The TREX (Toxicity Remifentanil DEXmedetomidine) Trial Investigators are pleased to announce the completion of enrollment of the 450 trial subjects. The TREX Trial is a multicenter, multinational study of two anesthetic regimens for prolonged anesthesia in infants and young children less than 2 years of age, to determine whether a dexmedetomidine-based anesthetic is associated with better neurodevelopmental outcomes. Funding for the TREX study has been provided by the International Anesthesia Research Society through the SmartTots public-private partnership, the Australian National Medical Research Council (NMRC), Italian Medicines Agency (AIFA), and internal funding from the enrollment sites. Dexmedetomidine is a relatively new sedative-analgesic agent that does not cause neurodegeneration in preclinical animal models, unlike the common inhaled anesthetics such as sevoflurane. One arm of the prospective, randomized trial receives a standard level of the common anesthetic gas sevoflurane, at 2.5-3% end-tidal concentration as the main anesthetic technique. The other arm receives loading doses and infusions of dexmedetomidine and remifentanil as the main anesthetic, along with a low dose of sevoflurane at 0.3-0.6% end-tidal concentration. A variety of surgeries, including urologic, abdominal, thoracic, and orthopedic are being studied, with 2 or more hours of planned anesthesia time as the criteria for enrollment. The children will return at age 3 years for a battery of neuropsychological testing, including general intelligence, language, fine and gross motor skills, behavioral testing and parent behavioral questionnaires. More than 100 subjects have already returned for the neuropsychological testing, and it is anticipated that the remainder will return over the next 2-3 years to complete the study.
The potential for pediatric anesthetic neurotoxicity has been a concern of clinicians and investigators for more than 20 years, ever since pre-clinical studies demonstrated neurodegeneration and adverse neurobehavioral effects in rodents and non-human primates. Effects of anesthesia exposure in human clinical and retrospective studies had been mixed; but in recent years studies such as PANDA, GAS, and MASK have demonstrated that a single short exposure to general anesthesia in young children is not associated with changes in IQ compared to unexposed children. However, prolonged exposure effects have not been well studied; the TREX Trial will bridge this important data gap.
Professor Andrew Davidson of the Royal Children’s Hospital and Murdoch Children’s Research Institute in Melbourne, Australia, is the Principal Investigator (PI) of the TREX Trial, and the PI of the Australian NMRC grant; Dean Andropoulos, M.D., of Texas Children’s Hospital, is the PI of the study in the United States and U.S. FDA Investigational New Drug Holder, Peter Szmuk, M.D. of the Children’s Medical Center in Dallas, Texas is the SmartTots grant PI, and Professor Nicola Disma of the Istituto Giannina Gaslini, Genova, Italy is the PI of the consortium funded by the AIFA of Italy. There are a total of 20 sites enrolling patients: 7 in Australia, 5 in the U.S. and 8 in Italy. When completed, the results will be reported at major scientific meetings, and submitted for publication to high impact scientific journals. The TREX Trial will make an important contribution to the knowledge about the effects of anesthesia in infants and young children; an issue that potentially affects millions of children globally who undergo anesthesia and surgery each year.