Effects of Remifentanil Gradual Withdrawal Combined with Postoperative Infusion on Postoperative Hyperalgesia in Patients Undergoing Laparoscopic hysterectomy: A Factorial Design, Double-Blind, Randomized Controlled Trial

Figures & data

Figure 1 Flow diagram of the study.

Table 1 Baseline Patient Characteristics and Anesthetic Management Parameters

Parameter	C Group (n=35)	P Group (n=35)	G Group (n=35)	GP Group (n=35)	P-value
Baseline data
Age (years)	50.26±1.05	50.61±0.68	50.14±0.93	50.17±1.08	1.000
Height (cm)	160.46±0.67	160.26±0.83	161.94±0.72	160.20±0.78	0.308
Weight (kg)	63.09±1.40	63.29±1.23	64.83±1.55	64.06±1.62	0.272
BMI (kg/m^2)	24.51±0.53	24.61±0.37	24.65±0.48	24.90±0.52	0.960
ASA score, n (%)					0.651
1	11 (31.4)	12 (34.3)	16 (45.7)	12 (34.3)
2	24 (68.6)	23 (65.7)	19 (54.3)	23 (65.7)
Comorbidities, n (%)
Hypertension	7 (20.0)	8 (22.9)	4 (11.4)	5 (14.3)	0.628
Diabetes mellitus	4 (11.4)	5 (14.3)	6 (17.1)	4 (11.4)	0.984
Fluid management
Crystalloid (mL)	800 (750, 900)	750 (700, 850)	800 (750, 850)	800 (750, 900)	0.611
Blood (mL)	0 (0, 0)	0 (0, 0)	0 (0, 0)	0 (0, 0)	0.557
Bleeding (mL)	30 (30, 50)	40 (30, 40)	30 (30, 40)	30 (20, 40)	0.155
Urine (mL)	100 (100, 100)	100 (80, 150)	100 (80, 100)	100 (100, 100)	0.879
Remifentanil (mg)	1.95 (1.55, 2.55)	2.15 (1.60, 2.40)	1.85 (1.40, 2.30)	1.80 (1.55, 2.15)	0.125
Vasoactive drug use, n (%)	23 (65.7)	22 (62.9)	20 (57.1)	25 (71.4)	0.676
Duration of surgery (min)	85.06±5.72	85.34±4.13	88.40±6.11	89.09±5.92	0.190
Duration of anesthesia (min)	115.06±5.99	114.69±4.70	111.06±6.00	110.46±6.40	0.340
Awakening time (min)	8 (5, 13)	8 (5, 9)	10 (6, 23)	9 (4, 15)	0.144
Extubation time (min)	9 (6, 13)	8 (6, 12)	11 (6, 25)	9 (6, 16)	0.136
PACU time (min)	44.11±1.51	46.63±1.32	41.94±1.75	44.89±1.31	0.166
Length of post-operative hospital stay (days)	4 (4, 4)	4 (3, 4)	4 (3, 4)	4 (3, 4)	0.353
First postoperative exhaust time (min)	1700 (1408, 2252)	1660 (1269, 1831)	1490 (1361, 2030)	1205 (960, 2147)	0.178

Notes: Values are presented as number of patients (%), mean ± SD, or median (interquartile range). C group, control group; P group, postoperative pump infusion of remifentanil group; G group, gradual withdrawal of remifentanil group; GP group, gradual withdrawal plus postoperative pump infusion of remifentanil group.

Abbreviations: BMI, body mass index; ASA, American Society of Anesthesiologist.

Figure 2 Perioperative changes of MAP and HR over time. (A) change of MAP. (B) change of HR. C group, control group; P group, postoperative pump infusion of remifentanil group; G group, gradual withdrawal of remifentanil group; GP group, gradual withdrawal plus postoperative pump infusion of remifentanil group.

Abbreviations: MAP, mean arterial pressure; HR, heart rate.

