Supplementary material · EACTAIC 41^st Annual Congress

Hormonal Stress Response After Opioid-Free Versus Opioid-Based Anaesthesia in Cardiac Surgery

Larissa Vozjaeva, Yulia Pinevich, Siarhei Soloviev

Department of Anaesthesiology and Intensive Care for Cardiac Surgery, Republican Clinical Medical Center, Minsk Region, Belarus

Contact: lorimar1006@gmail.com

Purpose of this file

This document provides the detailed study protocol, predefined sampling schedule, complete group-level biomarker tables, baseline and operative characteristics, percentage changes from baseline, and statistical definitions supporting the e-poster.

Study design and population

Prospective, non-randomised, parallel-group comparative pilot study. Twenty-four patients were included: 12 in the opioid-free anaesthesia (OFA) group and 12 in the opioid-based anaesthesia (OBA) group. Patients were scheduled for coronary artery bypass grafting with or without concomitant aortic valve replacement.

Exactly one patient in each group underwent concomitant AVR (1/12; 8.3% in each group); because this was balanced and n = 1 per group, AVR was not analysed as a subgroup.

Table S1. Baseline and operative characteristics

Parameter	OFA (n = 12)	OBA (n = 12)	p
Age, years	65.0 [57.5; 68.2]	61.5 [54.0; 71.0]	0.885
Female	1 (8.3%)	2 (16.7%)	> 0.99
Male	11 (91.7%)	10 (83.3%)	—
Weight, kg	83.5 [78.4; 97.2]	76.0 [74.8; 99.5]	0.402
Height, cm	172.0 [167.5; 175.2]	166.5 [163.8; 176.2]	0.370
BMI, kg/m²	29.1 [27.4; 30.7]	29.5 [24.6; 32.8]	0.795
Diabetes mellitus	4 (33.3%)	4 (33.3%)	> 0.99
ASA III	12 (100.0%)	11 (91.7%)	> 0.99
ASA IV	0	1 (8.3%)	—
EuroSCORE	1.1 [1.0; 1.4]	1.4 [1.0; 2.1]	0.642
Grafts: 2	1 (8.3%)	3 (25.0%)	0.394
Grafts: 3	10 (83.3%)	7 (58.3%)	—
Grafts: 4	1 (8.3%)	2 (16.7%)	—
LVEF, %	56.0 [53.0; 64.0]	58.5 [56.5; 59.5]	0.839
Surgery duration, min	380.0 [347.5; 422.5]	360.0 [330.0; 446.2]	0.817
CPB duration, min	117.0 [105.0; 140.8]	120.0 [107.5; 149.0]	0.751
Cross-clamp time, min	81.5 [60.8; 97.5]	86.5 [70.2; 104.5]	0.488
ICU ventilation, min	120.0 [97.5; 131.2]	107.5 [82.5; 172.5]	0.664
Concomitant AVR	1/12 (8.3%)	1/12 (8.3%)	—

Table S2. Monitoring schedule

Parameter	T1 pre-induction	T2 pre-CPB	T3 1 h post-extub.	T4 24 h	T5 48 h
Serum cortisol	✓	✓	✓	✓	✓
Salivary cortisol	✓	—	✓	✓	—
DHEA-S	✓	✓	✓	✓	✓
Cortisol / DHEA-S ratio	✓	✓	✓	✓	✓
VAS pain	—	—	✓	✓	✓

Anaesthesia protocols

Table S3. Key protocol differences

Stage	OFA	OBA
Premedication	Gabapentin 600 mg PO 1.5–2 h before surgery; midazolam 5 mg IM 0.5–1 h before surgery	Midazolam 5 mg IM 0.5–1 h before surgery
Induction	Propofol 2 mg/kg + muscle relaxant; IV ketamine 12.5 mg, lidocaine 1 mg/kg, dexmedetomidine 1 μg/kg, dexamethasone 8 mg, magnesium sulfate 25% 10 mL	Propofol 2 mg/kg + fentanyl 3–5 μg/kg + muscle relaxant
Maintenance	Sevoflurane; propofol 2–4 mg/kg/h, BIS 40–50; ketamine 0.1 mg/kg/h; lidocaine 1 mg/kg/h; dexmedetomidine 0.5 μg/kg/h; paracetamol 1000 mg at end of surgery	Sevoflurane; propofol 2–4 mg/kg/h, BIS 40–50; fentanyl 3 μg/kg/h; muscle relaxant as required
ICU	Ketamine up to 0.05 mg/kg/h; lidocaine 1 mg/kg/h; magnesium sulfate 25% 2 mL/h up to 24 h; paracetamol 1000 mg q6h; gabapentin 900–1200 mg/day PO	Paracetamol 1000 mg q6h; gabapentin 900–1200 mg/day PO

Biomarker measurement and definitions

Serum cortisol, DHEA-S and salivary cortisol were measured by electrochemiluminescence on a Cobas e 411 analyzer (Roche Diagnostics, Switzerland). Serum cortisol and DHEA-S were assessed at T1–T5; salivary cortisol at T1, T3 and T4.

