independent reviewers using the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) quality-assessment tool was used to assess outcomes (30-d survival, 1-yr survival and cardiac transplantation following LVAD therapy) across studies. Results: From a total of 2843 citations identified, 7 studies met all inclusion criteria. Studies were generally of good quality, but reporting of patient demographic characteristics, outcomes and complications was heterogeneous. We found no significant difference in 30-day or 1-year survival or in cardiac transplantation rates after device implantation between the NICM and ICM groups. Patients in the 2 groups had similar outcomes up to 1 year with LVAD therapy. Conclusion: Early outcomes of LVAD therapy do not appear to be affected by heart failure etiology. Ongoing investigation is required to determine the long-term outcomes of LVAD therapy in ICM and NICM. Systematic review registration: PROSPERO register, record ID 76483.

Contexte: Les professionnels de la santé peuvent être moins enclins à envisager un traitement à long terme par dispositif d'assistance ventriculaire gauche (DAVG) en cas d'insuffisance cardiaque terminale résultant d'une myocardiopathie non ischémique plutôt que d'une myocardiopathie ischémique, en raison du risque potentiellement accru d'atteinte du ventricule droit dans le premier cas. Cependant, on ne sait pas si la cause de l'insuffisance cardiaque a un effet clinique significatif sur les issues après l'implantation d'un DAVG. Dans cette revue systématique, nous avons voulu déterminer si l'étiologie ischémique ou non ischémique a une incidence sur les issues pour les patients. Méthodes: Nous avons interrogé MEDLINE, Embase, PubMed et la Bibliothèque Cochrane pour trouver les études publiées en anglais entre le 1er janvier 2000 et le 22 novembre 2018 qui examinaient la survie et le taux de greffe après l'implantation d'un DAVG chez les patients atteints d'une insuffisance cardiaque ischémique ou non ischémique. Les essais cliniques randomisés, les études de cohorte, les études cas­témoins, les études transversales et les séries de cas ayant un échantillon d'au moins 8 patients étaient admissibles pour inclusion. Pour qu'une publication soit incluse dans la méta-analyse, les issues à l'étude devaient comprendre au minimum les décès dans les 30 jours ou dans l'année suivant l'implantation du DAVG. La qualité des études retenues a été évaluée par 2 évaluateurs indépendants au moyen de l'échelle Newcastle­Ottawa pour l'évaluation de la qualité des études de cohorte. L'outil GRADE (Grading of Recommendations Assessment, Development and Evaluation) a servi à évaluer la qualité des données sur les issues (survie après 30 jours, survie après 1 an et greffe cardiaque après le traitement par DAVG) dans l'ensemble des études. Résultats: Sur les 2843 citations recensées, 7 études respectaient tous les critères d'inclusion. Elles étaient généralement de bonne qualité, mais l'indication des caractéristiques démographiques des patients, des issues et des complications était hétérogène. Nous n'avons trouvé aucune différence significative dans la survie après 30 jours ou après 1 an, ni dans le taux de greffe cardiaque après l'implantation du dispositif entre les groupes ischémique et non ischémique. Les patients des 2 groupes avaient des issues similaires jusqu'à 1 an après le traitement par DAVG. Conclusion: Les issues à court terme du traitement par DAVG ne semblent pas influencées par l'étiologie de l'insuffisance cardiaque. Il faudra faire d'autres études pour caractériser les issues à long terme en présence d'insuffisance cardiaque ischémique et non ischémique. Enregistrement de la revue systématique: Registre PROSPERO, numéro 76483.

Integrating the multiple breath washout test into international multicentre trials.

BACKGROUND: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials. METHODS: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial. RESULTS: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%). CONCLUSION: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome.

Effect of changes in tidal volume on multiple breath washout outcomes.

