Publications by authors named "Ari R Joffe"

152 Publications

Hypothalamic function in patients diagnosed as brain dead and its practical consequences.

Handb Clin Neurol 2021 ;182:433-446

Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.

Some patients who have been diagnosed as "dead by neurologic criteria" continue to exhibit certain brain functions, most commonly, neuroendocrine functions. In this chapter, we review the pathophysiology of brain death that can lead either to neuroendocrine failure or to preserved neuroendocrine functioning. We review the evidence on continued hypothalamic functioning in patients who have been declared "brain dead," examine potential mechanisms that would explain these findings, and discuss how these findings create additional confounds for brain death testing. We conclude by reviewing the evidence for the management of hypothalamic-pituitary failure in the setting of brain death and organ transplantation.
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http://dx.doi.org/10.1016/B978-0-12-819973-2.00029-0DOI Listing
January 2021

The World Brain Death Project: The More You Say It Does Not Make It True.

J Clin Ethics 2021 ;32(2):97-108

Pediatric Intensive Care Unit, Royal Children's Hospital, 50 Flemington Rd., Parkville, Melbourne, 3052 Australia.

The World Brain Death Project clarified many aspects of the diagnosis of brain death/death by neurologic criteria. Clearer descriptions than previously published were presented concerning the etiology, prerequisites, minimum clinical criteria, apnea testing targets, and indications for ancillary testing. Nevertheless, there remained many epistemic and metaphysical assertions that were either false, ad hoc, or confused. Epistemically, the project was not successful in explaining away remaining brain functions, complex reflexes as "spinal," the risk and lack of utility of the apnea test, the ignored and often present confounders of central endocrine dysfunction and high-cervical-spinal-cord injury, the limitations of ancillary tests, or the cases of reversibility of some findings of brain death/death by neurologic criteria. Metaphysically, the World Brain Death Project variously suggested different concepts of death that were not supported with argument. Concepts offered included simply restating the criterion of brain death/death by neurologic criteria; personhood, without recognizing it is a higher-brain concept; and emergent functions of the organism as a whole, without specifying what these might be, if not biologic anti-entropic integration that actually remains after brain death/death by neurologic criteria. The World Brain Death Project only offered confused metaphysical discussion, and gave no reason why the state they described as brain death/death by neurologic criteria should be considered death itself. The main epistemic and metaphysical problems with brain death/death by neurologic criteria remain untouched by the World Brain Death Project.
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June 2021

COVID-19: Rethinking the Lockdown Groupthink.

Authors:
Ari R Joffe

Front Public Health 2021;9:625778. Epub 2021 Feb 26.

Division of Critical Care Medicine, Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused the Coronavirus Disease 2019 (COVID-19) worldwide pandemic in 2020. In response, most countries in the world implemented lockdowns, restricting their population's movements, work, education, gatherings, and general activities in attempt to "flatten the curve" of COVID-19 cases. The public health goal of lockdowns was to save the population from COVID-19 cases and deaths, and to prevent overwhelming health care systems with COVID-19 patients. In this narrative review I explain why I changed my mind about supporting lockdowns. The initial modeling predictions induced fear and crowd-effects (i.e., groupthink). Over time, important information emerged relevant to the modeling, including the lower infection fatality rate (median 0.23%), clarification of high-risk groups (specifically, those 70 years of age and older), lower herd immunity thresholds (likely 20-40% population immunity), and the difficult exit strategies. In addition, information emerged on significant collateral damage due to the response to the pandemic, adversely affecting many millions of people with poverty, food insecurity, loneliness, unemployment, school closures, and interrupted healthcare. Raw numbers of COVID-19 cases and deaths were difficult to interpret, and may be tempered by information placing the number of COVID-19 deaths in proper context and perspective relative to background rates. Considering this information, a cost-benefit analysis of the response to COVID-19 finds that lockdowns are far more harmful to public health (at least 5-10 times so in terms of wellbeing years) than COVID-19 can be. Controversies and objections about the main points made are considered and addressed. Progress in the response to COVID-19 depends on considering the trade-offs discussed here that determine the wellbeing of populations. I close with some suggestions for moving forward, including focused protection of those truly at high risk, opening of schools, and building back better with a economy.
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http://dx.doi.org/10.3389/fpubh.2021.625778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952324PMC
March 2021

Serum Creatinine Monitoring After Acute Kidney Injury in the PICU.

Pediatr Crit Care Med 2021 04;22(4):412-425

Division of Nephrology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada.

Objectives: It is unknown whether children with acute kidney injury during PICU admission have kidney function monitored after discharge. Objectives: 1) describe postdischarge serum creatinine monitoring after PICU acute kidney injury and 2) determine factors associated with postdischarge serum creatinine monitoring.

Design: Secondary analysis of longitudinal cohort study data.

Setting: Two PICUs in Montreal and Edmonton, Canada.

Patients: Children (0-18 yr old) surviving PICU admission greater than or equal to 2 days from 2005 to 2011. Exclusions: postcardiac surgery and prior kidney disease. Exposure: acute kidney injury by Kidney Disease: Improving Global Outcomes serum creatinine definition.

Interventions: None.

Measurements: Primary outcome: postdischarge serum creatinine measured by 90 days, 1 year, and 5-7 years.

Secondary Outcomes: Healthcare events and nephrology follow-up.

Analysis: Proportions with outcomes; logistic regression to evaluate factors associated with the primary outcome. Kaplan-Meier analysis of time to serum creatinine measurement and healthcare events.

