Importance: Evidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children. Unfortunately such evidence is not always available. Objectives: To describe the RCT research enterprise in pediatric critical care — the evidence and the process of creating it, along with problems and some solutions. Methods: To meet these objectives I undertook a series of 5 related studies. First a scoping review to describe the output of the research enterprise. Second, a social network analysis of coauthorship patterns to describe the community of researchers who produce this evidence. Third, a survey to investigate the importance of RCTs in clinicians’ decision-making. Fourth, a survey of trialists to identify barriers and facilitators of high quality RCTs. Fifth, a qualitative interview study to identify acceptable, feasible and effective strategies to improve the evidence available from RCTs in pediatric critical care. Results and conclusions: The number of RCTs in pediatric critical care is increasing but there is a preponderance of small, single-centred RCTs focusing on laboratory or physiological outcomes that are often stopped early because of feasibility problems or futility. The research community is highly fragmented and highly clustered. Experienced trialists identified approaches to improve the pediatric critical care research enterprise, including building a sense of community and ensuring key training and relevant practical experiences for new investigators. Because of the barriers that researchers face and their ethical obligation to undertake trials that are feasible and make a meaningful contribution to advancing the care of critically ill children, individuals and groups must take an active role in building a healthy research community. Only by changing how we function as a research community can we train the next generation of investigators and undertake the type of trials needed to improve the care of critically ill children. / Thesis / Doctor of Philosophy (PhD) / Evidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children. Unfortunately such evidence is not always available. My objectives in this thesis are to describe the RCT research enterprise in pediatric critical care — the evidence and the process of creating it, along with problems and some solutions. To meet these objectives I undertook a series of 5 related studies: to identify and describe the RCTs, describe how researchers collaborate, understand how clinicians use RCTs, identify barriers and facilitators of conducting high quality RCTs, and understand how we can improve the evidence available from RCTs in pediatric critical care. We found that the number of RCTs is increasing but there are opportunities to improve the methods, outcome measures, and quality of reporting. We identified strategies that researchers can adopt to facilitate the rigorous RCTs that are needed to improve the care of critically ill children.

This study examined illness-related uncertainty and primary appraisals of threat, centrality, and challenge as predictors of acute stress disorder (ASD) symptoms in parents of children hospitalized in a pediatric intensive care unit (PICU). Ultimately, a mediational pathway was tested to determine if primary appraisal was a mechanism that accounted for the impact of uncertainty on ASD symptoms. Ancillary study aims were to assess the degree to which parents perceived uncertainty in the PICU environment, and to determine the prevalence of ASD among parents in this setting. Self-report data was collected from 77 parents (57 mothers, 19 fathers) of children hospitalized in a PICU for a minimum of 48 hours. Descriptive analyses showed that parents perceived a high degree of uncertainty and 57% of parents met diagnostic criteria for ASD. Unexpected admission was the only objective medical status variable significantly related to uncertainty, threat appraisal, and ASD symptoms. Consistent with hypotheses, results from hierarchical regression analyses showed that perceived uncertainty and primary appraisals of threat accounted for significant variance in parents’ ASD symptoms; however, neither centrality nor challenge appraisals were related to parents’ ASD symptoms. Because threat was the only appraisal dimension found to be directly related to ASD symptoms, it was the only dimension tested in the mediational model. Consistent with the hypothesis, threat appraisals fully mediated the effect of uncertainty on ASD symptoms; results from a Sobel test confirmed the significance of full mediation. This study is the first to examine uncertainty, primary appraisal, and ASD symptoms in this population. Results clarify that it is not the mere perception of uncertainty that adversely impacts parental adjustment, but rather how it is appraised, and therefore, point to a practical area for in-hospital interventions targeting parents’ pediatric medical traumatic stress symptoms. Although a substantial body of empirical research supports a relation between uncertainty and maladaptive outcomes, studies also link uncertainty to positive outcomes. Future research should include positive indicators of adjustment and examine how appraisals vary according to sources of uncertainty.