The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early obstructive airway disease. For the MBW test to accurately reflect a subject's gas mixing within the lungs, the breathing pattern should represent physiologically appropriate tidal volumes (VT) and respiratory rate (RR). We aimed to assess whether changes in VT impact MBW outcome measures with a series of prospective and retrospective studies. MBW testing was performed using the Exhalyzer ® D (EcoMedics AG, Switzerland). Healthy adult subjects performed MBW with uninstructed tidal breathing and a series of instructed tidal breathing tests, designed to isolate specific features of the breathing pattern. In addition, we retrospectively analyzed MBW data from two pediatric multi-centre interventional studies of cystic fibrosis (CF) subjects to determine the range of VT observed during uninstructed breathing, and whether breathing outside this range impacted results. The LCI was lower, but not significantly different between deep breathing at 20 ml/kg body weight and uninstructed tidal breathing; whereas LCI was significantly higher during shallow breathing compared with normal tidal breathing. For the majority of subjects with CF (80%), VT ranged from 9-15mL/kg. Within the observed VT range, LCI was similar in trials with mean VT /kg below this range compared to trials with VT /kg within the range. If subjects breathe naturally and are not instructed to use specific targets, the range of VT is within physiologically appropriate limits and normal variations observed do not impact MBW outcomes.

Oral Azithromycin and Response to Pulmonary Exacerbations Treated with Intravenous Tobramycin in Children with Cystic Fibrosis.

Rationale: Intravenous tobramycin is frequently used to treat pulmonary exacerbations (PExs) in patients with cystic fibrosis (CF), but there is concern that azithromycin may interact with tobramycin, making it less effective against Pseudomonas aeruginosa. Objectives: The objective of this study was to determine whether oral azithromycin use was associated with worse lung function response to intravenous tobramycin treatment for PExs in a cohort of pediatric patients with CF with chronic P. aeruginosa infection. Methods: Pediatric patients from the Toronto CF database were included if they had at least one PEx and had chronic P. aeruginosa infection. Response to treatment was defined as change in forced expiratory volume in 1 second (FEV1) from start to end of treatment as well as recovery of FEV1 to greater than or equal to 90% of baseline (best FEV1 in the previous 6 mo). Response to treatment was compared between patients who had received chronic azithromycin (azithromycin users) and those who had not (azithromycin nonusers), using marginal structural modeling to account for baseline FEV1 as both a confounder and mediator. Results: There were 67 exacerbations (33 patients). Overall, 69% of azithromycin users and 61% of azithromycin nonusers returned to greater than or equal to 90% of baseline FEV1. However, after taking into account that azithromycin users had worse baseline FEV1 than azithromycin nonusers, relative improvement in FEV1 was 9.5% (95% confidence interval, -18.7 to -0.3) lower in azithromycin users than azithromycin nonusers. Conclusions: Although a similar proportion of children with CF with chronic P. aeruginosa infection on azithromycin recovered lung function compared with those not on azithromycin, when we consider these patients are sicker, azithromycin use was associated with less improvement in relative (but not absolute) FEV1 in patients treated with intravenous tobramycin for PExs.

The CF Canada-Sick Kids Program in individual CF therapy: A resource for the advancement of personalized medicine in CF.

BACKGROUND: Therapies targeting certain CFTR mutants have been approved, yet variations in clinical response highlight the need for in-vitro and genetic tools that predict patient-specific clinical outcomes. Toward this goal, the CF Canada-Sick Kids Program in Individual CF Therapy (CFIT) is generating a "first of its kind", comprehensive resource containing patient-specific cell cultures and data from 100 CF individuals that will enable modeling of therapeutic responses. METHODS: The CFIT program is generating: 1) nasal cells from drug naïve patients suitable for culture and the study of drug responses in vitro, 2) matched gene expression data obtained by sequencing the RNA from the primary nasal tissue, 3) whole genome sequencing of blood derived DNA from each of the 100 participants, 4) induced pluripotent stem cells (iPSCs) generated from each participant's blood sample, 5) CRISPR-edited isogenic control iPSC lines and 6) prospective clinical data from patients treated with CF modulators. RESULTS: To date, we have recruited 57 of 100 individuals to CFIT, most of whom are homozygous for F508del (to assess in-vitro: in-vivo correlations with respect to ORKAMBI response) or heterozygous for F508del and a minimal function mutation. In addition, several donors are homozygous for rare nonsense and missense mutations. Nasal epithelial cell cultures and matched iPSC lines are available for many of these donors. CONCLUSIONS: This accessible resource will enable development of tools that predict individual outcomes to current and emerging modulators targeting F508del-CFTR and facilitate therapy discovery for rare CF causing mutations.

