Short-term Outcomes in Infants after General Anesthesia with Low dose Sevoflurane/ Dexmedetomidine/ Remifentanil versus Standard-dose Sevoflurane (the TREX Trial)
Anesthesiology 2024; 141:1075–85
DOI: 10.1097/ALN.0000000000005232
What's the question?
-
In children less than 2 years of age having general anaesthesia lasting 2 hours or more, do short-term perioperative outcomes differ between low-dose sevoflurane/dexmedetomidine/remifentanil (LD-SEVO) and standard-dose sevoflurane (STD-SEVO) anaesthesia?
Background Information
-
Concerns about anaesthesia-induced developmental neurotoxicity from agents such as propofol, sevoflurane, and ketamine persist, driven by animal model findings; human studies show conflicting results.
-
The FDA issued a safety warning in 2016 that repeated or lengthy use of general anaesthetics in children younger than 3 years may affect brain development; label changes for anaesthetic agents followed in 2017.
-
The SmartTots group (a partnership between the FDA and the International Anesthesia Research Society) called for a trial examining the effects of single, prolonged general anaesthetic exposures in young children.
-
The primary aim of the TREX (Trial Remifentanil DEXmedetomidine) trial is to determine whether LD-SEVO is superior to STD-SEVO for global cognitive function at 3 years of age; the primary neurodevelopmental outcome is not yet available.
The study
-
Phase III randomised, active-controlled, parallel-group, assessor-blinded, multicentre, superiority trial across 20 centres in Australia, Italy, and the United States (August 2017 to April 2023).
-
455 children enrolled; 428 included in the modified intention-to-treat analysis (207 LD-SEVO, 221 STD-SEVO); patients were well matched at baseline.
-
Eligible patients: age less than 2 years, expected anaesthesia duration at least 2 hours; exclusions included known neurological or chromosomal anomaly, prematurity less than 36 weeks, and congenital cardiac disease requiring surgery.
-
LD-SEVO protocol: dexmedetomidine infusion (1 mcg/kg/hr) plus remifentanil infusion (³0.1 mcg/kg/min) plus low-dose sevoflurane (target end-tidal ²0.6–0.8%). STD-SEVO protocol: standard-dose sevoflurane (target end-tidal ³2.5–3.0%).
-
Less intraoperative hypotension in LD-SEVO (12% vs 24%; risk difference –11.6%, 95% CI –18.9 to –4.3%; p=0.002).
-
More intraoperative bradycardia in LD-SEVO (24% vs 5%; risk difference 18.2%, 95% CI 8.8 to 27.7%; p<0.001).
-
Many more episodes of light anaesthesia in LD-SEVO (43% vs 4%; risk difference 39.8%; p<0.001); protocol abandoned in only 1 of 428 patients (0.2%).
-
Lower FLACC postoperative pain scores in LD-SEVO (median difference –0.52; p=0.004), though the difference was small and not considered clinically meaningful; analgesic administration rates were similar.
-
Faster time to eye opening (16 vs 25 min; p=0.004) and departure from the operating room (14 vs 16 min; p=0.012) in LD-SEVO; PACU stay duration was similar in both groups.
-
Rates of postoperative readmission, prolonged hospitalisation, and serious morbidity were similar at 5 days. One life-threatening event occurred in each arm (severe bradycardia/asystole in LD-SEVO; bradycardia with hypothermia in STD-SEVO); both patients recovered fully with no long-term sequelae. There were no deaths.
Strengths and Weaknesses
-
Strengths: Prospective international multicentre RCT with standardised protocols; good baseline demographic matching; clear pre-specified definitions for hypotension, bradycardia, and light anaesthesia; modified intention-to-treat analysis.
-
Weaknesses: Power was calculated for the primary neurodevelopmental outcome, not these short-term outcomes. Light anaesthesia episodes were not recorded in more than 50% of STD-SEVO patients initially, limiting comparison. Rescue treatment data for bradycardia were missing in 68% of episodes. Surgical suitability and the impact of patient movement on operative outcomes were not assessed. Postoperative hyperalgesia from remifentanil and total opioid consumption were not measured. No data were collected after PACU discharge. No reliable monitor for intraoperative awareness exists for children under 1 year of age, so unrecognised awareness in the LD-SEVO arm cannot be excluded.
PHRACC's Conclusions
-
The two anaesthetic techniques are broadly clinically similar in terms of short-term perioperative outcomes; there is no clear evidence to favour one over the other.
-
LD-SEVO produces less intraoperative hypotension but more bradycardia and substantially more episodes of light anaesthesia than STD-SEVO.
-
LD-SEVO is associated with faster emergence from anaesthesia but similar PACU duration and 5-day morbidity and mortality.
-
Definitive guidance on technique selection awaits the primary neurodevelopmental outcome data at 3 years of age.
This page is part of the PHRACC AI-assisted education series. AI has been used to help synthesise information from carefully hand-picked peer-reviewed recent publications which relate to the delivery of healthcare in both the United Kingdom and Australia. Content has been reviewed and edited by the author to minimise the risk of error and incorrect information. PHRACC.com and the author(s) can not be held responsible or liable in any way for any errors in this article and resulting sequelae. The responsibility rests solely with the reader to confirm the accuracy of all information contained here with independent reputable sources before using it for any purpose.