Main Results: Of n = 277, 69 (25%) had acute kidney injury; 29/69 (42%), 34/69 (49%), and 51/69 (74%) had serum creatinine measured by 90 days, 1 year, and 5-7 year postdischarge, respectively. Acute kidney injury survivors were more likely to have serum creatinine measured versus nonacute kidney injury survivors at all time points (p ≤ 0.01). Factors associated with 90-day serum creatinine measurement were inpatient nephrology consultation (unadjusted odds ratio [95% CI], 14.9 [1.7-127.0]), stage 2-3 acute kidney injury (adjusted odds ratio, 3.4 [1.1-10.2]), and oncologic admission diagnosis (adjusted odds ratio, 10.0 [1.1-93.5]). A higher proportion of acute kidney injury versus nonacute kidney injury survivors were readmitted by 90 days (25 [36%] vs 44 [21%]; p = 0.01) and 1 year (33 [38%] vs 70 [34%]; p = 0.04). Of 24 acute kidney injury survivors diagnosed with chronic kidney disease or hypertension at 5-7 year follow-up, 16 (67%) had serum creatinine measurement and three (13%) had nephrology follow-up postdischarge.

Conclusions: Half of PICU acute kidney injury survivors have serum creatinine measured within 1-year postdischarge and follow-up is suboptimal for children developing long-term kidney sequelae. Knowledge translation strategies should emphasize the importance of serum creatinine monitoring after childhood acute kidney injury.
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http://dx.doi.org/10.1097/PCC.0000000000002662DOI Listing
April 2021

Magnetic Resonance Imaging Provides Useful Diagnostic Information Following Equivocal Ultrasound in Children With Suspected Appendicitis.

Can Assoc Radiol J 2021 Mar 1:846537121993797. Epub 2021 Mar 1.

Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.

Purpose: In Canada, ultrasonography is the primary imaging modality for children with suspected appendicitis, yet equivocal studies are common. Magnetic resonance imaging provides promise as an adjunct imaging strategy. The primary objective of this study was to determine the proportion of children with suspected appendicitis and equivocal ultrasound where magnetic resonance imaging determined a diagnosis.

Methods: A prospective consecutive cohort of children aged 5-17 years presenting to a tertiary pediatric Emergency Department with suspected appendicitis were enrolled. Participants underwent diagnostic and management strategies according to our local suspected appendicitis pathway, followed by magnetic resonance (Siemens Avanto 1.5 Tesla) imaging. Sub-specialty pediatric radiologists reported all images.

Results: Magnetic resonance imaging was performed in 101 children with suspected appendicitis. The mean age was 11.9 (SD 3.4) years and median Pediatric Appendicitis Score was 6 [IQR 4,8]. Ultrasonography was completed in 98/101 (97.0%). Of 53/98 (54.1%) with equivocal ultrasound, magnetic resonance imaging provided further diagnostic information in 41 (77.4%; 10 positive, 31 negative; 12 remained equivocal). Secondary findings of appendicitis on magnetic resonance imaging in children with equivocal ultrasound included abdominal free fluid (24, 45.3%), peri-appendiceal fluid (12, 22.6%), intraluminal appendiceal fluid (9, 17.0%), fat stranding (8, 15.1%), appendicolith (2, 3.8%), and peri-appendiceal abscess (1, 1.9%). The observed agreement between magnetic resonance imaging results and final diagnosis was 94.9% (kappa = 0.89).
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http://dx.doi.org/10.1177/0846537121993797DOI Listing
March 2021

Outcomes of Preterm Infants With Congenital Heart Defects After Early Surgery: Defining Risk Factors at Different Time Points During Hospitalization.

Front Pediatr 2020 28;8:616659. Epub 2021 Jan 28.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Compared with those born at term gestation, infants with complex congenital heart defects (CCHD) who were delivered before 37 weeks gestational age and received neonatal open-heart surgery (OHS) have poorer neurodevelopmental outcomes in early childhood. We aimed to describe the growth, disability, functional, and neurodevelopmental outcomes in early childhood of preterm infants with CCHD after neonatal OHS. Prediction models were evaluated at various timepoints during hospitalization which could be useful in the management of these infants. We studied all preterm infants with CCHD who received OHS within 6 weeks of corrected age between 1996 and 2016. The Western Canadian Complex Pediatric Therapies Follow-up Program completed multidisciplinary comprehensive neurodevelopmental assessments at 2-year corrected age at the referral-site follow-up clinics. We collected demographic and acute-care clinical data, standardized age-appropriate outcome measures including physical growth with calculated scores; disabilities including cerebral palsy, visual impairment, permanent hearing loss; adaptive function (Adaptive Behavior Assessment System-II); and cognitive, language, and motor skills (Bayley Scales of Infant and Toddler Development-III). Multiple variable logistic or linear regressions determined predictors displayed as Odds Ratio (OR) or Effect Size (ES) with 95% confidence intervals. Of 115 preterm infants (34 ± 2 weeks gestation, 2,339 ± 637 g, 64% males) with CCHD and OHS, there were 11(10%) deaths before first discharge and 21(18%) deaths by 2-years. Seven (6%) neonates had cerebral injuries, 7 had necrotizing enterocolitis; none had retinopathy of prematurity. Among 94 survivors, 9% had cerebral palsy and 6% had permanent hearing loss, with worse outcomes in those with syndromic diagnoses. Significant predictors of mortality included birth weight score [OR 0.28(0.11,0.72), = 0.008], single-ventricle anatomy [OR 5.92(1.31,26.80), = 0.021], post-operative ventilation days [OR 1.06(1.02,1.09), = 0.007], and cardiopulmonary resuscitation [OR 11.58 (1.97,68.24), = 0.007]; for adverse functional outcome in those without syndromic diagnoses, birth weight 2,000-2,499 g [ES -11.60(-18.67, -4.53), = 0.002], post-conceptual age [ES -0.11(-0.22,0.00), = 0.044], post-operative lowest pH [ES 6.75(1.25,12.25), = 0.017], and sepsis [ES -9.70(-17.74, -1.66), = 0.050]. Our findings suggest preterm neonates with CCHD and early OHS had significant mortality and morbidity at 2-years and were at risk for cerebral palsy and adverse neurodevelopment. This information may be important for management, parental counseling and the decision-making process.
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http://dx.doi.org/10.3389/fped.2020.616659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876369PMC
January 2021

Music Use for Sedation in Critically ill Children (MUSiCC trial): a pilot randomized controlled trial.