The impact of delayed critical care outreach team activation on in-hospital mortality and other patient outcomes: a historical cohort study.

PURPOSE: Early warning scores (EWS) and critical care outreach teams (CCOT) have been developed to respond to decompensating patients. Nevertheless, controversy exists around their effectiveness. The primary objective of this study was to determine if a delay of ≥ 60 min between when a patient was identified as meeting EWS criteria and the CCOT was activated impacted in-hospital mortality. METHODS: This was a historical cohort study evaluating all new CCOT activations over a four-year study period (1 June 2007 to 31 August 2011) for inpatients ≥ 18 yr of age at two academic tertiary care hospitals in London, Ontario, Canada. Multivariable logistic regression accounting for repeated measures was used to determine the effect of delayed CCOT activation on in-hospital mortality (primary outcome). Differences in outcomes between medical and surgical patients were also examined. RESULTS: There were 3,133 CCOT activations for 1,684 (53.8%) medical patients and 1,449 (46.2%) surgical patients during the study period. The CCOT was activated < 60 min of a patient meeting EWS criteria in 2,160 (68.9%) cases and ≥ 60 min in 973 (31.1%) cases. Patients with ≥ 60 min delay were more likely be admitted to the intensive care unit (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.07 to 1.47) and to suffer in-hospital mortality (OR, 1.30; 95% CI, 1.08 to 1.56). Irrespective of delay, surgical patients were less likely to experience in-hospital mortality than medical patients (OR, 0.46; 95% CI, 0.39 to 0.55). CONCLUSION: Including the rates of delay in CCOT activation and the admitting service could be an additional step in exploring the conflicting results seen in the current literature assessing the impact of CCOT on patient outcomes.

Epidemiology of Clonal Pseudomonas aeruginosa Infection in a Canadian Cystic Fibrosis Population.

RATIONALE: The extent of the genetic relatedness among Pseudomonas aeruginosa isolates and its impact on clinical outcomes in the cystic fibrosis (CF) population is poorly understood. OBJECTIVES: The objectives of this study were to determine the prevalence of clonal P. aeruginosa infection in Canada and to associate P. aeruginosa genotypes with clinical outcomes. METHODS: This was an observational study of adult and pediatric patients with CF across Canada. Isolates were typed using multilocus sequence typing. A clone was defined as sharing at least six of seven alleles. Genotyping results were associated with clinical outcomes, including forced expiratory volume in 1 second, body mass index, rate of pulmonary exacerbation, and death/transplant. RESULTS: A total of 1,537 P. aeruginosa isolates were genotyped to 403 unique sequence types (STs) in 402 individuals with CF. Although 39% of STs were shared, most were shared only among a small number of subjects, and the majority (79%) of the genetic diversity in P. aeruginosa isolates was observed between patients. There were no significant differences in clinical outcomes according to genotype. However, patients with a dynamic, changing ST infection pattern had both a steeper decline in forced expiratory volume in 1 second (-2.9% predicted change/yr, 95% confidence interval [CI] = -3.8 to -1.9 compared with 0.4, 95% CI = -0.3 to 1.0; P < 0.001) and body mass index (-1.0 percentile change/yr, 95% CI = -1.6 to -0.3 compared with -0.1, 95% CI = -0.7 to 0.5; P = 0.047) than those with a stable infection with the same ST. CONCLUSIONS: There was no widespread sharing of dominant clones in our CF population, and the majority of the genetic diversity in P. aeruginosa was observed between patients. Changing genotypes over time within an individual was associated with worse clinical outcomes.