CDR was calculated for each individual patient at each predefined time point as serum cortisol (nmol/L) divided by DHEA-S (nmol/L). DHEA-S reported in μg/dL was converted to nmol/L using × 27.59. Group-level CDR values are reported as median [IQR]. CDR is treated here as an exploratory composite marker of relative glucocorticoid-to-adrenal androgen balance, not as a standalone diagnostic test for adrenal insufficiency.

Postoperative pain was assessed using a 10-point visual analogue scale (VAS): 0 = no pain, 10 = maximum pain intensity; 1–3 mild, 4–6 moderate, 7–10 severe.

Serum cortisol

Table S4. Serum cortisol concentrations, nmol/L

Time point	OFA	OBA	p	r_rb	95% CI	Effect
T1 Pre-induction	406.4 [369.3; 499.1]	433.4 [310.7; 467.9]	0.630	+0.12	−0.33 to +0.54	Small
T2 Pre-CPB	525.1 [369.4; 699.0]	444.7 [327.8; 525.4]	0.291	+0.26	−0.20 to +0.63	Medium
T3 1 h post-extubation	811.0 [564.6; 1486.2]	1208.0 [922.2; 1483.0]	0.242	−0.29	−0.65 to +0.17	Medium
T4 24 h	200.0 [109.9; 328.2]	315.5 [267.4; 471.8]	0.089	−0.42	−0.72 to +0.03	Very large
T5 48 h	372.7 [226.7; 504.6]	545.6 [347.7; 629.9]	0.166	−0.34	−0.68 to +0.12	Large

Table S5. Serum cortisol change from baseline, %

Time point	OFA	within p	OBA	within p	between p	r_rb (95% CI)	Effect
T2 Pre-CPB	+28.7 [−10.4; +60.9]	0.204	+11.6 [−40.0; +60.7]	0.339	< 0.99	0.00	Tiny
T3 1 h post-extubation	+132.8 [+5.7; +211.2]	0.012	+221.4 [+120.7; +305.5]	< 0.001	0.114	−0.39 (−0.71 to +0.06)	Large
T4 24 h	−51.6 [−72.2; −11.1]	0.034	−13.7 [−37.8; +31.2]	0.894	0.068	−0.44 (−0.74 to −0.01)	Very large
T5 48 h	−1.9 [−38.2; +16.1]	0.569	+19.4 [−7.9; +45.8]	0.092	0.114	−0.39 (−0.71 to +0.06)	Large

Salivary cortisol

Table S6. Salivary cortisol concentrations, nmol/L

Time point	OFA	OBA	p
T1 Pre-induction	15.5 [10.1; 20.4]	13.6 [12.2; 20.5]	0.840
T3 1 h post-extubation	77.0 [39.9; 130.6]	54.3 [34.4; 157.8]	0.755
T4 24 h	10.3 [7.3; 36.2]	39.3 [19.0; 77.9]	0.033

DHEA-S

Table S7. Serum DHEA-S concentrations, μg/dL

Time point	OFA	OBA	p
T1 Pre-induction	91.9 [62.5; 153.1]	94.9 [82.8; 128.0]	0.887
T2 Pre-CPB	84.2 [55.1; 130.1]	76.9 [64.2; 130.4]	0.755
T3 1 h post-extubation	111.6 [99.9; 159.3]	140.8 [107.0; 173.3]	0.410
T4 24 h	90.6 [71.1; 126.5]	111.6 [64.8; 156.3]	0.630
T5 48 h	67.8 [42.4; 113.8]	86.0 [55.4; 125.0]	0.513

Table S8. DHEA-S change from baseline, %

Time point	OFA	within p	OBA	within p	between p
T2 Pre-CPB	−14.8 [−18.3; −9.6]	0.003	−4.7 [−19.7; +18.9]	0.791	0.219
T3 1 h post-extubation	+35.5 [+7.5; +49.5]	0.003	+52.6 [+41.4; +65.2]	< 0.001	0.073
T4 24 h	−2.8 [−22.6; +8.9]	0.850	+3.2 [−10.8; +42.4]	0.380	0.319
T5 48 h	−27.6 [−28.9; −22.5]	< 0.001	−14.7 [−32.1; +8.5]	0.092	0.219