Table 2 Mechanical Pain Thresholds in the Medial Forearm and Around the Incision

Mechanical Pain Thresholds	Group	Before Surgery	1 Hour After Surgery	6 Hours After Surgery	24 Hours After Surgery	24 Hours After Surgery
In the medial forearm (g)	Without G	26 (15, 26)	8 (6, 15)	8 (6, 15)	15 (8, 26)	15 (8, 26)
	With G	26 (15, 26)	15 (10, 26) *	15 (10, 26) *	15 (15, 26) *	26 (15, 26) *
	Without P	26 (13.75, 26)	10 (6, 15)	10 (8, 15)	15 (8, 26)	15 (8, 26)
	With P	26 (15, 26)	15 (8, 26)	15 (8, 26)	15 (10, 26)	26 (15, 26)
Around the incision (g)	Without G	15 (8, 26)	4 (1.85, 8)	4 (2, 8)	8 (6, 15)	15 (8, 26)
	With G	26 (15, 26)	6 (2, 10) *	8 (4, 11.25) *	15 (8, 26) *	15 (15, 26) *
	Without P	15 (15, 26)	4 (2, 8)	5 (2, 8)	9 (7.5, 15)	15 (8, 26)
	With P	26 (15, 26)	4 (2, 8)	6 (4, 10)	10 (8, 26)	15 (9.5, 26)

Notes: Values are presented as median (interquartile range). Without G, control group + postoperative pump infusion of remifentanil group; With G, gradual withdrawal of remifentanil group + gradual withdrawal plus postoperative pump infusion of remifentanil group; Without P, control group + gradual withdrawal of remifentanil group; With P, postoperative pump infusion of remifentanil group + gradual withdrawal plus postoperative pump infusion of remifentanil group. *compared to control group + postoperative pump infusion of remifentanil group, P<0.05.

Table 3 Comparison of Mechanical Pain Thresholds and NRS Scores in Four Groups of Patients

Parameter	Time	C Group (n=35)	P Group (n=35)	G Group (n=35)	GP Group (n=35)	P-value
Mechanical pain thresholds in the medial forearm (g)	Before surgery	15 (10, 26)	26 (15, 26)	26 (15, 26)	26 (15, 26)	0.878
	1 h	8 (4, 15) ^#	8 (6, 15) ^#	15 (10, 26) ^a, #	15 (10, 26) ^a, b	<0.001
	6 h	8 (6, 15) ^#	10 (6, 15) ^#	15 (10, 26) ^a, #	15 (15, 26) ^a, b	<0.001
	24 h	8 (8, 26) ^#	15 (8, 26) ^#	15 (15, 26) ^#	26 (15, 26) ^a	0.006
	48 h	15 (8, 26) ^#	15 (10, 26) ^#	26 (15, 26)	26 (15, 60) ^a	0.017
Mechanical pain thresholds around the incision (g)	Before surgery	15 (8, 26)	26 (8, 26)	26 (15, 26)	26 (15, 26)	0.733
	1 h	2 (1.4, 8) ^#	4 (2, 8) ^#	8 (2, 10) ^#	6 (2, 10) ^#	0.033
	6 h	4 (1.4, 8) ^#	6 (2, 8) ^#	8 (4, 10) ^#	8 (4, 15) ^a, b, #	0.004
	24 h	8 (6, 15) ^#	8 (6, 15) ^#	15 (8, 15) ^#	15 (8, 26) ^a, #	0.049
	48 h	10 (8, 26) ^#	15 (8, 26) ^#	15 (15, 26) ^#	15 (10, 26) ^a	0.034
NRS scores	Before surgery	0 (0, 0)	0 (0, 0)	0 (0, 0)	0 (0, 0)	0.158
	Immediately	1 (1, 2) ^#	1 (1, 1) ^#	1 (1, 2) ^#	1 (1, 2) ^#	0.593
	10 min	3 (2, 4) ^#	2 (2, 3) ^a, #	3 (2, 3) ^b, #	1 (1, 3) ^a, c, #	<0.001
	20 min	4 (3, 4) ^#	3 (2, 3) ^a, #	3 (3, 4) ^#	2 (1, 3) ^a, c, #	<0.001
	30 min	4 (3, 4) ^#	3 (2, 4) ^#	3 (3, 4) ^#	2 (2, 3) ^a, b, c, #	<0.001
	1 h	3 (3, 4) ^#	3 (3, 3) ^#	3 (2, 3) ^#	2 (2, 3) ^a, b, c, #	<0.001
	6 h	5 (4, 5) ^#	5 (4, 5) ^#	4 (4, 5) ^#	4 (2, 5) ^a, b, c, #	0.007
	12 h	3 (3, 4) ^#	4 (3, 4) ^#	3 (3, 4) ^#	2 (2, 3) ^a, b, c, #	<0.001
	24 h	3 (2, 4) ^#	3 (3, 3) ^#	3 (2, 3) ^#	2 (2, 2) ^a, b, c, #	<0.001
	48 h	2 (2, 3) ^#	2 (2, 3) ^#	2 (2, 2) ^#	1 (1, 2) ^a, b, c, #	<0.001

