Publications by authors named "John Granton"

189 Publications

Pulmonary referrals to specialist palliative medicine: a survey.

BMJ Support Palliat Care 2021 Dec 3. Epub 2021 Dec 3.

Department of Supportive Care, University Health Network, Toronto, Ontario, Canada

Objectives: Patients with chronic respiratory disease have significant palliative care needs, but low utilisation of specialist palliative care (SPC) services. Decreased access to SPC results in unmet palliative care needs among this patient population. We sought to determine the referral practices to SPC among respirologists in Canada.

Methods: Respirologists across Canada were invited to participate in a survey about their referral practices to SPC. Associations between referral practices and demographic, professional and attitudinal factors were analysed using regression analyses.

Results: The response rate was 64.7% (438/677). Fifty-nine per cent of respondents believed that their patients have negative perceptions of palliative care and 39% were more likely to refer to SPC earlier if it was renamed supportive care. While only 2.7% never referred to SPC, referral was late in 52.6% of referring physicians. Lower frequency of referral was associated with equating palliative care to end-of-life care (p<0.001), male sex of respirologist (p=0.019), not knowing referral criteria of SPC services (p=0.015) and agreement that SPC services prioritise patients with cancer (p=0.025); higher referral frequency was associated with satisfaction with SPC services (p=0.001). Late referral was associated with equating palliative care to end-of-life care (p<0.001) and agreement that SPC services prioritise patients with cancer (p=0.013).

Conclusions: Possible barriers to respirologists' timely SPC referral include misperceptions about palliative care, lack of awareness of referral criteria and the belief that SPC services prioritise patients with cancer. Future studies should confirm these barriers and evaluate the effectiveness of strategies to overcome them.
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http://dx.doi.org/10.1136/bmjspcare-2021-003386DOI Listing
December 2021

Global trends in chronic thromboembolic pulmonary hypertension clinical trials and dissemination of results.

Pulm Circ 2021 Oct-Dec;11(4):20458940211059994. Epub 2021 Nov 18.

Division of Thoracic Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Treatment options for chronic thromboembolic pulmonary hypertension (CTEPH) are rapidly expanding. The purpose of this study is to identify trends in CTEPH clinical trials and the publication of results. We performed a worldwide review of completed and ongoing clinical trials through searching the ClinicalTrials.gov database and the World Health Organization International Clinical Trials Registry Platform for "CTEPH" and related terms. Entries were classified as pharmaceutical/procedural interventions (Group 1), all other clinical trials (Group 2) and patient registries (Group 3). Trial characteristics and national affiliation were recorded. PubMed was searched for related publications. There were 117 clinical trials registry entries after removing duplicates and non-target records. Group 1 comprised 29 pharmaceutical, 15 procedural, and four combined interventions starting in 2005, 2010, and 2016, respectively. Riociguat and balloon pulmonary angioplasty were the most frequent pharmaceutical and procedural interventions, respectively. The proportion of procedural trials increased over time from 0% of those in 2005-2009 to 29% in 2010-2014 and 54% in 2015-2020. There were 56 entries in Group 2 and 13 in Group 3. Japan was the most frequent national affiliation and the most frequent participating country, present in 28% of all trials. The proportion of entries with published results was highest with Group 3 (62%) and lowest with Group 1 (27%). Thirty percent of all publications occurred in 2020. In conclusion, CTEPH clinical trials are increasingly procedural based, with growth largely attributable to Japan and balloon pulmonary angioplasty. Most trials have not published, but results from balloon pulmonary angioplasty clinical trials are anticipated soon.
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http://dx.doi.org/10.1177/20458940211059994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606729PMC
November 2021

Hospital outbreak of the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) delta variant in partially and fully vaccinated patients and healthcare workers in Toronto, Canada.

Infect Control Hosp Epidemiol 2021 Oct 28:1-4. Epub 2021 Oct 28.

Infection Prevention and Control Department, University Health Network, Toronto, Ontario, Canada.

The severe acute respiratory coronavirus virus 2 (SARS-CoV-2) delta variant is highly transmissible, and current vaccines may have reduced effectiveness in preventing symptomatic infection. Using epidemiological and genomic analyses, we investigated an outbreak of the variant in an acute-care setting among partially and fully vaccinated individuals. Effective outbreak control was achieved using standard measures.
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http://dx.doi.org/10.1017/ice.2021.471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593380PMC
October 2021

Effect of Probiotics on Incident Ventilator-Associated Pneumonia in Critically Ill Patients: A Randomized Clinical Trial.

JAMA 2021 09;326(11):1024-1033

Université de Sherbrooke, Sherbrooke, Canada.

Importance: Growing interest in microbial dysbiosis during critical illness has raised questions about the therapeutic potential of microbiome modification with probiotics. Prior randomized trials in this population suggest that probiotics reduce infection, particularly ventilator-associated pneumonia (VAP), although probiotic-associated infections have also been reported.

Objective: To evaluate the effect of Lactobacillus rhamnosus GG on preventing VAP, additional infections, and other clinically important outcomes in the intensive care unit (ICU).