J Intensive Care 2021 Jan 12;9(1). Epub 2021 Jan 12.

Department of Pediatrics, University of Alberta, Room 4-548 11405 87 Avenue, Edmonton, AB, T6G 1C9, Canada.

Objective: To demonstrate feasibility of a music medicine intervention trial in pediatric intensive care and to obtain information on sedation and analgesia dose variation to plan a larger trial.

Material And Methods: Pilot randomized controlled trial (RCT) was conducted at the Stollery Children's Hospital general and cardiac intensive care units (PICU/PCICU). The study included children 1 month to 16 years of age on mechanical ventilation and receiving sedation drugs. Patients were randomized in a 1:1:1 ratio to music, noise cancellation or control. The music group received classical music for 30 min three times/day using headphones. The noise cancellation group received the same intervention but with no music. The control group received usual care.

Results: A total of 60 patients were included. Average enrollment rate was 4.8 patients/month, with a consent rate of 69%. Protocol adherence was achieved with patients receiving > 80% of the interventions. Overall mean (SD) daily Sedation Intensity Score was 52.4 (30.3) with a mean (SD) sedation frequency of 9.75 (7.21) PRN doses per day. There was a small but statistically significant decrease in heart rate at the beginning of the music intervention. There were no study related adverse events. Eighty-eight percent of the parents thought the headphones were comfortable; 73% described their child more settled during the intervention.

Conclusions: This pilot RCT has demonstrated the feasibility of a music medicine intervention in critically ill children. The study has also provided the necessary information to plan a larger trial.
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http://dx.doi.org/10.1186/s40560-020-00523-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802123PMC
January 2021

Post-operative fluid overload as a predictor of hospital and long-term outcomes in a pediatric heart transplant population.

Pediatr Transplant 2021 May 1;25(3):e13897. Epub 2020 Nov 1.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Background: Pediatric patients undergoing heart transplant have a number of factors predisposing them to become fluid-overloaded, including capillary leak syndrome. Capillary leak and FO are associated with organ injury and may influence both short- and long-term outcomes. This study aimed to 1) determine the extent, timing, and predictors of post-operative FO and 2) investigate the association of FO with clinically important outcomes.

Methods: Between 2000 and 2012, 70 children less than 6 years old had a heart transplant at our institution. This was a secondary analysis of data from an ongoing prospective cohort study.

Results: FO, defined as cumulative fluid balance greater than 10% of body weight in the first 5 post-operative days, occurred in 16/70 patients (23%); 7 of these had more than 20% FO. Shorter donor ischemic time and longer cardiopulmonary bypass time were independently associated with increased risk of FO. FO >20% was a statistically significant independent predictor of mortality (P = .005), ventilation time, and PICU length of stay. There was no statistically significant association between identified neurodevelopment domains and FO.

Conclusions: Our single-center experience demonstrates that FO was common after pediatric heart transplant and was associated with worse clinical outcomes. FO is a potentially modifiable factor, and research is needed to better determine risk factors and whether intervention to reduce FO can improve outcomes in pediatric heart transplant patients.
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http://dx.doi.org/10.1111/petr.13897DOI Listing
May 2021

Health-related quality of life after pediatric heart transplantation in early childhood.

Pediatr Transplant 2020 11 1;24(7):e13822. Epub 2020 Sep 1.

Division of Pediatric Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Background: There is limited information about HRQL after pediatric heart transplantation at a young age.

Methods: Prospective follow-up study of children who received a heart transplant at age ≤4 years. HRQL was assessed using the PedsQL 4.0 at age 4.5 years. This cohort was compared with healthy children, children with CHD, and with chronic conditions. Peri-operative factors associated with HRQL were also explored.

Results: Of 66 eligible patients, 15 (23%) died prior to the HRQL assessment and 2 (3%) were lost to follow-up, leaving 49 patients. Indication for transplantation was CHD in 27 (55%) and CMP in 22 (45%). Median age (IQR) at transplant was 9 (5-31) months. HRQL was significantly lower in transplanted children compared to population norms (65.3 vs 87.3, P < .0001), children with chronic conditions (65.3 vs 76.1, P = .001), and children with CHD (65.3 vs 81.1, P < .0001). Transplanted children with CHD had lower HRQL than those with a prior diagnosis of CMP (59.5 vs 72.5, P-value = .020). Higher creatinine pretransplant and higher lactate post-operatively were associated with lower HRQL.

Conclusion: Children after heart transplant had significantly lower HRQL, as reported by their parents, than the normative population, children with chronic conditions, and children with CHD.
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http://dx.doi.org/10.1111/petr.13822DOI Listing
November 2020

Fluid Accumulation in Critically Ill Children.

Crit Care Med 2020 07;48(7):1034-1041

Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Objectives: To describe the characteristics of fluid accumulation in critically ill children and evaluate the association between the degree, timing, duration, and rate of fluid accumulation and patient outcomes.

Design: Retrospective cohort study.

Setting: PICUs in Alberta, Canada.

Patients: All children admitted to PICU in Alberta, Canada, between January 1, 2015, and December 31, 2015.

Interventions: None.

