S-Ketamine Improves Slow Wave Sleep and the Associated Changes in Serum Protein Among Gynecological Abdominal Surgery Patients: A Randomized Controlled Trial

Figures & data

Figure 1 CONSORT flow diagram. CONSORT indicates Consolidated Standards of Reporting Trials.

Abbreviation: PCIA, patient-controlled intravenous analgesia.

Table 1 Patient Demographics and Perioperative Characteristics

	Group C (n=31)	Group S (n=33)	P value
Patient age, mean±SD, y	54.3±4.5	53.6±5.6	0.341
BMI, mean±SD, kg/m^2	25.5±2.8	24.9±3.5	0.063
ASA physical status, n (%)
I	11 (35.5)	9 (27.3)	0.479
II	20 (64.5)	24 (72.7)
Preoperative comorbidity, n (%)
Hypertension	11 (35.5)	6 (18.2)	0.117
Diabetes mellitus	4 (12.9)	2 (6.1)	0.610
Anemia	1 (3.2)	3 (9.1)	0.651
Peripheral neuritis	3 (9.7)	7 (21.2)	0.355
History of surgery	16 (51.6)	18 (54.5)	0.814
Type of cancer, n (%)
Cervical cancer	12 (38.7)	5 (15.2)	0.082
Endometrial cancer	4 (12.9)	4 (12.1)
Ovarian cancer	15 (48.4)	24 (72.7)
PSQI of the recent 1 month, M (P 25, P 75)	4.0 (2.0, 8.0)	2.0 (1.0, 6.5)	0.073
RCSQ of the night before surgery,
M (P 25, P 75)	80 (70, 90)	80 (70, 85)	0.273

Abbreviations: BMI, body mass index; ASA, American Society of Anesthesiologists; PSQI, Pittsburgh Sleep Quality Index; RCSQ, Richards-Campbell Sleep Questionnaire.

Table 2 Intraoperative Characteristics

	Group C (n=31)	Group S (n=33)	P value
Study drug infusion
S-ketamine, mean ± SD, mg	–	35.0±15.0	–
Intravascular volume status
Total intraoperative infusion, M (P 25, P 75), mL	1600 (1500, 2000)	2000 (1500, 2500)	0.159
Red blood cell transfusion requirement, n (%)	3 (9.7)	4 (12.1)	>0.999
Blood loss, M (P 25, P 75), mL	150 (100, 300)	200 (100, 350)	0.258
Total urine output, M (P 25, P 75), mL	200 (150, 350)	250 (175, 550)	0.357
Duration of general anesthesia, mean ± SD, h	3.7±1.0	3.6±1.2	0.864

Table 3 Postoperative Variables

	Group C (n=31)	Group S (n=33)	95% CI	P value
Percentage of stage N3 sleep, M (P 25, P 75), %	8.9 (6.3, 12.5)	15.6 (12.4, 18.8)	4.0 to 8.5	<0.001
Percentage of stage N2 sleep, M (P 25, P 75), %	52.3 (47.5, 57.3)	51.2 (46.1, 55.9)	−5.0 to 1.1	0.138
Percentage of stage N1 sleep, M (P 25, P 75), %	16.3 (10, 22.3)	13.2 (8.5, 17.7)	−6.5 to 1.1	0.209
Percentage of stage REM sleep, M (P 25, P 75), %	20.9 (12.8, 30.3)	18.9 (11.9, 24.7)	−8.0 to 1.0	0.160
Total sleep time, mean ± SD, minutes	488.9±60.4	502.7±93.4	−25.8 to 53.4	0.489
Sleep efficiency, M (P 25, P 75), %	69.7 (56.1, 78.4)	73.9 (66.7, 77.6)	−2.4 to 9.6	0.323
RCSQ of the surgery tonight, M (P 25, P 75)	60 (50, 65)	60 (50, 70)	0 to 10	0.213
RCSQ of the next night of surgery, M (P 25, P 75)	77 (70, 80)	80 (70, 80)	−3 to 5	0.561
Daytime sleep after surgery, mean ± SD, minutes	74.6±28.9	75.6±28.9	−13.5 to 15.4	0.894
VAS score after surgery 24 h, M (P 25, P 75)	4 (3.0, 4.5)	3 (2.0, 4.0)	−1.0 to 0	0.015
VAS score after surgery 48 h, M (P 25, P 75)	2 (1.0, 2.5)	1.5 (1.0, 2.6)	−0.9 to 0.2	0.345
Additional requirement of analgesic drugs, n (%)	1 (3.2)	1 (3.0)	–	>0.999

Abbreviations: REM, rapid eye movement; RCSQ, Richards-Campbell Sleep Questionnaire; VAS, Visual Analogue Scale.