Design, Setting, And Participants: Randomized placebo-controlled trial in 44 ICUs in Canada, the United States, and Saudi Arabia enrolling adults predicted to require mechanical ventilation for at least 72 hours. A total of 2653 patients were enrolled from October 2013 to March 2019 (final follow-up, October 2020).

Interventions: Enteral L rhamnosus GG (1 × 1010 colony-forming units) (n = 1321) or placebo (n = 1332) twice daily in the ICU.

Main Outcomes And Measures: The primary outcome was VAP determined by duplicate blinded central adjudication. Secondary outcomes were other ICU-acquired infections including Clostridioides difficile infection, diarrhea, antimicrobial use, ICU and hospital length of stay, and mortality.

Results: Among 2653 randomized patients (mean age, 59.8 years [SD], 16.5 years), 2650 (99.9%) completed the trial (mean age, 59.8 years [SD], 16.5 years; 1063 women [40.1%.] with a mean Acute Physiology and Chronic Health Evaluation II score of 22.0 (SD, 7.8) and received the study product for a median of 9 days (IQR, 5-15 days). VAP developed among 289 of 1318 patients (21.9%) receiving probiotics vs 284 of 1332 controls (21.3%; hazard ratio [HR], 1.03 (95% CI, 0.87-1.22; P = .73, absolute difference, 0.6%, 95% CI, -2.5% to 3.7%). None of the 20 prespecified secondary outcomes, including other ICU-acquired infections, diarrhea, antimicrobial use, mortality, or length of stay showed a significant difference. Fifteen patients (1.1%) receiving probiotics vs 1 (0.1%) in the control group experienced the adverse event of L rhamnosus in a sterile site or the sole or predominant organism in a nonsterile site (odds ratio, 14.02; 95% CI, 1.79-109.58; P < .001).

Conclusions And Relevance: Among critically ill patients requiring mechanical ventilation, administration of the probiotic L rhamnosus GG compared with placebo, resulted in no significant difference in the development of ventilator-associated pneumonia. These findings do not support the use of L rhamnosus GG in critically ill patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02462590.
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http://dx.doi.org/10.1001/jama.2021.13355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456390PMC
September 2021

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

J Heart Lung Transplant 2021 11 3;40(11):1301-1326. Epub 2021 Aug 3.

Pulmonary Hypertension and CTEPH Research Program, Temple Heart and Vascular Institute, Temple University, Lewis Katz School of Medicine, Philadelphia, Pennsylvania.

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.
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http://dx.doi.org/10.1016/j.healun.2021.07.020DOI Listing
November 2021

Pulmonary arterial hypertension in pregnancy-a systematic review of outcomes in the modern era.

Pulm Circ 2021 Apr-Jun;11(2):20458940211013671. Epub 2021 May 14.

Division of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada.

Pregnancy is hazardous with pulmonary arterial hypertension, but maternal mortality may have fallen in recent years. We sought to systematically evaluate pulmonary arterial hypertension and pregnancy-related outcomes in the last decade. We searched for articles describing outcomes in pregnancy cohorts published between 2008 and 2018. A total of 3658 titles were screened and 13 studies included for analysis. Pooled incidences and percentages of maternal and perinatal outcomes were calculated. Results showed that out of 272 pregnancies, 214 pregnancies advanced beyond 20 gestational weeks. The mean maternal age was 28 ± 2 years, mean pulmonary artery systolic pressure on echocardiogram was 76 ± 19 mmHg. Etiologies include idiopathic pulmonary arterial hypertension (22%), congenital heart disease (64%), and others (15%). Majority (74%) had good functional class I/II. Only 48% of women received pulmonary arterial hypertension-specific therapy. Premature deliveries occur in 58% of pregnancies at mean of 34 ± 1 weeks, most (76%) had Cesarean section. Maternal mortality rate was 12% overall ( = 26); even higher for idiopathic pulmonary arterial hypertension etiology alone (20%). Reported causes of death included right heart failure, cardiac arrest, pulmonary arterial hypertension crises, pre-eclampsia, and sepsis; 61% of maternal deaths occur at 0-4 days postpartum. Stillbirth rate was 3% and neonatal mortality rate was 1%. In conclusion, pulmonary arterial hypertension in pregnancy continues to be perilous with high maternal mortality rate. Continued prospective studies are needed.
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http://dx.doi.org/10.1177/20458940211013671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172332PMC
May 2021

Pseudo Heparin Resistance After Pulmonary Endarterectomy: Role of Thrombus Production of Factor VIII.

Semin Thorac Cardiovasc Surg 2021 May 10. Epub 2021 May 10.

Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada; Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Pulmonary endarterectomy (PEA) is the main treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative unfractionated heparin dosing can be monitored by activated partial thromboplastin time (APTT) or by anti-factor Xa activity (anti-Xa). In pseudo heparin resistance, APTT response to heparin is blunted due to elevated Factor VIII (FVIII) which can underestimate anticoagulation. We examined possible pseudo heparin resistance after PEA and assessed the impact of FVIII. APTT response to heparin before and after operation was determined in 13 PEA patients anticoagulated with unfractionated heparin. APTT and anti-Xa concordance was analyzed from paired postoperative samples, and antithrombin, fibrinogen and FVIII levels were measured. Single-cell RNA sequencing was used to characterize FVIII gene expression in PEA specimens of 5 patients. APTT response to heparin was blunted after PEA. APTT and anti-Xa were discordant in 36% of postoperative samples and most common discordant patterns were subtherapeutic APTT with therapeutic (16%) or supratherapeutic (11%) anti-Xa. Overall, APTT underestimated anticoagulation relative to anti-Xa in one-third of the samples. FVIII levels were elevated before surgery, increased substantially 1 and 3 days (median 4.32 IU/mL) after PEA, and were higher in discordant than concordant samples. Single-cell RNA sequencing showed FVIII gene expression in PEA specimen endothelial cells. Pseudo heparin resistance is common after PEA likely due to highly elevated postoperative FVIII levels indicating that anti-Xa reflects postoperative heparinization better than APTT in these patients. FVIII production by the pulmonary artery endothelium may participate in local prothrombotic processes important for CTEPH pathogenesis.
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http://dx.doi.org/10.1053/j.semtcvs.2021.03.042DOI Listing
May 2021

Contrasting haemodynamic effects of exercise and saline infusion in older adults with pulmonary arterial hypertension.

ERJ Open Res 2021 Jan 22;7(1). Epub 2021 Mar 22.

Division of Cardiology, Mount Sinai Hospital/University Health Network, Toronto, Canada.

https://bit.ly/35Mb0dv.
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http://dx.doi.org/10.1183/23120541.00183-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983276PMC
January 2021

Clinical Implications of Body Composition and Exercise Capacity Following Pulmonary Endarterectomy.

Ann Thorac Surg 2022 Feb 3;113(2):444-451. Epub 2021 Mar 3.

Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Respirology, Lung Transplant Program, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: Pulmonary endarterectomy (PEA) is a curative procedure for patients with chronic thromboembolic pulmonary hypertension. Body composition and exercise capacity have been associated with adverse outcomes in patients undergoing cardiothoracic operations, but their significance with PEA is unclear. We evaluated the association of body composition and 6-minute walk distance (6MWD) with disease severity, hospital length of stay, discharge disposition, and postoperative functional recovery.

Methods: This was a retrospective, single-center cohort study of patients who underwent PEA (January 2014-December 2017). Body composition (skeletal muscle mass and adiposity cross-sectional area) was quantified using thoracic computed tomography with sliceOmatic (TomoVision, Magog, QC, Canada) software. Body mass index was calculated. Association of body composition measures and 6MWD with clinical outcomes was evaluated using multivariable regression models.

Results: The study included 127 patients (42% men), aged 58 ± 14 years; body mass index was 31 ± 7 kg/m and 6MWD was 361 ± 165 m). Muscle and 6MWD were associated with disease severity measures. Of those surviving hospitalization (n = 125), a greater 6MWD was associated with a shorter hospital stay (1.9 median days per 100 m; p < .001) and higher likelihood of being discharged directly home from hospital (odds ratio, 2.1 per 100 m; P = .004), independent of age, sex, and body mass index. Those with a lower preoperative 6MWD (per 100 m) had a greater increase in their postoperative 6MWD (52 m; P < .0001), independent of age, sex, and body mass index. Body composition measures were not associated with hospital outcomes or exercise capacity in the first year postoperatively.

Conclusions: Exercise capacity was a more prognostic marker of PEA outcomes compared with body composition. Future research is needed to explore pre-PEA rehabilitation strategies.
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http://dx.doi.org/10.1016/j.athoracsur.2021.01.066DOI Listing
February 2022

Quantitative assessment of pulmonary artery occlusion using lung dynamic perfusion CT.

Sci Rep 2021 01 12;11(1):483. Epub 2021 Jan 12.

Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.

Quantitative measurement of lung perfusion is a promising tool to evaluate lung pathophysiology as well as to assess disease severity and monitor treatment. However, this novel technique has not been adopted clinically due to various technical and physiological challenges; and it is still in the early developmental phase where the correlation between lung pathophysiology and perfusion maps is being explored. The purpose of this research work is to quantify the impact of pulmonary artery occlusion on lung perfusion indices using lung dynamic perfusion CT (DPCT). We performed Lung DPCT in ten anesthetized, mechanically ventilated juvenile pigs (18.6-20.2 kg) with a range of reversible pulmonary artery occlusions (0%, 40-59%, 60-79%, 80-99%, and 100%) created with a balloon catheter. For each arterial occlusion, DPCT data was analyzed using first-pass kinetics to derive blood flow (BF), blood volume (BV) and mean transit time (MTT) perfusion maps. Two radiologists qualitatively assessed perfusion maps for the presence or absence of perfusion defects. Perfusion maps were also analyzed quantitatively using a linear segmented mixed model to determine the thresholds of arterial occlusion associated with perfusion derangement. Inter-observer agreement was assessed using Kappa statistics. Correlation between arterial occlusion and perfusion indices was evaluated using the Spearman-rank correlation coefficient. Our results determined that perfusion defects were detected qualitatively in BF, BV and MTT perfusion maps for occlusions larger than 55%, 80% and 55% respectively. Inter-observer agreement was very good with Kappa scores > 0.92. Quantitative analysis of the perfusion maps determined the arterial occlusion threshold for perfusion defects was 50%, 76% and 44% for BF, BV and MTT respectively. Spearman-rank correlation coefficients between arterial occlusion and normalized perfusion values were strong (- 0.92, - 0.72, and 0.78 for BF, BV and MTT, respectively) and were statically significant (p < 0.01). These findings demonstrate that lung DPCT enables quantification and stratification of pulmonary artery occlusion into three categories: mild, moderate and severe. Severe (occlusion ≥ 80%) alters all perfusion indices; mild (occlusion < 55%) has no detectable effect. Moderate (occlusion 55-80%) impacts BF and MTT but BV is preserved.
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http://dx.doi.org/10.1038/s41598-020-80177-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804280PMC
January 2021

