A total of 159 patients were included in the study based on the inclusion and exclusion criteria. The number of patients in group A-E was 27, 34, 29, 39, and 28 respectively. There were no significant differences in the age and weight of patients in the five groups (TableⅠ).
Table I. Dose gradients of remimazolam and propofol and patients' baseline characteristics.
Group
|
Remimazolam (mg/kg)
|
Propofol (mg/kg)
|
n
|
No eye opening
|
Age
[y, Q2(IQR)]
|
Weight
[kg, Q2(IQR)]
|
A
|
0.1
|
0
|
2
|
2
|
54(17)
|
57(14)
|
|
0.08
|
0
|
6
|
5
|
|
|
|
0.064
|
0
|
12
|
7
|
|
|
|
0.051
|
0
|
7
|
0
|
|
|
B
|
0
|
0.9
|
5
|
5
|
51(17.5)
|
61(21)
|
|
0
|
0.72
|
14
|
10
|
|
|
|
0
|
0.58
|
12
|
3
|
|
|
|
0
|
0.46
|
3
|
0
|
|
|
C
|
0.016
|
0.62
|
7
|
7
|
53.5(13.8)
|
55.5(17.5)
|
|
0.016
|
0.49
|
13
|
6
|
|
|
|
0.016
|
0.39
|
7
|
2
|
|
|
|
0.016
|
0.32
|
2
|
0
|
|
|
D
|
0.033
|
0.31
|
2
|
2
|
50.5(20.8)
|
57.3(14)
|
|
0.033
|
0.25
|
9
|
8
|
|
|
|
0.033
|
0.20
|
15
|
9
|
|
|
|
0.033
|
0.16
|
11
|
2
|
|
|
|
0.033
|
0.13
|
2
|
0
|
|
|
E
|
0.049
|
0.15
|
6
|
6
|
51.5(16.8)
|
60(15.5)
|
|
0.049
|
0.12
|
12
|
6
|
|
|
|
0.049
|
0.10
|
8
|
3
|
|
|
|
0.049
|
0.08
|
2
|
0
|
|
|
Patients in group A were administered remimazolam in combination with 0.1 µg/kg sufentanil to determine the ED50 of remimazolam in this combination. Intra-group remimazolam efficacy measurements were carried out with a 1:0.8 increments/decrement ratio. In the pretest, the ED50 of remimazolam was estimated to be 0.08 mg/kg; hence, this was taken as the intermediate dose. Doses of 0.125, 0.1, 0.08, 0.064, and 0.051 mg/kg were chosen for evaluation (Table 1). The ED50 of remimazolam was found to be 0.065 mg/kg (CI: 0.057−0.074 mg/kg) in combination with 0.1 µg/kg sufentanil.
Patients in group B were administered propofol in combination with 0.1 µg/kg sufentanil for the determination of propofol ED50 in this combination. Naguib and coworkers reported that propofol has an ED50 value of 0.9 mg/kg in this combination [12]. Based on these data and using the 1:0.8 increment/decrement ratio, the selected doses of propofol were 1.41, 1.13, 0.9, 0.72, 0.58, and 0.46 mg/kg (Table 1). The ED50 of propofol was found to be 0.657 mg/kg (CI: 0.59−0.724 mg/kg) when used in combination with 0.1 µg/kg sufentanil(Fig. 1).
The ED50 of propofol was determined in groups C-E using the same method as group B. Thus, the ED50 of propofol in combination with 0.1 µg/kg sufentanil and doses of 0.25, 0.5, and 0.75 ED50s of remimazolam were evaluated.
Group C patients were administered 0.1 µg/kg sufentanil, 0.25 ED50 (0.016 mg/kg) remimazolam, and varying propofol doses. The propofol 0.75 ED50 (0.49 mg/kg) was chosen as the central point. The propofol ED50 value was 0.476 mg/kg (CI: 0.411–0.545 mg/kg)
Group D patients were administered 0.1 µg/kg sufentanil, 0.5 ED50 (0.033 mg/kg) remimazolam, and varying propofol doses. The 0.5 The ED50 of propofol (0.25 mg/kg) was used as the central point. The propofol ED50 value was 0.194 mg/kg (CI: 0.171−0.217 mg/kg).
Group E patients were administered 0.1 µg/kg sufentanil, 0.75 ED50 (0.049 mg/kg) remimazolam, and varying propofol doses. The 0.25 The ED50 of propofol (0.15 mg/kg) was used as the central. The propofol ED50 value was 0.114 mg/kg (CI: 0.095−0.132 mg/kg).
An isoradiometric diagram (Fig. 2) and algebraic analysis (Table Ⅱ) showed that the synergistic coefficients of remimazolam and propofol were 1.03, 1.26, and 1.08with doses of remimazolam equivalent to 0.25, 0.5, and 0.75 ED50s, respectively, in combination with sufentanil (0.1 µg/kg). The synergy coefficient of group E was 1.08, but the 95% CI of the propofol dose was within the 95% CI of additive action (Fig. 2).
Table II. Interactions of remimazolam and propofol, in combination with 0.1 μg/kg sufentanil, evaluated through observation of eyelash reflex inhibition.
Group
|
Remimazolam
|
Propofol
|
Coefficient sum
|
Expected value of additive action
|
Interaction coefficient
|
ED50 coefficient
|
ED50 (mg/kg)
|
ED50 coefficient
|
ED50 (mg/kg)
|
A
|
1
|
0.065 (0.057-0.074)
|
0
|
0
|
1
|
1
|
1
|
B
|
0
|
0
|
1
|
0.657 (0.590-0.724)
|
1
|
1
|
1
|
C
|
0.25
|
0.016
|
0.725
|
0.476 (0.411-0.545)
|
0.975
|
1
|
1.03
(p=0.154)
|
D
|
0.5
|
0.033
|
0.295
|
0.194 (0.171-0.217)
|
0.795
|
1
|
1.20
(p=0.000)
|
E
|
0.75
|
0.049
|
0.174
|
0.114 (0.095-0.132)
|
0.924
|
1
|
1.08
(p=0.000)
|
The table shows median effective dose (ED50) equivalent doses of remimazolam and propofol in combination with 0.1 μg/kg sufentanil.
|