Notes: Values are presented as median (interquartile range). C group, control group; P group, postoperative pump infusion of remifentanil group; G group, gradual withdrawal of remifentanil group; GP group, gradual withdrawal plus postoperative pump infusion of remifentanil group. 1 h, 1 hour after surgery; 6 h, 6 hours after surgery; 24 h, 24 hours after surgery; 48 h, 48 hours after surgery; Immediately, immediately after tracheal extubation; 10 min, 10 minutes after tracheal extubation; 20 min, 20 minutes after tracheal extubation; 30 min, 30 minutes after tracheal extubation. ^acompared to C group, P<0.05; ^bcompared to P group, P<0.05; ^ccompared to G group, P<0.05; ^#compared to preoperative level, P<0.05 (generalized estimating equation).

Figure 3 Mechanical pain thresholds of patients in C, P, G, and GP groups at different time points. (A) mechanical pain thresholds in the medial forearm of patients in C, P, G, and GP groups at different time points. (B) mechanical pain thresholds around the incision of patients in C, P, G, and GP groups at different time points. C group, control group; P group, postoperative pump infusion of remifentanil group; G group, gradual withdrawal of remifentanil group; GP group, gradual withdrawal plus postoperative pump infusion of remifentanil group. ^acompared to C group, P<0.05; ^bcompared to P group, P<0.05; ^#compared to preoperative level, P<0.05 (generalized estimating equation).

Table 4 Comparison of Postoperative Conditions Among the Four Groups

Parameter	C Group (n=35)	P Group (n=35)	G Group (n=35)	GP Group (n=35)	P-value
Analgesic use
Fentanyl, n (%)	20 (57.1)	15 (42.9)	19 (54.3)	6 (17.1) ^a, b, c	0.003
Flurbiprofen axetil, n (%)	13 (37.1)	10 (28.6)	10 (28.6)	7 (20.0)	0.515
Total flurbiprofen axetil use (mg)	0 (0, 50)	0 (0, 50)	0 (0, 50)	0 (0, 0)	0.449
QoR-15 scores
Before surgery	148.49±2.38	148.74±2.57	149.43±1.27	148.54±2.68	0.295
24 h	126.83±5.27	126.51±5.41	126.80±5.91	132.17±6.09 ^a, b, c	<0.001
48 h	138.14±5.19	138.20±5.82	139.71±4.21	142.86±3.86 ^a, b, c	<0.001
Agitation scores	4 (4, 4)	4 (3, 4)	4 (4, 4)	4 (3, 4)	0.421
Ramsay sedation scores
Immediately	3 (2, 3)	3 (3, 3)	3 (2, 3)	3 (2, 3)	0.080
10 min	2 (2, 3)	2 (2, 3)	2 (2, 2)	2 (2, 3)	0.074
20 min	2 (2, 2)	2 (2, 3)	2 (2, 2)	2 (2, 3)	0.163
30 min	2 (2, 2)	2 (2, 2)	2 (2, 2)	2 (2, 2)	0.306
1 h	2 (2, 2)	2 (2, 2)	2 (2, 2)	2 (2, 2)	0.569
Adverse reactions, n (%)
PONV	16 (45.7)	21 (60.0)	17 (48.6)	14 (40.0)	0.436
Dizziness	4 (11.4)	4 (11.4)	6 (17.1)	3 (8.6)	0.801
Shivering	3 (8.6)	1 (2.9)	5 (14.3)	3 (8.6)	0.448
Else	1 (2.9)	0 (0.0)	0 (0.0)	0 (0.0)	1.000

Notes: Values are presented as number of patients (%), mean ± SD, or median (interquartile range). C group, control group; P group, postoperative pump infusion of remifentanil group; G group, gradual withdrawal of remifentanil group; GP group, gradual withdrawal plus postoperative pump infusion of remifentanil group. 24 h, 24 hours after surgery; 48 h, 48 hours after surgery; Immediately, immediately after tracheal extubation; 10 min, 10 minutes after tracheal extubation; 20 min, 20 minutes after tracheal extubation; 30 min, 30 minutes after tracheal extubation; 1 h, 1 hour after surgery. QoR-15, 15-item quality of recovery. ^acompared to C group, P<0.05; ^bcompared to P group, P<0.05; ^ccompared to G group, P<0.05.

Abbreviation: PONV, postoperative nausea and vomiting.