Importance of computed tomography in defining segmental disease in chronic thromboembolic pulmonary hypertension.

ERJ Open Res 2020 Oct 7;6(4). Epub 2020 Dec 7.

Division of Thoracic Surgery, Dept of Surgery, University of Toronto, Toronto, ON, Canada.

Background: Radiological assessment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is critical to decide whether patients should be treated with pulmonary endarterectomy (PEA). Although computed tomography pulmonary angiography (CTPA) is increasingly used for decision making in CTEPH, the value of CTPA to predict surgical findings and outcome has never been explored.

Methods: We retrospectively reviewed 100 consecutive patients with high-quality CTPA undergoing PEA for CTEPH between May 2015 and December 2017. The most proximal level of disease in the pulmonary artery on CTPA was classified by two blinded radiologists as level 1 (main pulmonary artery), 2a (lobar pulmonary artery), 2b (origin of basal segmental pulmonary artery), 3 (segmental pulmonary artery) or 4 (predominantly subsegmental pulmonary artery).

Results: CTPA demonstrated level 1 in 20%, level 2a in 43%, level 2b in 11%, level 3 in 23% and level 4 in 3%. A majority of males presented with level 1 (55%) and level 2 (57%), and a majority of females (83%) with level 3 (p=0.01). Levels 3 and 4 were associated with longer duration of circulatory arrest (p=0.03) and higher frequency of Jamieson type III disease at surgery (p<0.0001). Requirement for targeted pulmonary hypertension therapy after PEA was 28% at 3 years in level 2b/3/4 compared with 6% in level 2a and 13% in level 1 (p=0.002). Level 2b/3/4 was an independent predictor for targeted pulmonary hypertension therapy after PEA (hazard ratio 4.23, 95% CI 1.24-14.39; p=0.02).

Conclusions: High-quality CTPA provides accurate evaluation of CTEPH patients. The level of disease on CTPA can help guide peri-operative planning and post-operative monitoring.
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http://dx.doi.org/10.1183/23120541.00461-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720691PMC
October 2020

Pregnant with pulmonary arterial hypertension - Can we handle the pressure?

Int J Cardiol 2021 04 18;328:180-181. Epub 2020 Nov 18.

Division of Respirology, University Health Network, Toronto, ON, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2020.11.036DOI Listing
April 2021

Normal and Abnormal Relationships of Pulmonary Artery to Wedge Pressure During Exercise.

J Am Heart Assoc 2020 11 6;9(22):e016339. Epub 2020 Nov 6.

Division of Cardiology Mount Sinai Hospital, Sinai Health Toronto Ontario Canada.

Background Resting right heart catheterization can assess both left heart filling and pulmonary artery (PA) pressures to identify and classify pulmonary hypertension. Although exercise may further elucidate hemodynamic abnormalities, current pulmonary hypertension classifications do not consider the expected interrelationship between PA and left heart filling pressures. This study explored the utility of this relationship to enhance the classification of exercise hemodynamic phenotypes in pulmonary hypertension. Methods and Results Data from 36 healthy individuals (55, 50-60 years, 50% male) and 85 consecutive patients (60, 49-71 years, 48% male) with dyspnea and/or suspected pulmonary hypertension of uncertain etiology were analyzed. Right heart catheterization was performed at rest and during semiupright submaximal cycling. To classify exercise phenotypes in patients, upper 95% CIs were identified from the healthy individuals for the change from rest to exercise in mean PA pressure over cardiac output (ΔmPAP/ΔCO ≤3.2 Wood units [WU]), pulmonary artery wedge pressure over CO (ΔPAWP/ΔCO ≤2 mm Hg/L per minute), and exercise PA pulse pressure over PAWP (PP/PAWP ≤2.5). Among patients with a ΔmPAP/ΔCO ≤3.2 WU, the majority (84%) demonstrated a ΔPAWP/ΔCO ≤2 mm Hg/L per minute, yet 23% demonstrated an exercise PP/PAWP >2.5. Among patients with a ΔmPAP/ΔCO >3.2 WU, 37% had an exercise PP/PAWP >2.5 split between ΔPAWP/ΔCO groups. Patients with normal hemodynamic classification declined from 52% at rest to 36% with exercise. Conclusions The addition of PP/PAWP to classify exercise hemodynamics uncovers previously unrecognized abnormal phenotypes within each ΔmPAP/ΔCO group. Our study refines abnormal exercise hemodynamic phenotypes based on an understanding of the interrelationship between PA and left heart filling pressures.
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http://dx.doi.org/10.1161/JAHA.120.016339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763717PMC
November 2020

Dosing Fluids in Early Septic Shock.