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment.

BACKGROUND: Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients. METHODS: Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent). RESULTS: Forty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10-6 µg/mL in Eradicated cases compared to 3 × 10-5 µg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection. CONCLUSIONS: Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates.

Echocardiography Grading for Pulmonary Arteriovenous Malformation Screening in Children with Hereditary Hemorrhagic Telangiectasia.

Transthoracic contrast echocardiography (TTCE) has high sensitivity but low specificity in screening for pulmonary arteriovenous malformations (pAVMs) in children with hereditary hemorrhagic telangiectasia (HHT). Here we describe characteristics of TTCE that might be used to reduce the need for confirmatory computed tomography scans in children with HHT.

Presentation and outcomes of necrotizing soft tissue infections.

BACKGROUND: Necrotizing soft tissue infections (NSTIs) are aggressive infections associated with significant morbidity, including amputation and organ failure, and high mortality. The rapid progression and significant risk of morbidity and mortality associated with NSTIs makes quick diagnosis and treatment critical. The objective of this study was to determine the presentation of patients diagnosed with NSTIs and their in-hospital outcomes. METHODS: This was a retrospective review of adult (>17 years) patients with a discharge diagnosis of necrotizing fasciitis at London Health Sciences Centre (annual census 125,000) over a 5-year period (April 2008-March 2013). RESULTS: Sixty patients with confirmed NSTI were included in this study. Common comorbidities at presentation included immunocompromise (58.3%), diabetes mellitus (41.7%), vascular disease (45.0%), and obesity (24.6%). Initial presentations included swelling (91.7%), erythema (86.7%), bullae (28.3%), petechiae (8.3%), and bruising (45.0%). Fifty (83.3%) underwent surgery, with a median (interquartile range) time from initial emergency department presentation to surgery of 15.5 hours (7.8, 74.9). In-hospital mortality among those who had surgical intervention was 14.0%, compared to 60.0% for patients who did not have surgery (Δ46.0%; 95% CI: 14.8% to 70.2%). CONCLUSION: Diabetes mellitus, immune-compromise, vascular disease, and obesity are common comorbidities of NSTIs. Survival is higher among patients who receive surgical treatment. Patients presenting with this clinical picture warrant a high degree of suspicion.

Extracorporeal membrane oxygenation (ECMO) as a treatment strategy for severe acute respiratory distress syndrome (ARDS) in the low tidal volume era: A systematic review.

OBJECTIVE: To evaluate the hospital survival in patients with severe ARDS managed with ECMO and low tidal volume ventilation as compared to patients managed with low tidal volume ventilation alone. METHODS: Electronic databases were searched for studies of at least 10 adult patients with severe ARDS comparing the use of ECMO with low tidal volume ventilation to mechanical ventilation with a low tidal volume alone. Only studies reporting hospital or ICU survival were included. All identified studies were assessed independently by two reviewers. RESULTS: Of 1782 citations, 27 studies (n=1674) met inclusion criteria. Hospital survival for ECMO patients ranged from 33.3 to 86%, while survival with conventional therapy ranged from 36.3 to 71.2%. Five studies were identified with appropriate control groups allowing comparison, but due to the high degree of variability between studies (I2=63%), their results could not be pooled. Two of these studies demonstrated a significant difference, both favouring ECMO over conventional therapy. CONCLUSION: Given the lack of studies with appropriate control groups, our confidence in a difference in outcome between the two therapies remains weak. Future studies on the use of ECMO for severe ARDS are needed to clarify the role of ECMO in this disease.

Pilot trial of tobramycin inhalation powder in cystic fibrosis patients with chronic Burkholderia cepacia complex infection.

