Humane care for critically ill pediatric patients supported on mechanical ventilation necessitates comfort management that includes sedation therapy. Critically ill patients quickly become tolerant to the opioids and benzodiazepines used for sedation therapy and require increasing doses of these medications to achieve the same therapeutic effect. In turn, after recovery from their primary illnesses, rapid weaning or abrupt cessation of sedative therapy in drug tolerant patients precipitates iatrogenic withdrawal syndrome - a problem that adds to the personal and financial burden of intensive care. While numerous studies have focused on illuminating iatrogenic withdrawal syndrome symptomatology, a new perspective for addressing this preventable complication of pediatric intensive care is now warranted. This dissertation will use data from the RESTORE clinical trial [U01HL086622 and U01HL086649 (PI: Curley & Wypij); 31-center cluster randomized trial of nurse-led sedation management on clinical outcomes in children requiring mechanical ventilation for acute respiratory failure] to conduct a series of analyses comparing patient-, process- and system-level data between those subjects who developed iatrogenic withdrawal syndrome and those who did not. By exploring variables at multiple levels, this study will be the most comprehensive evaluation of iatrogenic withdrawal syndrome ever completed and will contribute new knowledge to the field. The studies will collectively answer the key question: What factors impact the development of iatrogenic withdrawal syndrome in pediatric patients recovering from critical illness? Furthermore, the relative contributions of patient, process, and systems factors will be combined to create a predictive model of patient risk for clinically significant iatrogenic withdrawal syndrome in pediatric patients recovering from critical illness. This dissertation will contextualize the phenomenon of iatrogenic withdrawal syndrome within the unique clinical circumstances in which it occurs. More importantly, risk factors identified through this study could lead to the development of personalized risk profiles and prevention protocols for vulnerable children in the pediatric intensive care unit.