Chest 2021 04 13;159(4):1493-1502. Epub 2020 Oct 13.

Department of Medicine, McMaster University, Hamilton, ON, Canada; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada. Electronic address:

Early IV fluid administration remains one of the modern pillars of sepsis treatment; however, questions regarding amount, type, rate, mechanism of action, and even the benefits of fluid remain unanswered. Administering the optimal fluid volume is important, because overzealous fluid resuscitation can precipitate multiorgan failure, prolong mechanical ventilation, and worsen patient outcomes. After the initial resuscitation, further fluid administration should be determined by individual patient factors and measures of fluid responsiveness. This review describes various static and dynamic measures that are used to assess fluid responsiveness and summarizes the evidence addressing these metrics. Subsequently, we outline a practical approach to the evaluation of fluid responsiveness in early septic shock and explore further areas crucial to ongoing research examining this topic.
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http://dx.doi.org/10.1016/j.chest.2020.09.269DOI Listing
April 2021

In-House, Overnight Physician Staffing: A Cross-Sectional Survey of Canadian Adult ICUs.

Crit Care Med 2020 12;48(12):e1203-e1210

Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Objectives: Overnight physician staffing in the ICU has been recommended by the Society of Critical Care Medicine and the Leapfrog Consortium. We conducted a survey to review practice in the current era and to compare this with results from a 2006 survey.

Design: Cross-sectional survey.

Setting: Canadian adult ICUs.

Participants: ICU directors.

Interventions: None.

Measurement And Main Results: A 29-question survey was sent to ICU directors describing overnight staffing by residents, fellows, nurse practitioners, and staff physicians, as well as duty duration, clinical responsibilities, and unit characteristics. We established contact with 122 ICU directors, of whom 107 (88%) responded. Of the 107 units, 60 (56%) had overnight in-house physicians. Compared with ICUs without overnight in-house physician coverage, ICUs with in-house physicians were in larger hospitals (p < 0.0001), had more beds (p < 0.0001), had more ventilated patients (p < 0.0001), and had more admissions (p < 0.0001). Overnight in-house physicians were first year residents (R1) in 20 of 60 (33%), second to fifth year residents (R2-R5) in 46 of 60 (77%), and Critical Care Medicine trainees in 19 of 60 (32%). Advanced practice nurses provided overnight coverage in four of 107 ICUs (4%). The most senior in-house physician was a staff physician in 12 of 60 ICUs (20%), a Critical Care Medicine trainee in 14 of 60 (23%), and a resident (R2-R5) in 20 of 60 (33%). The duration of overnight duty was on average 20-24 hours in 22 of 46 units (48%) with R2-R5 residents and 14 of 19 units (74%) covered by Critical Care Medicine trainees.

Conclusions: Variability of in-house overnight physician presence in Canadian adult ICUs is linked to therapeutic complexity and unit characteristics and has not changed significantly over the decade since our 2006 survey. Additional evidence about patient and resident outcomes would better inform decisions to revise physician scheduling in Canadian ICUs.
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http://dx.doi.org/10.1097/CCM.0000000000004598DOI Listing
December 2020

Incident pulmonary arterial hypertension associated with Bosutinib.

Pulm Circ 2020 Jul-Sep;10(3):2045894020936913. Epub 2020 Aug 21.

Division of Respirology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Pulmonary arterial hypertension is associated with tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia. Dasatinib is a known cause of drug-induced pulmonary arterial hypertension. There have been case reports linking Bosutinib with deterioration of pre-existing pulmonary arterial hypertension. Here, we present a case of a 37-year-old woman with chronic myeloid leukemia treated with Bosutinib who was diagnosed with pulmonary arterial hypertension. Prior to Bosutinib, she had received Dasatinib without documented cardiopulmonary toxicity. Withdrawal of Bosutinib led to partial reversal of pulmonary arterial hypertension, and with the addition of pulmonary arterial hypertension-targeted treatment, there was near normalization of hemodynamics.
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http://dx.doi.org/10.1177/2045894020936913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443988PMC
August 2020

Augmentation of pulmonary blood flow and cardiac output by non-invasive external ventilation late after Fontan palliation.

Heart 2021 01 6;107(2):142-149. Epub 2020 Jul 6.

Toronto Congenital Cardiac Center for Adults, Peter Munk Cardiac Center, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada

Objectives: Although a life-preserving surgery for children with single ventricle physiology, the Fontan palliation is associated with striking morbidity and mortality with advancing age. Our primary objective was to evaluate the impact of non-invasive, external, thoraco-abdominal ventilation on pulmonary blood flow (PBF) and cardiac output (CO) as measured by cardiovascular magnetic resonance (CMR) imaging in adult Fontan subjects.

Methods: Adults with a dominant left ventricle post-Fontan palliation (lateral tunnel or extracardiac connections) and healthy controls matched by sex and age were studied. We evaluated vascular flows using phase-contrast CMR imaging during unassisted breathing, negative pressure ventilation (NPV) and biphasic ventilation (BPV). Measurements were made within target vessels (aorta, pulmonary arteries, vena cavae and Fontan circuit) at baseline and during each ventilation mode.

