Effect of Xenon Anesthesia Compared to Sevoflurane and Total Intravenous Anesthesia for Coronary Artery Bypass Graft Surgery on Postoperative Cardiac Troponin Release: An International, Multicenter, Phase 3, Single-blinded, Randomized Noninferiority Trial

Hofland J, Ouattara A, Fellahi JL et al

Anesthesiology 2017: 12 (127): 918-33

doi:10.1097/ALN.0000000000001873

 

Aim of Study

Stated hypothesis: In patients undergoing elective on-pump CABG surgery, is xenon non inferior to sevoflurane by favorably limiting postoperative myocardial damage compared to propofol-based TIVA

 

Design and Location

Prospective, randomized, three-arm, single-blinded, international, multicenter, phase 3, noninferiority study

 

Methodology

Random assignment of 3 groups of ~150 patients for maintenance anaesthesia: Xenon anaesthesia, Sevoflurane anaesthesia and Propofol based TIVA

 

Primary Outcome

Troponin concentration (cTnI) at 24 h after the end of surgery for all centers

 

Secondary Outcomes

  • Troponin concentrations at ICU admission and at 12 and 48 h after the end of surgery
  • Peak postoperative blood concentrations of TnI, CK-MB, NT-proBNP, and CRP
  • Feasibility of Xe anesthesia assessed by: BIS index, perioperative hemodynamic variables, blood oxygen concentration and saturation, need for vasoactive or inotropic support, number of patients with perioperative atrial fibrillation
  • Confusion Assessment Method (CAM) for postoperative delirium at inclusion (baseline), 24 and 48 h after surgery (in extubated patients), at ICU discharge, and at the hospital discharge visit.
  • Adverse events (AEs) were collected from the selection visit through hospital discharge or until 30 days after general anesthesia.

 

Statistics

Mean values for the treatment groups were compared using three-armed analysis of covariance (ANCOVA) tests on log-transformed data.

For significant global treatment effects, pairwise comparisons of the mean values of the treatment groups were performed using the Tukey test.

 

Results

At 24 h after the end of surgery, mean cTnI concentrations in the blood were 2.12 ng/ml (95% CI, 1.61 to 2.64) in the xenon group, 2.59 ng/ml (95% CI, 1.87 to 3.30) in the sevoflurane group, and 2.90 ng/ml (95% CI, 2.18 to 3.61) in the TIVA group in the PP population

Xenon was noninferior to sevoflurane both in the Per Protocol (PP) population (P = 0.02) and in the (Intention to Treat) ITT population (P = 0.01). In superiority analysis, xenon was not superior to sevoflurane in either population (ITT: P = 0.32; PP: P = 0.36) but was superior to TIVA in both populations (ITT: P = 0.05; PP: P = 0.02). Sevoflurane was not superior to TIVA in either population (P ≥ 0.15)

Perioperative variables and postoperative outcomes were comparable across all groups, with no safety concerns.

 

Conclusions/Discussions

First large randomized clinical trial conducted for Xe anesthesia in patients undergoing low-risk cardiac surgery

Xe noninferior to sevoflurane anesthesia in preventing cTnI release at 24 h after on-pump CABG surgery.

Xe not superior to sevoflurane, xenon superior to TIVA, sevoflurane not significantly superior to TIVA

Authors concluded that this study demonstrates that xenon anesthesia is feasible and safe for CABG surgery. Overall, postoperative recoveries and AEs were similar for all three groups.

 

Stated Limitations from the Study

Strengths:

  • Large, international, three-arm trial comparing xenon to two standard anesthetics.
  • The central lab was blinded to patient treatments, and the baseline characteristics of the patients and the characteristics of the performed surgeries were very similar across the study centers

Limitations:

  • Blinding incomplete however the consistency of the perioperative characteristics suggests that there was minimal bias.
  • Xe and Sevo had to be interrupted with TIVA during the CPB period which may have reduced the differences between groups
  • Study not powered to assess clinical outcomes so benefit of a potential cardioprotective effect of Xe on the overall outcome of these patients unknown.
  • Study not designed to draw detailed conclusions on the aspect of safety.
  • The selection of relatively low-risk cardiac surgery patients for the study was ethically justified by the fact that, before this trial, no large study investigating xenon for CABG surgery had ever been conducted.

 

Discussion from Journal Club Meeting (?Change of Practice)

Value of study: large randomised phase 3 trial. Only low risk cardiology patients chosen. More evidence needed in high risk cardiology patients and non-cardiology patients.

Discussion regarding mechanism of action of cardioprotection by volatiles: Administration of volatile anesthetic gases was protective for patients undergoing cardiac surgery through manipulation of the potassium ATP (KATP) channel, mitochondrial permeability transition pore (mPTP), reactive oxygen species (ROS) production, as well as through cytoprotective Akt and extracellular-signal kinases (ERK) pathways.

Will Xenon ever be available due to high cost?

Can recycling occur intra-operatively?

What are the benefits/risks in high risk patients?

Clinical outcomes are not measures but only a surrogate marker. Preamble for further studies?

Summary by Dr R. Hreiche. Journal Club 18 January 2018.

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