Measurements And Main Results: A total of 1,017 patients were included. Fluid overload % increased from median (interquartile range) 1.58% (0.23-3.56%; n = 1,017) on day 1 to 16.42% (7.53-27.34%; n = 111) on day 10 among those remaining in PICU. The proportion of patients (95% CI) with peak fluid overload % greater than 10% and greater than 20% was 32.7% (29.8-35.7%) and 9.1% (7.4-11.1%), respectively. Thirty-two children died (3.1%) in PICU. Peak fluid overload % was associated with greater PICU mortality (odds ratio, 1.05; 95% CI, 1.02-1.09; p = 0.001). Greater peak fluid overload % was associated with Major Adverse Kidney Events within 30 days (odds ratio, 1.05; 95% CI, 1.02-1.08; p = 0.001), length of mechanical ventilation (B coefficient, 0.66; 95% CI, 0.54-0.77; p < 0.001), and length of PICU stay (B coefficient, 0.52; 95% CI, 0.46-0.58; p < 0.001). The rate of fluid accumulation was associated with PICU mortality (odds ratio, 1.15; 95% CI, 1.01-1.31; p = 0.04), Major Adverse Kidney Events within 30 days (odds ratio, 1.16; 95% CI, 1.03-1.30; p = 0.02), length of mechanical ventilation (B coefficient, 0.80; 95% CI, 0.24-1.36; p = 0.005), and length of PICU stay (B coefficient, 0.38; 95% CI, 0.11-0.66; p = 0.007).

Conclusions: Fluid accumulation occurs commonly during PICU course and is associated with considerable mortality and morbidity. These findings highlight the need for the development and evaluation of interventional strategies to mitigate the potential harm associated with fluid accumulation.
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http://dx.doi.org/10.1097/CCM.0000000000004376DOI Listing
July 2020

Pre-school neurocognitive and functional outcomes after liver transplant in children with early onset urea cycle disorders, maple syrup urine disease, and propionic acidemia: An inception cohort matched-comparison study.

JIMD Rep 2020 Mar 27;52(1):43-54. Epub 2020 Jan 27.

Department of Pediatrics University of Alberta Edmonton Alberta Canada.

Background: Urea cycle disorders (UCD) and organic acid disorders classically present in the neonatal period. In those who survive, developmental delay is common with continued risk of regression. Liver transplantation improves the biochemical abnormality and patient survival is good. We report the neurocognitive and functional outcomes post-transplant for nine UCD, three maple syrup urine disease, and one propionic acidemia patient.

Methods: Thirteen inborn errors of metabolism (IEM) patients were individually one-to-two matched to 26 non-IEM patients. All patients received liver transplant. Wilcoxon rank sum test was used to compare full-scale intelligence-quotient (FSIQ) and Adaptive Behavior Assessment System-II General Adaptive Composite (GAC) at age 4.5 years. Dichotomous outcomes were reported as percentages.

Results: FSIQ and GAC median [IQR] was 75 [54, 82.5] and 62.0 [47.5, 83] in IEM compared with 94.5 [79.8, 103.5] and 88.0 [74.3, 97.5] in matched patients (-value <.001), respectively. Of IEM patients, 6 (46%) had intellectual disability (FSIQ and GAC <70), 5 (39%) had autism spectrum disorder, and 1/13 (8%) had cerebral palsy, compared to 1/26 (4%), 0, 0, and 0% of matched patients, respectively. In the subgroup of nine with UCDs, FSIQ (64[54, 79]), and GAC (56[45, 75]) were lower than matched patients (100.5 [98.5, 101] and 95 [86.5, 99.5]), = .005 and .003, respectively.

Conclusion: This study evaluated FSIQ and GAC at age 4.5 years through a case-comparison between IEM and matched non-IEM patients post-liver transplantation. The neurocognitive and functional outcomes remained poor in IEM patients, particularly in UCD. This information should be included when counselling parents regarding post-transplant outcome.
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http://dx.doi.org/10.1002/jmd2.12095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052695PMC
March 2020

Survival, Neurocognitive, and Functional Outcomes After Completion of Staged Surgical Palliation in a Cohort of Patients With Hypoplastic Left Heart Syndrome.

J Am Heart Assoc 2020 02 11;9(4):e013632. Epub 2020 Feb 11.

Department of Pediatrics University of Alberta Edmonton Alberta Canada.

Background Management of patients with hypoplastic left heart syndrome has benefited from advancements in medical and surgical care. Outcomes have improved, although survival and long-term functional and cognitive deficits remain a concern. Methods and Results This is a cohort study of all consecutive patients with hypoplastic left heart syndrome undergoing surgical palliation at a single center. We aimed to examine demographic and perioperative factors from each surgical stage for their association with survival and neurocognitive outcomes. A total of 117 consecutive patients from 1996 to 2010 underwent surgical palliation. Seventy patients (60%) survived to the Fontan stage and 68 patients (58%) survived to undergo neurocognitive assessment at a mean (SD) age of 56.6 months (6.4 months). Full-scale, performance, and verbal intelligence quotient, as well as visual-motor integration mean (SD) scores were 86.7 (16.1), 86.3 (15.8), 88.8 (17.2), and 83.2 (14.8), respectively. On multivariable analysis, older age at Fontan, sepsis peri-Norwood, lowest arterial partial pressure of oxygen postbidirectional cavopulmonary anastomosis, and presence of neuromotor disability pre-Fontan were strongly associated with lower scores for all intelligence quotient domains. Older age at Fontan and sepsis peri-Norwood remained associated with lower scores for all intelligence quotient domains in a subgroup analysis excluding patients with disability pre-Fontan or with chromosomal abnormalities. Conclusions Older age at Fontan and sepsis are among independent predictors of poor neurocognitive outcomes for patients with hypoplastic left heart syndrome. Further studies are required to identify the appropriate age range for Fontan completion, balancing a lower risk of acute and long-term hemodynamic complications while optimizing long-term neurocognitive outcomes.
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http://dx.doi.org/10.1161/JAHA.119.013632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070198PMC
February 2020

Kidney and blood pressure abnormalities 6 years after acute kidney injury in critically ill children: a prospective cohort study.