Cortisol / DHEA-S ratio

Table S9. Serum cortisol/DHEA-S ratio (CDR)

Time point	OFA	OBA	p
T1 Pre-induction	0.12 [0.07; 0.24]	0.11 [0.08; 0.15]	0.755
T2 Pre-CPB	0.17 [0.06; 0.34]	0.14 [0.07; 0.22]	0.590
T3 1 h post-extubation	0.22 [0.11; 0.36]	0.25 [0.18; 0.28]	0.932
T4 24 h	0.07 [0.02; 0.09]	0.10 [0.06; 0.16]	0.160
T5 48 h	0.13 [0.09; 0.24]	0.16 [0.10; 0.29]	0.843

CDR was calculated for each patient at each corresponding time point before group-level summarisation. No significant between-group CDR differences were observed. The predefined adaptive range is 0.05–0.20.

Statistical analysis

Analyses included: (1) within-group and between-group assessment of absolute biomarker values at each study time point; (2) between-group comparison of absolute values at each time point; and (3) within-group percentage change from baseline and between-group comparison of those changes, with effect-size estimation.

R version 4.3 was used. Quantitative data are presented as median [Q1; Q3]. Between-group comparisons of independent observations used the Mann–Whitney U test; within-group paired comparisons used the Wilcoxon signed-rank test. Holm correction was applied to multiple comparisons. Effect size was expressed as the rank-biserial correlation coefficient (r_rb) with 95% confidence intervals where reported in the source. The two-sided significance level was set at α = 0.05.

Eligibility and exclusion criteria

Eligibility was defined by the source protocol as patients scheduled for coronary artery bypass grafting (CABG) with or without aortic valve replacement (AVR).

Exclusion criteria

Domain	Criteria
Organ function / endocrine	Severe hepatic impairment; severe renal impairment (creatinine > 200 μmol/L or clearance < 30 mL/min) or maintenance dialysis; severe LV dysfunction (EF < 35–40%); severe respiratory failure requiring preoperative oxygen or non-invasive ventilation; history of adrenal insufficiency and/or long-term systemic corticosteroid therapy.
Cardiac / vascular	Severe conduction disorders (Mobitz II or third-degree AV block without a pacemaker, sick sinus syndrome, prolonged QTc > 480 ms); baseline haemodynamic instability; acute myocardial infarction / ischaemia.
Pharmacological	Chronic use of opioids or anticonvulsants; use of antidepressants or antipsychotics; known allergy or hypersensitivity to any component of the study protocol.
Neurological / cognitive	Pre-existing cognitive disorder or inability to establish adequate contact with the patient (e.g. due to deafness); uncontrolled epilepsy; increased intracranial pressure or stroke / TIA shortly before surgery.
Surgical / administrative	Urgent surgery within 24 h; cardiac procedure other than CABG with/without aortic valve surgery; age > 80 years.

Methodological considerations

Study design. The cohort is a prospective, non-randomised pilot comparison with n = 12 per group; findings are hypothesis-generating rather than confirmatory.
Operative comparability. The groups were comparable in the reported baseline and operative characteristics. Concomitant AVR occurred in one patient in each group (8.3% vs 8.3%); subgroup inference was not performed because n = 1 per group.
Serum cortisol. No statistically significant between-group difference in absolute serum cortisol was observed at any measured time point. The largest directional effects occurred at T3 and T4.
Temporal kinetics. Although serum cortisol and DHEA-S were measured at the same predefined time points, their responses to acute surgical stress may not be temporally synchronous. CDR therefore represents the balance at each sampled time point rather than the ratio of their respective peak responses.
Salivary cortisol. Postoperative measurements may reflect the combined effects of surgical stress and postoperative conditions, including pain, medication exposure and altered circadian context. They were interpreted as indicators of the overall postoperative stress response rather than isolated measures of HPA-axis function.

Abbreviations

AVR, aortic valve replacement; BIS, bispectral index; BMI, body mass index; CDR, cortisol/DHEA-S ratio; CPB, cardiopulmonary bypass; DHEA-S, dehydroepiandrosterone sulfate; LVEF, left ventricular ejection fraction; OFA, opioid-free anaesthesia; OBA, opioid-based anaesthesia; PO, postoperative; r_rb, rank-biserial correlation; VAS, visual analogue scale.