Results: Ten Fontan subjects (50% male, 24.5 years (IQR 20.8-34.0)) and 10 matched controls were studied. Changes in PBF and CO, respectively, were greater following BPV as compared with NPV. In subjects during NPV, PBF increased by 8% (Δ0.20 L/min/m (0.10-0.53), p=0.011) while CO did not change significantly (Δ0.17 L/min/m (-0.11-0.23), p=0.432); during BPV, PBF increased by 25% (Δ0.61 L/min/m (0.20-0.84), p=0.002) and CO increased by 16% (Δ0.47 L/min/m (0.21-0.71), p=0.010). Following BPV, change in PBF and CO were both significantly higher in subjects versus controls (0.61 L/min/m (0.2-0.84) vs -0.27 L/min/m (-0.55-0.13), p=0.001; and 0.47 L/min/m (0.21-0.71) vs 0.07 L/min/m (-0.47-0.33), p=0.034, respectively).

Conclusion: External ventilation acutely augments PBF and CO in adult Fontan subjects. Confirmation of these findings in larger populations with longer duration of ventilation and extended follow-up will be required to determine sustainability of haemodynamic effects.
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http://dx.doi.org/10.1136/heartjnl-2020-316613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788264PMC
January 2021

Association of preoperative spirometry with cardiopulmonary fitness and postoperative outcomes in surgical patients: .

EClinicalMedicine 2020 Jun 6;23:100396. Epub 2020 Jun 6.

Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, ON, Canada.

Background: Preoperative spirometry and cardiopulmonary exercise testing (CPET) may stratify risk for respiratory complications. This secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) study examined whether CPET performance (i.e., cardiopulmonary fitness) confounds associations of spirometry with outcomes.

Methods: The analysis included 1200 participants having major non-cardiac surgery at 25 hospitals in Canada, Australia, New Zealand and UK. Forced expiratory volume in 1 s (FEV), and ratio of FEV to forced vital capacity (FVC) were measured during preoperative spirometry, and peak oxygen consumption and ventilatory efficiency during preoperative CPET. Outcomes were respiratory morbidity (Postoperative Morbidity Survey) and pulmonary complications (pneumonia or respiratory failure). We used multivariable logistic regression models to estimate associations of FEV with outcomes after adjustment for risk factors and either peak oxygen consumption or ventilatory efficiency.

Findings: 128 participants (11%) developed respiratory morbidity, and 48 (4%) developed pulmonary complications. There was no strong evidence that FEV predicted respiratory morbidity after adjustment for peak oxygen consumption ( = 0·80) or ventilatory efficiency ( = 0·76), or FEV predicted pulmonary complications after adjustment for ventilatory efficiency ( = 0·37). Peak oxygen consumption (odds ratio 0·66 per 5 mL/kg/min increase; 95% CI, 0·54-0·82) was associated with respiratory morbidity. Ventilatory efficiency was associated with respiratory morbidity ( = 0·04) and pulmonary complications ( = 0·02). Peak oxygen consumption also confounded the association between FEV and respiratory morbidity.

Interpretation: After accounting for fitness and clinical factors, FEV was not strongly predictive of respiratory complications. Prior associations between FEV and respiratory morbidity may be explained by confounding by peak oxygen consumption.

Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research, Innovation and Science, UK National Institute of Academic Anaesthesia, UK Clinical Research Collaboration, Australian and New Zealand College of Anaesthetists, and Monash University.
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http://dx.doi.org/10.1016/j.eclinm.2020.100396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280772PMC
June 2020

Lung Ultrasound for Cardiologists in the Time of COVID-19.

Can J Cardiol 2020 07 19;36(7):1144-1147. Epub 2020 May 19.

Division of Respirology, University of Toronto, Toronto, Ontario, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.

Lung ultrasound (LUS) is a point-of-care ultrasound technique used for its portability, widespread availability, and ability to provide real-time diagnostic information and procedural guidance. LUS outperforms lung auscultation and chest X-ray, and it is an alternative to chest computed tomography in selected cases. Cardiologists may enhance their physical and echocardiographic examination with the addition of LUS. We present a practical guide to LUS, including device selection, scanning, findings, and interpretation. We outline a 3-point scanning protocol using 2-dimensional and M-mode imaging to evaluate the pleural line, pleural space, and parenchyma. We describe LUS findings and interpretation for common causes of respiratory failure. We provide guidance specific of COVID-19, which at the time of writing is a global pandemic. In this context, LUS emerges as a particularly useful tool for the diagnosis and management of patients with cardiopulmonary disease.
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http://dx.doi.org/10.1016/j.cjca.2020.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235628PMC
July 2020

Skeletal muscle oxygenation and regional blood volume during incremental limb loading in interstitial lung disease.

ERJ Open Res 2020 Jan 27;6(1). Epub 2020 Jan 27.

Dept of Physical Therapy, University of Toronto, Toronto, ON, Canada.

Introduction: Individuals with interstitial lung disease (ILD) exhibit reduced exercise capacity and exertional hypoxaemia. The role of peripheral (muscle) limitation to exercise tolerance in ILD is not well studied to date.