There is no effective chronic suppressive therapy Burkholderia cepacia complex infection in cystic fibrosis (CF) patients. This was a pilot, open-label clinical trial of tobramycin inhalation powder (TIP) delivered via Podhaler twice daily for 28days in adults and children with CF and chronic B. cepacia complex infection in Toronto, Canada. A total of 10 subjects (4 pediatric, 6 adult patients) were treated. There was a mean drop of 1.4 log (CFU/ml) in sputum bacterial density (p=0.01) and sputum IL-8 levels decreased significantly after 28days of TIP (p=0.04). The mean relative change in FEV1 (L) from Day 0 to Day 28 of TIP administration was a 4.6% increase but this was not statistically significant. The majority of patients (70%) had no or mild adverse events.

Longitudinal study of Stenotrophomonas maltophilia antibody levels and outcomes in cystic fibrosis patients.

BACKGROUND: Previous studies have shown an association between higher Stenotrophomonas maltophilia antibody levels and decreased lung function in patients with cystic fibrosis (CF). The purpose of this study was to assess the serologic response to S. maltophilia over time and to determine whether changes in antibody levels could predict clinical outcomes. METHODS: Changes in S. maltophilia antibody levels in adult and pediatric patients with CF from 2008 to 2014 were assessed between groups of infection patterns. Regression models accounting for repeated measures were used to assess whether antibody levels could predict subsequent S. maltophilia microbiological status, and whether they are associated with lung function and subsequent pulmonary exacerbation. RESULTS: A total of 409 S. maltophilia antibody samples from 135 CF patients showed that antibody levels did not change significantly between study visits, regardless of infection group. Higher antibody levels were independently associated with future culture positivity (OR 1.62; 95% CI 1.09, 2.41; p=0.02). While higher antibody levels were not independently associated with decreases in FEV1% predicted, they were associated with an increased hazard ratio for subsequent pulmonary exacerbation (HR 1.3; 95% CI 1.1, 1.6; p<0.001). CONCLUSIONS: S. maltophilia antibody levels may be helpful to identify individuals at risk of exacerbation who may benefit from earlier antimicrobial treatment.

Reducing length of stay and satisfying learner needs.

A complicated relationship exists between emergency department (ED) learner needs and patient flow with solutions to one issue often negatively affecting the other. Teaching shifts that allow clinical teachers and learners to interact without the pressure of patient care may offer a mutually beneficial solution. This study investigated the relationship between teaching shifts on ED length of stay, student self-efficacy and knowledge application.In 2012-2013, a prospective, cohort study was undertaken in a large Canadian acute-care teaching centre. All 132 clinical clerks completing their mandatory two-week emergency medicine rotation participated in three teaching shifts supervised by one faculty member without patient care responsibilities. The curriculum emphasized advanced clinical skills and included low fidelity simulation exercises, a suturing lab, image interpretation modules and discussion about psychosocial issues in emergency medicine. The clerks then completed seven clinical shifts in the traditional manner caring for patients under the supervision of an ED attending physician. Length of stay was compared during and one week following teaching shifts. A self-efficacy questionnaire was validated through exploratory factor analysis. Pre/post knowledge application was assessed using a paper-based clinical case activity.Across 40.998 patient visits, median length of stay was shortened overall by 5 minutes (95 % CI:1.2, 8.8) when clerks were involved in their teaching shifts. In the first academic block, median length of stay was reduced by 20 minutes per patient (95 % CI:12.7, 27.3). Self-efficacy showed significant improvement post teaching shifts (p < 0.001) with large effect sizes (d > 1.25) on dimensions of knowledge base, suturing, trauma and team efficacy. Students' knowledge application scores improved from pre to post (p < 0.01), with notable gains in the generation of differential diagnoses.Teaching shifts are an effective educational intervention that has a positive relation to ED patient flow while successfully attending to learner needs. Teaching shifts for the most naïve clerks in the first academic block appear to maximally benefit length of stay. Students demonstrated improved self-efficacy and knowledge application after their teaching shifts.

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality.

BACKGROUND: Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria. METHODS: 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic). RESULTS: Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53-0.83%) to (κ 0.73-0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis. CONCLUSIONS: The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.