Figure 2 The sleep patterns and the label-free proteomic analysis of differentially expressed proteins of the patients in the control and S-ketamine groups. (A) Representative sleep architecture during the period of polysomnographic traces of patients in the control group (upper) and S-ketamine group (lower). (B) The major pathways involved of proteins obtained from the serum of top 10 level of SWS and the bottom 10 level of SWS patients. (C) The Gene Ontology analysis of proteins obtained from the serum of top 10 level of SWS and the bottom 10 level of SWS patients. (D) Volcano plot of differential expressed proteins in top 10 level of SWS and the bottom 10 level of SWS patients. (|fold change|>1.5 and P<0.05). (E) Hierarchical clustering analysis of differentially expressed proteins in top 10 level of SWS and the bottom 10 level of SWS patients.

Abbreviations: N1, stage N1 sleep; N2, stage N2 sleep; N3, stage N3 sleep; WK, wakefulness; SWS, slow wave sleep.

Table 4 Adverse Events and Postoperative Complications

	Group C (n=31)	Group S (n=33)	P value
Adverse events, n (%)	(n=13/31)	(n=15/33)
Dizziness	9 (29)	11 (33.3)	0.711
Nausea	8 (25.8)	9 (27.3)	0.894
Vomiting	3 (9.7)	7 (21.2)	0.355
Flatulence/Bloating	8 (25.8)	4 (12.1)	0.161
Postoperative complications, n (%)	(n=0/31)	(n=0/33)
Respiratory depression	0 (0)	0 (0)	–
Postoperative delirium	0 (0)	0 (0)	–
Oliguria	0 (0)	0 (0)	–
Emergence agitation	0 (0)	0 (0)	–

Table 5 Different Proteins Upregulated in Top 10 Level of SWS Group and the Bottom 10 Level of SWS Group Patients

Protein	Description	P value	Fold Change (Top 10 Group/Bottom 10 Group)
D6RE86	Ceruloplasmin (Fragment)	0.000313206	1.51
Q9UL88	Myosin-reactive immunoglobulin heavy chain variable region (Fragment)	0.000384708	1.55
A2J1N4	Rheumatoid factor RF-IP24 (Fragment)	0.000546202	2.36
A0A2U8J8Z6	Ig heavy chain variable region (Fragment)	0.002032146	1.88
E1B4S8	Apolipoprotein B (Fragment)	0.002527981	1.74
Q6N041	Uncharacterized protein DKFZp686O16217 (Fragment)	0.005270901	4.28
A0A024RDY3	Lysosomal-associated membrane protein 1, isoform CRA_a	0.00759411	1.82
S6BGD4	IgG H chain	0.007873663	2.19
Q5CZ94	Uncharacterized protein DKFZp781M0386	0.010250511	2.23
Q9UL86	Myosin-reactive immunoglobulin kappa chain variable region (Fragment)	0.010378728	3.39
A2N0S9	VH6DJ protein (Fragment)	0.012041998	2.56
A2VDG3	CSF1R protein (Fragment)	0.013188728	3.04
Q96SB0	Anti-streptococcal/anti-myosin immunoglobulin lambda light chain variable region (Fragment)	0.0142915	2.69
A0A024RDE1	SPARC-like 1 (Mast9, hevin), isoform CRA_a	0.01810455	1.60
P00915	Carbonic anhydrase 1	0.018836469	2.42
A0A2U8J8K4	Ig heavy chain variable region (Fragment)	0.01954871	1.58
A0A024R374	Cathepsin B, isoform CRA_a	0.022508851	1.90
A2NYV1	Heavy chain Fab (Fragment)	0.023338112	1.98
Q6N097	Uncharacterized protein DKFZp686H20196	0.023398486	2.49
A0A2U8J8P8	Ig heavy chain variable region (Fragment)	0.024675531	1.76
A0A286YES1	Immunoglobulin heavy constant gamma 3 (Fragment)	0.027884151	1.92
A0A125QYY3	GCT-A6 light chain variable region (Fragment)	0.028989337	1.84

Abbreviation: SWS, slow wave sleep.

Data Sharing Statement

The datasets generated during the current study are available in the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD040679 (https://www.iprox.cn/page/project.html?id=IPX0006049000).