Pediatr Res 2020 08 2;88(2):271-278. Epub 2020 Jan 2.

Formerly, McGill University Health Centre Research Institute, McGill University Health Centre, Montreal, QC, Canada.

Background: Acute kidney injury (AKI) in pediatric intensive care unit (PICU) children may be associated with long-term chronic kidney disease or hypertension.

Objectives: To estimate (1) prevalence of kidney abnormalities (low estimated glomerular filtration rate (eGFR) or albuminuria) and blood pressure (BP) consistent with pre-hypertension or hypertension, 6 years after PICU admission; (2) if AKI is associated with these outcomes.

Methods: Longitudinal study of children admitted to two Canadian PICUs (January 2005-December 2011). Exposures (retrospective): AKI or stage 2/3 AKI (KDIGO creatinine-based definition) during PICU. Primary outcome (single visit 6 years after admission): presence of (a) low eGFR (<90 ml/min/1.73 m) or albuminuria (albumin to creatinine ratio >30 mg/g) (termed "CKD signs") or (b) BP consistent with ≥pre-hypertension (≥90th percentile) or hypertension (≥95th percentile).

Results: Of 277 children, 25% had AKI. AKI and stage 2/3 AKI were associated with 2.2- and 6.6-fold higher adjusted odds, respectively, for the 6-year outcomes. Applying new hypertension guidelines attenuated associations; stage 2/3 AKI was associated with 4.5-fold higher adjusted odds for 6-year CKD signs or ≥elevated BP.

Conclusions: Kidney and BP abnormalities are common 6 years after PICU admission and associated with AKI. Other risk factors must be elucidated to develop follow-up recommendations and reduce cardiovascular risk.
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http://dx.doi.org/10.1038/s41390-019-0737-5DOI Listing
August 2020

Parental opinions regarding consent for observational research of no or minimal risk in the pediatric intensive care unit.

J Intensive Care 2019 16;7:60. Epub 2019 Dec 16.

1Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stollery Children's Hospital and University of Alberta, Edmonton, Alberta Canada.

Background: The aim of the study was to determine opinions and knowledge regarding the process of obtaining informed consent to participate in observational research in pediatric intensive care.

Methods: Survey 1 asked decision makers what model(s) of consent was acceptable for each type of observational research both before and after background information. Survey 2 asked decision makers about the experience of being asked for consent to observational research, and knowledge regarding the consent process both before and after background information.

Results: Cooperation rate was 100/117 (85%). The proportion in favor of any of the offered alternatives to signed informed consent for observational research, after receiving all the background information, was 74-80%, lowest for observational prospective research with a minimal risk intervention 37/50 (74%; 95% CI 60-84%). The proportion who agreed they felt overwhelmed by being approached for consent to observational research was 26 (52%; 95% CI 39-65%). Most respondents (from 60 to 74%) felt they understood the concepts regarding observational research; however, after reading background information, most (from 60 to 74%) felt their understanding had improved "a great deal".

Conclusion: Understanding of risk, practical difficulties, consent bias, and Research Ethics Board safeguards was poor. Future study is needed to confirm our finding that most agreed with alternative methods of consent for observational research.
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http://dx.doi.org/10.1186/s40560-019-0411-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916229PMC
December 2019

Association Between Maternal Fluoride Exposure and Child IQ.

JAMA Pediatr 2020 02;174(2):214

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1001/jamapediatrics.2019.5254DOI Listing
February 2020

Kindergarten-age neurocognitive, functional, and quality-of-life outcomes after liver transplantation at under 6 years of age.

Pediatr Transplant 2020 03 12;24(2):e13624. Epub 2019 Dec 12.

Department of Pediatrics, Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada.

Background: We aimed to describe school-entry age neurocognitive, functional, and HRQL outcomes and their predictors after liver transplant done at age <6 years.

Methods: A prospective cohort of all (n = 69) children surviving liver transplant from 1999 to 2014 were assessed at age 55.4 (SD 7.2) months and 38.6 (12.4) months after transplant. Assessment included: the Wechsler Preschool and Primary Scales of Intelligence, Beery-Buktenica Developmental Test of VMI, Adaptive Behavior Assessment System caregiver-completed questionnaire, and PedsQL 4.0 Generic Core Scales. Univariate and multiple linear regression determined predictors of outcomes at P < .05.

Results: Neurocognitive and functional outcomes were on average within 1 SD of population norms, although shifted to the left (P ≤ .03), with more patients than expected having scores >2 (3.7-5.9 times more, P ≤ .007) SD below population norms. Total and Summary HRQL scores were statistically significantly lower than the healthy normative population (P ≤ .02) and a congenital heart disease group (P ≤ .02), but similar to children with other chronic health conditions; differences often exceeded the MCID and were lowest in the School functioning domain. There were few predictors on multiple linear regressions, and we could not confirm previous studies that suggested various inconsistent predictors of outcomes. Neurocognitive and functional outcomes scores were highly correlated with HRQL scores except for the School functioning domain, but did not fully explain them.

Conclusions: Long-term follow-up of this vulnerable population is important in order to facilitate support for the patient and family, and early intervention for any difficulties identified.
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http://dx.doi.org/10.1111/petr.13624DOI Listing
March 2020

Family Visitation Policies in the ICU and Delirium.