Methods: A prospective cross-sectional study examined skeletal muscle oxygen saturation ( ) and regional blood volume of the knee extensors and elbow flexors during incremental limb loading in healthy people and people with varying severity of ILD. Isotonic concentric exercise was performed on an isokinetic dynamometer. and regional blood volume were measured by near-infrared spectroscopy over the vastus lateralis and biceps.

Results: Thirteen people who were dependent on oxygen, candidates for lung transplant and with severe ILD (forced vital capacity (FVC) 59±20% predicted), 10 people who were not oxygen dependent with mild ILD (FVC 81±17% predicted) and 13 healthy people (FVC 101±14% predicted) were included. Total haemoglobin, a marker of regional blood volume, was lower at task failure in the knee extensors in participants with severe ILD compared to healthy participants (p=0.05). At task failure for both knee-extensor loading and elbow-flexor loading, was decreased to similar levels across all groups, but occurred at lower total workloads in the ILD groups (all p<0.01).

Conclusions: Overall, people with severe ILD had lower levels of total work and experienced less increase in blood volume in the knee extensors after knee-extensor loading compared to healthy people. Peripheral muscle dysfunction in severe ILD may have contributed to muscle deoxygenation at lower workloads.
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http://dx.doi.org/10.1183/23120541.00083-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983499PMC
January 2020

Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis.

EClinicalMedicine 2020 Feb 17;19:100249. Epub 2020 Jan 17.

Clinical Epidemiology Program (CEP), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012-2019, we performed an updated systematic review to further characterize the MSC safety profile.

Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively.

Findings: 7473 citations were reviewed and 55 studies met inclusion criteria ( = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2·48, 95% Confidence Interval (CI) = 1·27-4·86; I = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/embolic events, death, or malignancy (RR = 1·16, 0·99, 1·14, 0·78, 0·93; 95% CI = 0·70-1·91, 0·81-1·21, 0·67-1·95, 0·65-0·94, 0·60-1·45; I = 0%, 0%, 0%, 0%, 0%). No included trials were ended prematurely due to safety concerns.

Interpretations: MSC therapy continues to exhibit a favourable safety profile. Future trials should continue to strengthen study rigor, reporting of MSC characterization, and adverse events.

Funding: Stem Cell Network, Ontario Institute for Regenerative Medicine and Ontario Research Fund.
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http://dx.doi.org/10.1016/j.eclinm.2019.100249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970160PMC
February 2020

Conversational avoidance during existential interviews with patients with progressive illness.

Psychol Health Med 2020 10 24;25(9):1073-1082. Epub 2020 Jan 24.

Department of Psychiatry, University of Toronto , Toronto, Canada.

We examined patterns of avoidance when existential emotional topics were raised during conversations with patients with pulmonary arterial hypertension (PAH), an incurable life-limiting disease. 30 adult outpatients with PAH were recruited for a 20 to 60-minute interview about their illness experience. Qualitative content analysis was used to identify avoidance strategies that patients employed. Participants averaged 58 years in age (SD = 18), 77% were female, and mean length of illness was 6.3 years (SD = 5.3). We found four avoidance strategies: (1) Reversal, when individuals would begin discussing a negative concern and then backtrack to more positive sentiments; (2) Diversion for when patients would sidetrack the conversation to a different and less uncomfortable topic; (3) Diminishment for when a concern is raised and then made to seem unimportant; and (4) Obstruction, when patients refuse to discuss a concern further. Exploration of existential concerns can elicit distress but may be necessary to promote adaptation to progressive illness and to the foreseeable challenges that may affect the sense of life meaning and value. By recognizing when existential concerns may be present but not adequately discussed, clinicians may be better able to assist patients to cope and prepare for the future.
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http://dx.doi.org/10.1080/13548506.2020.1719282DOI Listing
October 2020

Bayesian Analysis in Critical Care Medicine.

Am J Respir Crit Care Med 2020 02;201(4):396-398

Institute of Health Management, Policy, and EvaluationUniversity of TorontoToronto, Ontario, Canada.

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http://dx.doi.org/10.1164/rccm.201910-2019EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049930PMC
February 2020

Pulmonary Arterial Hypertension: A Palliative Medicine Review of the Disease, Its Therapies, and Drug Interactions.

J Pain Symptom Manage 2020 04 2;59(4):932-943. Epub 2019 Dec 2.

Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.11.023DOI Listing
April 2020

Interval aerobic exercise in individuals with advanced interstitial lung disease: a feasibility study.

Physiother Theory Pract 2021 Sep 18;37(9):1034-1042. Epub 2019 Oct 18.

Department of Physical Therapy, University of Toronto, Toronto, ON, Canada.