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Les transfusions de plasma sont un traitement fréquent en réanimation, pour traiter ou prévenir un saignement. Or, des données observationnelles suggèrent que les transfusions de plasma sont associées à une augmentation de la morbidité et de la mortalité, sauf chez les patients qui souffrent d’hémorragie massive. Des données adultes suggèrent que les transfusions de plasma n’ont que peu d’effet sur les tests de coagulations.L’objectif de ce travail de thèse de sciences est d’effectuer quatre études préliminaires qui permettront ensuite de définir le protocole d’une étude randomisée contrôlée.La première étude présentée dans notre mémoire de thèse, une étude observationnelle dans 101 réanimations pédiatriques, a conclu que le plasma est souvent transfusé à des enfants qui ne saignent pas, et que, chez la grande majorité des patients, les transfusions de plasma n’ont que très peu d’effet sur les tests de coagulation. La deuxième étude a montré que les divers types de plasma actuellement sur le marché ont peut-être des effets différents, en terme de mortalité. La troisième étude a montré que les facteurs influençant la prescription de transfusions de plasma sont souvent des croyances non-fondées sur la capacité des transfusions de plasma à prévenir et arrêter le saignement. Et la quatrième étude a démontré que la mesure de la sévérité de la maladie, selon un score de défaillance multiviscérale, était adéquate dans une sous-population d’enfants recevant des transfusions de plasma. Ces quatre études nous ont donc permis d’esquisser le protocole de l’étude randomisée, qui permettra de comparer deux stratégies de transfusions de plasma. / Plasma transfusions are frequently used to treat or prevent bleeding in critically ill children. However, little is known about the proper indications. Observational data both in children and adults indicate that plasma transfusions are associated with increased morbidity and mortality, except in massively bleeding patients. Adult data suggest that plasma transfusions have little effect on coagulation tests and that a large proportion of plasma transfusions are not given according to the international recommendations.The objective of this thesis is to perform four preliminary studies that will allow designing the protocol of a randomized controlled trial. This trial will evaluate the cost-benefit relationship of plasma transfusion strategies in critically ill children.The first study in this thesis, an observational study in 101 centers, concluded that plasma was often transfused to non-bleeding children and that plasma transfusions had little effect on coagulation tests. The second study showed that the different types of plasma products had different clinical effects, in terms of morbidity and mortality. The third study showed that unfounded beliefs on plasma’s ability to prevent or stop bleeding influenced the prescription of plasma transfusions. The fourth study showed that measuring the severity of the disease with a multiple-organ dysfunction score was appropriate in a sub-population of critically ill children requiring plasma transfusion.These four studies allowed designing the protocol for the randomized controlled trial, comparing plasma transfusion strategies.

Les cardiopathies congénitales (CC) représentent l’une des anomalies congénitales les plus communes. Près de la moitié des nouveau-nés atteints nécessitent une chirurgie cardiaque au cours de leur premier mois de vie, ce qui les expose à un risque accru d’atteintes cérébrales et a été associé à un développement neurologique altéré. Il est donc nécessaire de trouver des stratégies neuroprotectrices efficaces pour améliorer leur évolution neurologique. Ce mémoire décrit l’influence des doses d’agents pharmacologiques administrées en période périopératoire sur la récupération de l’EEG en postopératoire, ainsi que sur les résultats neurodéveloppementaux évalués à 12 et 24 mois. Nous avons émis l'hypothèse que l’administration de certains agents pharmacologiques de sédation, d’anesthésie et d’analgésie en période intra- et postopératoire pourrait avoir un effet bénéfique au niveau de la récupération cérébrale à court- et long-terme, soit en réduisant la discontinuité observée sur l’EEG postopératoire et/ou en améliorant la performance obtenue lors de divers tests neurodéveloppementaux standardisés. Nos résultats semblent préconiser l’administration de plus fortes doses d’opioïdes en période périopératoire pour réduire la douleur et le stress induit par la chirurgie cardiaque, ce qui serait associé avec une amélioration du pronostic neurodéveloppemental. L’administration de plus fortes doses de dexmédétomidine et de midazolam était marquée par une récupération retardée de l’activité cérébrale après la chirurgie cardiaque sans aucun impact remarquable sur les résultats neurodéveloppementaux dans notre cohorte. Similairement, les doses de kétamine n’ont eu aucun impact sur la récupération cérébrale post-opératoire ou les bilans neurodéveloppementaux. / Congenital heart disease (CHD) is one of the most common congenital defects. Almost half of neonates affected require heart surgery during their first month of life, which exposes them to an increased risk of brain damage and has been associated with impaired neurodevelopment. It is therefore important to identify effective neuroprotective strategies to improve their neurological outcomes. This thesis describes the influence of the administration of pharmacological agents during the perioperative period on postoperative EEG recovery and neurodevelopmental outcomes at 12 and 24 months. We hypothesized that the administration of certain pharmacological agents for sedation, anesthesia and analgesia given during the intra- and post-operative period could have a beneficial effect on cerebral recovery, by decreasing the postoperative EEG discontinuity and/or improving neurodevelopmental outcomes. Our results suggest that the administration of higher doses of opioids during the perioperative period could reduce the pain and stress induced by cardiac surgery and are thus associated with improved neurodevelopmental outcomes. The administration of higher doses of dexmedetomidine and midazolam was marked by a delayed recovery of brain activity after cardiac surgery without any noticeable impact on neurodevelopmental outcomes in our cohort. Similarly, the doses of ketamine had no impact on postoperative brain recovery and on their long-term development.