JAMA 2019 11;322(19):1924

Division of Pediatric Critical Care, Stollery Children's Hospital, Edmonton, Alberta, Canada.

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http://dx.doi.org/10.1001/jama.2019.15591DOI Listing
November 2019

Unreliable Early Neuroprognostication After Severe Carbon Monoxide Poisoning Is Likely Due to Cytopathic Hypoxia: A Case Report and Discussion.

J Child Neurol 2020 02 17;35(2):111-115. Epub 2019 Oct 17.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, Stollery Children's Hospital and University of Alberta, Edmonton, Alberta, Canada.

A 17-year-old girl was found unconscious in a running vehicle. She developed very severe acute respiratory distress syndrome (which was treated with rescue high-frequency oscillation), hemodynamic instability, acute kidney injury, rhabdomyolysis, and remained comatose with a Glasgow Coma Scale score of 3 and gasping respirations for 67 hours (when the Glasgow Coma Scale score improved to 6, with tachypnea to Paco 28 and pH 7.5). By 92 hours, she was obeying commands, and she was extubated at 96 hours, shortly after which she was conversing with family and texting on her phone. A magnetic resonance imaging (MRI) scan 6 days after being found showed subacute infarctions affecting the medial aspect of the globus pallidus bilaterally as well as a small cortical/subcortical infarction in the right parietal lobe. At a 7-week follow-up, she had no delayed-onset signs of brain injury. This case demonstrated that neurologic prognostication after carbon monoxide poisoning may be unreliable for more than 72 hours after injury. We discuss that it is possible that the mitochondrial dysfunction induced by carbon monoxide was responsible for a functional coma without irreversible brain injury, similar to the mechanism of cytopathic hypoxia in multiple-organ dysfunction that allows some other organ recovery without necrosis in survivors.
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http://dx.doi.org/10.1177/0883073819879833DOI Listing
February 2020

Misinterpretations of Guidelines Leading to Incorrect Diagnosis of Brain Death: A Case Report and Discussion.

J Child Neurol 2020 01 30;35(1):49-54. Epub 2019 Sep 30.

Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, Edmonton, AB, Canada.

Guidelines describe the process necessary for the diagnosis of brain death. We present a case of a 3-month-old former 36-week-gestation infant after a prolonged out-of-hospital cardiac arrest of 37 minutes who was clinically diagnosed as brain dead at 120 hours after the event. Unusual findings included a normal slightly sunken anterior fontanelle, normal cerebral blood flow perfusion scan at 73 hours after the event, only localized parieto-temporal edema on the latest computed tomographic (CT) scan of the brain at 48 hours after the event, and discussion of whether nonconvulsive seizures could have confounded the examination for brain death. In light of these unusual findings, we discuss and highlight what may be common misinterpretations of brain death guidelines that led to the mistaken diagnosis of death (as opposed to severe neurologic injury) in this child.
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http://dx.doi.org/10.1177/0883073819876474DOI Listing
January 2020

Efficacy of music on sedation, analgesia and delirium in critically ill patients. A systematic review of randomized controlled trials.

J Crit Care 2019 10 4;53:75-80. Epub 2019 Jun 4.

Department of Pediatrics, University of Alberta, Edmonton, AB, Canada. Electronic address:

Purpose: To systematically synthesize randomized controlled trial data on the efficacy of music to provide sedation and analgesia, and reduce incidence of delirium, in critically ill patients.

Material And Methods: Relevant databases (Medline, PubMed, Embase, CINAHL, Cochrane, Alt Healthwatch, LILACS, PsycINFO, CAIRSS, RILM) were searched from inception to April 26, 2018. We also searched the reference lists of included publications and for ongoing trials. The selection of relevant articles was conducted by two researchers at two levels of screening. Data collection followed the recommendations from the Cochrane Systematic Reviews Handbook. We used the Cochrane Collaboration's tool for assessing risk of bias. Quality of the evidence was rated according to GRADE.

Results: The review identified six adult studies and no neonatal or pediatric studies. A descriptive analysis of study results was performed. Meta-analysis was not feasible due to heterogeneity. One study reported a reduction in sedation requirements with the use of music while the other five did not find any significant differences across groups.

Conclusions: This systematic review revealed limited evidence to support or refute the use of music to reduce sedation/analgesia requirements, or to reduce delirium in critically ill adults, and no evidence in pediatric and neonatal critically ill patients.
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http://dx.doi.org/10.1016/j.jcrc.2019.06.006DOI Listing
October 2019

Not Enough Evidence to Use Plasma Exchange for Sepsis or Thrombocytopenia-Associated Multiple Organ Failure in Children.

Crit Care Med 2019 06;47(6):e533-e534

Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alberta and Stollery Children's Hospital, Edmonton, AB, Canada.

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http://dx.doi.org/10.1097/CCM.0000000000003695DOI Listing
June 2019

Neurocognitive outcomes in survivors of pediatric E-CPR: Has the Golden age arrived?

Resuscitation 2019 06 13;139:353-355. Epub 2019 Apr 13.

Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stollery Children's Hospital and University of Alberta, Edmonton, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.resuscitation.2019.04.001DOI Listing
June 2019

Cytokines and Chemokines in Pediatric Appendicitis: A Multiplex Analysis of Inflammatory Protein Mediators.

Mediators Inflamm 2019 21;2019:2359681. Epub 2019 Feb 21.

Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary AB, Canada.

Objectives: We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein-CRP, procalcitonin-PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1-MCP-1, and serum amyloid A-SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population.

Methods: We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated.

