Evaluation of the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children: study protocol for a prospective, multicenter, randomized, open-label, parallel-group, pragmatic clinical trial

Background: Inadequate postoperative pain management increases the risk of adverse events after the surgery and aggressive perioperative pain prevention has both short-term and long-term benefits. S(+)-ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist with a strong analgesic effect and can significantly relieve postoperative acute pain and reduce opioid consumption. However, for children, it still needs to be confirmed by large sample clinical studies. Methods: This is a pragmatic, randomized controlled trial which will evaluate the effect of perioperative administration of S(+/-)-ketamine hydrochloride injection for postoperative acute pain in children in a pragmatic clinical setting. A total of 3000 children (<= 17 years old) undergoing surgery will be included in this protocol. Subjects will be randomized 2:1 to either receive S(+)-ketamine hydrochloride injection or conventional therapy without S(+)-ketamine during the entire perioperative period. The primary endpoints are the area under the receiver operating characteristic (ROC) curve of Face Legs Activity Cry and Consolability (FLACC, 0-7 years old) scale score or Numerical Rating Scale (NRS, 8-17 years old) score within 48 h after surgery, and the consumption of opioids within 48 h after surgery. The secondary endpoints include the time of first use of rescue analgesics after surgery, rescue analgesia rate within 48 h after surgery, anesthesia recovery time, incidence of emergency delirium (for 0-7 years old), changes of anxiety and depression scale scores at 48 h after surgery (for 8-17 years old), incidence of intraoperative adverse events (AEs), and incidence of postoperative AEs and pharmacoeconomic indicators. AEs and serious AEs were recorded to evaluate safety. Discussion: This trial will be the first pragmatic clinical trial to prospectively assess the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children, which is of great significance to the continuous optimization of clinical anesthesia and analgesia programs for children.