L’anémie est fréquente chez les patients pédiatriques en postopératoire de chirurgie cardiaque. Malgré le nombre important de patients transfusés, le taux d’hémoglobine (Hb) pour lequel les bénéfices surpassent les risques est inconnu chez ces patients. Récemment, Lacroix et al. ont démontré qu’une stratégie transfusionnelle restrictive n’était pas inférieure à une stratégie libérale en ce qui concerne le développement ou la progression du syndrome de défaillance multiviscérale (SDMV) et la mortalité chez les patients de soins intensifs pédiatriques (SIP).Devant le manque d’évidence, une analyse de sous-groupes des patients en postopératoire de chirurgie cardiaque de l’étude Transfusion Requirements in Pediatric Intensive Care (TRIPICU) a été réalisée. L’objectif de cette étude était de déterminer l’impact d’une stratégie transfusionnelle restrictive comparée à une stratégie libérale sur l’acquisition ou l’aggravation du syndrome de défaillance multiviscérale (SDMV) chez les enfants en postopératoire de chirurgie cardiaque. Cette étude n’a pas démontré de différences statistiquement, ni cliniquement significatives du nombre de patients ayant acquis ou aggravés un SDMV, ni des issues secondaires entre les stratégies transfusionnelles restrictive et libérale. L’analyse de sous-groupes permet de générer une hypothèse de recherche et les résultats devraient être confirmés par un essai randomisé contrôlé. / Anemia is frequent in pediatric patients following cardiac surgery. Despite frequent transfusions, the optimal hemoglobin threshold where benefits surpass risks is still unknown for these patients. Recently, Lacroix et al. showed that a restrictive transfusion strategy was not inferior to a liberal strategy concerning the development or progression of multiple organ dysfunction syndrome (MODS) and mortality in pediatric intensive care patients. In the absence of evidence, the aim of this study was to determine the impact of a restrictive versus a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome (MODS) in children following cardiac surgery. We conducted a subgroup analysis of the postoperative cardiac surgery patients of the Transfusion Requirements in Pediatric Intensive Care Unit (TRIPICU) study. Our study showed no statistically and clinically significant differences in the number of patients who acquired or worsened MODS, nor secondary outcomes between a restrictive and a liberal transfusion strategy. This subgroup analysis generates a research hypothesis that should be confirmed by a randomized controlled trial.

L’anémie est fréquente chez les patients pédiatriques en postopératoire de chirurgie cardiaque. Malgré le nombre important de patients transfusés, le taux d’hémoglobine (Hb) pour lequel les bénéfices surpassent les risques est inconnu chez ces patients. Récemment, Lacroix et al. ont démontré qu’une stratégie transfusionnelle restrictive n’était pas inférieure à une stratégie libérale en ce qui concerne le développement ou la progression du syndrome de défaillance multiviscérale (SDMV) et la mortalité chez les patients de soins intensifs pédiatriques (SIP).Devant le manque d’évidence, une analyse de sous-groupes des patients en postopératoire de chirurgie cardiaque de l’étude Transfusion Requirements in Pediatric Intensive Care (TRIPICU) a été réalisée. L’objectif de cette étude était de déterminer l’impact d’une stratégie transfusionnelle restrictive comparée à une stratégie libérale sur l’acquisition ou l’aggravation du syndrome de défaillance multiviscérale (SDMV) chez les enfants en postopératoire de chirurgie cardiaque. Cette étude n’a pas démontré de différences statistiquement, ni cliniquement significatives du nombre de patients ayant acquis ou aggravés un SDMV, ni des issues secondaires entre les stratégies transfusionnelles restrictive et libérale. L’analyse de sous-groupes permet de générer une hypothèse de recherche et les résultats devraient être confirmés par un essai randomisé contrôlé. / Anemia is frequent in pediatric patients following cardiac surgery. Despite frequent transfusions, the optimal hemoglobin threshold where benefits surpass risks is still unknown for these patients. Recently, Lacroix et al. showed that a restrictive transfusion strategy was not inferior to a liberal strategy concerning the development or progression of multiple organ dysfunction syndrome (MODS) and mortality in pediatric intensive care patients. In the absence of evidence, the aim of this study was to determine the impact of a restrictive versus a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome (MODS) in children following cardiac surgery. We conducted a subgroup analysis of the postoperative cardiac surgery patients of the Transfusion Requirements in Pediatric Intensive Care Unit (TRIPICU) study. Our study showed no statistically and clinically significant differences in the number of patients who acquired or worsened MODS, nor secondary outcomes between a restrictive and a liberal transfusion strategy. This subgroup analysis generates a research hypothesis that should be confirmed by a randomized controlled trial.