Results: 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP ( < 0.001). Expansive proteomic analysis demonstrated 6 patterns in inflammatory mediator profiles based on severity of illness. A decision tree incorporating the proteins CRP, ferritin, SAA, regulated on activation normal T-cell expressed and secreted (RANTES), monokine induced by gamma interferon (MIG), and PCT demonstrated excellent specificity (0.920) and negative predictive value (0.882) for children with appendicitis.

Conclusions: Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine.
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http://dx.doi.org/10.1155/2019/2359681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409077PMC
July 2019

Neurocognitive and functional outcomes at 5 years of age after renal transplant in early childhood.

Pediatr Nephrol 2019 05 15;34(5):889-895. Epub 2018 Dec 15.

Department of Pediatrics, Edmonton Clinic Health Academy, University of Alberta, 11405 - 87 Ave, Edmonton, AB, T6G 1C9, Canada.

Background: Clinicians often use information about developmental outcomes in decision-making around offering complex, life-saving interventions in children such as dialysis and renal transplant. This information in children with end-stage renal disease (ESRD) is limited, particularly when ESRD onset is in infancy or early childhood.

Methods: Using data from an ongoing prospective, longitudinal, inception cohort study of children with renal transplant before 5 years of age, we evaluated (1) the risk of adverse neurocognitive and functional outcomes at 5 years of age and (2) predictors of developmental outcomes.

Results: We found evidence of neurocognitive sequelae of ESRD in very young children; however, developmental outcomes appear remarkably better when compared with findings of two or three decades ago. Less time on dialysis predicted higher developmental scores, and hemodialysis was associated with poorer developmental outcomes.

Conclusions: Our data suggest that renal replacement therapies in young children are associated with acceptable developmental outcome. Programs to identify those with developmental delays and provide early intervention may allow achievement of the child's full potential.
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http://dx.doi.org/10.1007/s00467-018-4158-1DOI Listing
May 2019

Avoiding Furosemide Ototoxicity Associated With Single-Ventricle Repair in Young Infants.

Pediatr Crit Care Med 2019 04;20(4):350-356

Department of Pediatrics, Division of Pediatric Critical Care, Stollery Children's Hospital and University of Alberta, Edmonton, AB, Canada.

Objective: To reduce bilateral delayed-onset progressive sensory permanent hearing loss using a systems-wide quality improvement project with adherence to best practice for the administration of furosemide.

Design: Prospective cohort study with regular audiologic follow-up assessment of survivors both before and after a 2007-2008 quality improvement practice change.

Setting: The referral center in Western Canada for complex cardiac surgery, with comprehensive multidisciplinary follow-up by the Complex Pediatric Therapies Follow-up Program.

Patients: All consecutive patients having single-ventricle palliative cardiac surgery at age 6 weeks old or younger.

Interventions: A 2007-2008 quality improvement practice change consisted of a Parenteral Drug Monograph revision indicating slow IV administration of furosemide, an educational program, and an evaluation.

Measurements And Main Results: The outcome measure was the prevalence of permanent hearing loss by 4 years old. Firth multiple logistic regression compared pre (1996-2008) to post (2008-2012) practice change occurrence of permanent hearing loss, adjusting for confounding variables, including all hospital days, extracorporeal membrane oxygenation, cardiopulmonary bypass time, age at first surgery, dialysis, and sepsis. From 1996 to 2012, 259 infants had single-ventricle palliative surgery at age 6 weeks old or younger, with 173 (64%) surviving to age 4 years. Of survivors, 106 (61%) were male, age at surgery was 11.6 days (9.0 d), and total hospitalization days by age 4 years were 64 (42); 18 (10%) had cardiopulmonary resuscitation and 38 (22%) had sepsis at any time. All 173 (100%) had 4-year follow-up. Pre- to postpractice change permanent hearing loss dropped from 17/100 (17%) to 0/73 (0%) of survivors. On Firth multiple logistic regression, the only variable statistically associated with permanent hearing loss was the pre- to postpractice change time period (odds ratio, 0.03; 95% CI, 0-0.35; p = 0.001).

Conclusions: A practice change to ensure slow IV administration of furosemide eliminated permanent hearing loss. Centers caring for critically ill infants, particularly those with single-ventricle anatomy or hypoxia, should review their drug administration guidelines and adhere to best practice for administration of IV furosemide.
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http://dx.doi.org/10.1097/PCC.0000000000001807DOI Listing
April 2019

Biomarker Phenotype for Early Diagnosis and Triage of Sepsis to the Pediatric Intensive Care Unit.

Sci Rep 2018 11 9;8(1):16606. Epub 2018 Nov 9.

Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.

Early diagnosis and triage of sepsis improves outcomes. We aimed to identify biomarkers that may advance diagnosis and triage of pediatric sepsis. Serum and plasma samples were collected from young children (1-23 months old) with sepsis on presentation to the Pediatric Intensive Care Unit (PICU-sepsis, n = 46) or Pediatric Emergency Department (PED-sepsis, n = 58) and PED-non-sepsis patients (n = 19). Multivariate analysis was applied to distinguish between patient groups. Results were compared to our results for older children (2-17 years old). Common metabolites and protein-mediators were validated as potential biomarkers for a sepsis-triage model to differentiate PICU-sepsis from PED-sepsis in children age 1 month-17 years. Metabolomics in young children clearly separated the PICU-sepsis and PED-sepsis cohorts: sensitivity 0.71, specificity 0.93, and AUROC = 0.90 ± 0.03. Adding protein-mediators to the model did not improve performance. The seven metabolites common to the young and older children were used to create the sepsis-triage model. Validation of the sepsis-triage model resulted in sensitivity: 0.83 ± 0.02, specificity: 0.88 ± 0.05 and AUROC 0.93 ± 0.02. The metabolic-based biomarkers predicted which sepsis patients required care in a PICU versus those that could be safely cared for outside of a PICU. This has potential to inform appropriate triage of pediatric sepsis, particularly in EDs with less experience evaluating children.
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http://dx.doi.org/10.1038/s41598-018-35000-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226431PMC
November 2018

Sex-hormone-driven innate antibodies protect females and infants against EPEC infection.

