Therapeutic plasma exchange (TPE) in pediatric patients presents many challenges, including management of a large extracorporeal volume (ECV) and calcium replacement for patients who may not be able to express signs of hypocalcemia or other associated adverse events with a large ECV. Pediatric patients who are critically ill on continuous renal replacement therapy (CRRT) and/or extracorporeal membrane oxygenation (ECMO) may have indications for TPE, such as sepsis or liver failure anticipating transplant. It may be difficult or clinically detrimental to take the patient off the CRRT or ECMO circuit to perform TPE. Connecting the TPE device into the preexisting circuit is feasible with the understanding of the principles of the circuit flow set up and monitoring to mitigate adverse events. Effective communication among clinical teams managing distinct extracorporeal circuits is critical to ensuring coordinated patient care.