: Aerobic exercise is used in the rehabilitation setting in people with interstitial lung disease (ILD), however little is known about interval exercise as a training strategy. The aim of this study was to compare the cardiorespiratory responses and preferences of a single bout of interval exercise with continuous exercise in individuals with advanced ILD. : Peak work (Wpeak) was obtained from a cardiopulmonary exercise test (CPET). The total volume of prescribed exercise was matched between a bout of interval cycling (alternating 30 seconds at 100% of Wpeak: 30 seconds total rest × 20 min) and continuous cycling (50% of Wpeak × 20 min). : Nine lung transplant candidates with ILD were included: 4 men; 62 (6) years; forced vital capacity (FVC) 60% of predicted; and all using supplemental oxygen. Eight (89%) participants reported a preference for interval exercise and one reported no preference (p = .01). One participant required two unintended breaks during continuous exercise. There were no large differences between interval and continuous exercise although some trends emerged. Interval exercise resulted in a lower peak heart rate (124 (12) vs. 132 (15), p = .04) and a trend toward less oxygen desaturation (drop of 8 (4)% vs. 11 (5)%, p = .05) and lower end-exercise Borg leg fatigue (3.8 (2) vs. 4.4 (2), p = .05). End-exercise dyspnea was similar between both exercise modes. : Interval exercise was well tolerated and preferred by participants with advanced ILD.
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http://dx.doi.org/10.1080/09593985.2019.1678207DOI Listing
September 2021

Preoperative Extracorporeal Membrane Oxygenation and Plasmapheresis for Urgent Pulmonary Endarterectomy in Heparin-Induced Thrombocytopenia-Positive Patient.

Ann Thorac Surg 2020 09 4;110(3):e231-e232. Epub 2019 Oct 4.

Division of Thoracic Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. This case report outlines the importance of venoarterial extracorporeal membrane oxygenation and plasmapheresis as two important options in the management of heparin-induced thrombocytopenia-positive patients requiring urgent pulmonary endarterectomy.
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http://dx.doi.org/10.1016/j.athoracsur.2019.08.092DOI Listing
September 2020

Heart rate variability in pulmonary hypertension with and without sleep apnea.

Heliyon 2019 Jul 3;5(7):e02034. Epub 2019 Jul 3.

Sleep Research Laboratory, Toronto Rehabilitation Institute, University Health Network, Toronto, ON, Canada.

Objectives: Our aims were to evaluate HRV in pulmonary hypertension (WHO Group 1 and 4) compared to control subjects, and to assess whether the presence of sleep apnea in those with pulmonary hypertension would be deleterious and cause greater impairment in HRV.

Methods: This retrospective case-control study analyzed electrocardiogram segments obtained from diagnostic polysomnography.

Results: Forty-one pulmonary hypertension patients were compared to 41 age, sex and apnea-hypopnea index matched healthy controls. The pulmonary hypertension group had decreased high frequency, very low frequency, low frequency, and percentage of normal R-R intervals that differ by > 50 ms compared to control subjects. Moderate to severe right ventricle dysfunction on echocardiography was a predictor of lower high frequency in pulmonary hypertension patients.

Conclusions: There were no differences in any HRV measures in pulmonary hypertension patients with or without sleep apnea. Impaired HRV was demonstrated in pulmonary hypertension patients however, the presence of sleep apnea did not appear to further reduce vagal modulation.
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http://dx.doi.org/10.1016/j.heliyon.2019.e02034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611942PMC
July 2019

Medical oncologists' and palliative care physicians' opinions towards thromboprophylaxis for inpatients with advanced cancer: a cross-sectional study.

BMJ Support Palliat Care 2019 Jul 11. Epub 2019 Jul 11.

Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Patients with advanced cancer are increasingly discharged from inpatient settings following focused symptom management admissions. Thromboprophylaxis (TP) is recommended for patients with cancer admitted to acute care settings; less is known about TP use in palliative care (PC) settings. This study explored the opinions of Canadian medical oncologists (MO) and PC physicians regarding the use of TP for inpatients with advanced cancer.

Methods: A fractional factorial survey designed to evaluate the impact of patient factors (age, clinical setting, reason for admission, pre-admission performance status (Eastern Cooperative Oncology Group; ECOG), and risk of bleeding on anticoagulation) and physician demographics on recommending TP was administered by email to Canadian MO and PC physicians. Each respondent received eight vignettes randomly selected from a set of 32. Hierarchical regression was used to evaluate the odds of prescribing TP adjusted for patient factors.

Results: 606 MO and 491 PC physicians were surveyed; response rates were 11.1% and 15.0%, respectively. MO were predominantly male (59.7%); PC female (60.3%); most worked in academic environments (90.3% MO; 73.9% PC). Multivariable hierarchical logistic regression demonstrated that all patient factors except age were associated with prescribing TP (ORs range: from 1.34 (95% CI 1.01 to 1.77) for good ECOG, to 2.53 (95% CI 1.9 to 3.37), for reversible reason for admission). Controlling for these factors, medical specialty was independently associated with recommending TP (OR for MO 2.09 (95% CI 1.56 to 2.8)).

Conclusions: MO have higher odds of recommending TP for inpatients with advanced cancer than PC physicians. Further research exploring the drivers of these differing practices is warranted.
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http://dx.doi.org/10.1136/bmjspcare-2019-001861DOI Listing
July 2019

Dyspnea after Pulmonary Embolism.

Ann Am Thorac Soc 2019 07;16(7):914-919

2 Division of Respirology, and.

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http://dx.doi.org/10.1513/AnnalsATS.201811-818CCDOI Listing
July 2019
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