Nat Immunol 2018 10 24;19(10):1100-1111. Epub 2018 Sep 24.

Calvin Phoebe & Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Females have an overall advantage over males in resisting Gram-negative bacteremias, thus hinting at sexual dimorphism of immunity during infections. Here, through intravital microscopy, we observed a sex-biased difference in the capture of blood-borne bacteria by liver macrophages, a process that is critical for the clearance of systemic infections. Complement opsonization was indispensable for the capture of enteropathogenic Escherichia coli (EPEC) in male mice; however, a faster complement component 3-independent process involving abundant preexisting antibodies to EPEC was detected in female mice. These antibodies were elicited predominantly in female mice at puberty in response to estrogen regardless of microbiota-colonization conditions. Estrogen-driven antibodies were maternally transferrable to offspring and conferred protection during infancy. These antibodies were conserved in humans and recognized specialized oligosaccharides integrated into the bacterial lipopolysaccharide and capsule. Thus, an estrogen-driven, innate antibody-mediated immunological strategy conferred protection to females and their offspring.
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http://dx.doi.org/10.1038/s41590-018-0211-2DOI Listing
October 2018

Predictors and outcomes of early post-operative veno-arterial extracorporeal membrane oxygenation following infant cardiac surgery.

J Intensive Care 2018 3;6:56. Epub 2018 Sep 3.

1Division of Pediatric Critical Care, Department of Pediatrics, University of Alberta, 4-546 Edmonton Clinic Health Academy, 11405 87 Avenue, Edmonton, Alberta T6G 1C9 Canada.

Background: We aimed to determine predictors of, and outcomes after, veno-arterial extracorporeal membrane oxygenation instituted within 48 h after cardiac surgery (early ECMO) in young infants.

Methods: Patients ≤ 6 weeks old having cardiac surgery from 2003 to 2012 were enrolled prospectively. Patients cannulated pre-operatively, intra-operatively, or ≥ 48 h post-operatively were excluded. Variables at  ≤ 0.1 on univariate regression were entered into multiple logistic regression to predict early ECMO. Early-ECMO cases were matched 1:2 for six demographic variables, and death by age 2 years old (determined using conditional logistic regression; presented as odds ratio (OR), 95% confidence interval (CI)) and General Adaptive Composite scores at age 2 years (determined using Wilcoxon rank sum) were compared;  ≤ 0.05 was considered statistically significant.

Results: Of 565 eligible patients over the 10-year period, 20 had early ECMO instituted at a mean (standard deviation) of 12.4 (11.4) h post-operatively, 10 of whom had extracorporeal cardiopulmonary resuscitation. Of early-ECMO patients, 8 (40%) were found to have residual anatomic defects requiring intervention with catheterization ( = 1) and/or surgery ( = 7). On multiple regression, the post-operative day 1 highest vasoactive-inotrope score (OR 1.02; 95%CI 1.06,1.08;  < 0.001), highest lactate (OR 1.2; 95%CI 1.06,1.35;  = 0.003), and lowest base deficit (OR 0.82; 95%CI 0.71,0.94;  = 0.004), CPB time (OR 1.01; 95%CI 1.00,1.02;  = 0.002), and single-ventricle anatomy (OR 5.35; 95%CI 1.66,17.31;  = 0.005) were associated with early ECMO. Outcomes at 2 years old compared between early-ECMO and matched patients were mortality 11/20 (55%) vs 11/40 (28%) (OR 3.22, 95%CI 0.98,10.63;  = 0.054) and General Adaptive Composite median 65 [interquartile range (IQR) 58, 81.5] in 9 survivors vs 93 [IQR 86.5, 102.5] in 29 survivors ( = 0.02).

Conclusions: The identified risk factors for, and outcomes after, having early ECMO may aid decision making in the acute period and confirm that neurodevelopmental follow-up for these children is necessary. The hypothesis that earlier institution of ECMO may improve long-term outcomes requires further study.
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http://dx.doi.org/10.1186/s40560-018-0326-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122608PMC
September 2018

A survey to understand public opinion regarding animal use in medical training.

Altern Lab Anim 2018 07;46(3):133-143

Department of Pediatrics, Division of Critical Care, University of Alberta, Edmonton, Alberta, Canada; John Dossetor Health Ethics Center, University of Alberta, Edmonton, Alberta, Canada.

A random survey was performed by ORC International Telephone CARAVAN®, on 24-27 March 2016, by trained interviewers. The aim of this survey was to gain further understanding of public perceptions in the United States of laboratory animal use, specifically for the purposes of medical training. Five statements were read in random order to the participants, who were then asked whether they agreed or disagreed with the statement. Survey responses were obtained from 1011 participants. For the combined statements: "If effective non-animal methods are available to train a) medical students and physicians, b) emergency physicians and paramedics, and c) paediatricians, those methods should be used instead of live animals", most respondents (82-83%) agreed. For the statement: "You want your doctor to be trained by using methods that replicate human anatomy instead of live animals", most respondents (84%) agreed. For the statement: "If effective non-animal methods are available, it is morally wrong or unethical to use live animals to train medical students, physicians and paramedics", 67% of respondents agreed. Responses were similar among the 15 pre-specified demographic subgroups. Given that effective non-animal training methods are readily available, the survey suggests that a substantial majority of the public wants the use of animals in medical training to cease.
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http://dx.doi.org/10.1177/026119291804600308DOI Listing
July 2018