Effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section

Abstract

BACKGROUND

Following cesarean section, a significant number of women encounter moderate to severe pain. Inadequate management of acute pain post-cesarean section can have far-reaching implications, adversely impacting maternal emotional well-being, daily activities, breastfeeding, and neonatal care. It may also impede maternal organ function recovery, leading to escalated opioid usage, heightened risk of postpartum depression, and the development of chronic postoperative pain. Both the Chinese Enhanced Recovery After Surgery (ERAS) guidelines and the American ERAS Society guidelines consistently advocate for the adoption of multimodal analgesia protocols in post-cesarean section pain management. Esketamine, functioning as an antagonist of the N-Methyl-D-Aspartate receptor, has been validated for pain management in surgical patients and has exhibited effectiveness in depression treatment. Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes. This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section.

AIM

To investigate the effect of intraoperative injection of esketamine on postoperative analgesia and postoperative rehabilitation after cesarean section.

METHODS

A total of 315 women undergoing elective cesarean section under combined spinal-epidural anesthesia were randomized into three groups: low-dose esketamine (0.15 mg/kg), high-dose esketamine (0.25 mg/kg), and control (saline). Postoperative Visual Analog Scale (VAS) scores were recorded at 6 hours, 12 hours, 24 hours, and 48 hours. Edinburgh Postnatal Depression Scale (EPDS) scores were noted on 2 days, 7 days and 42 days. Ramsay sedation scores were assessed at specified intervals post-injection. Postoperative adverse reactions were also recorded.

RESULTS

Low-dose group and high-dose group compared to control group, had significantly lower postoperative VAS pain scores at 6 hours 12 hours, and 24 hours (P < 0.05), with reduced analgesic usage (P < 0.05). EPDS scores and postpartum depression rates were significantly lower on 2 days and 7 days (P < 0.05). No significant differences in first exhaust and defecation times were observed (P > 0.05), but ambulation times were shorter (P < 0.05). Ramsay scores were higher at 5 minutes, 15 minutes, and upon room exit (P < 0.05). Low-dose group and high-dose group had higher incidences of hallucination, lethargy, and diplopia within 2 hours (P < 0.05), and with low-dose group had lower incidences of hallucination, lethargy, and diplopia than high-dose group (P < 0.05).

CONCLUSION

Esketamine enhances analgesia and postpartum recovery; a 0.15 mg/kg dose is optimal for cesarean sections, balancing efficacy with minimized adverse effects.

Key Words: Maternity, Cesarean section, Depression, Esketamine, Postoperative analgesia

Core Tip: Esketamine, as an antagonist of the N-Methyl-D-Aspartate receptor, has been validated for pain control in surgical patients and has demonstrated efficacy in treating depression. Studies have indicated that the use of esketamine in postoperative pain pumps can improve short-term depression and pain outcomes. This study investigates the efficacy and safety of a single administration of esketamine during cesarean section, aiming to provide insights into the clinical application of esketamine for post-cesarean section pain management and the promotion of rapid postoperative recovery.

INTRODUCTION

Following cesarean section, a significant number of women encounter moderate to severe pain[1-3]. Inadequate management of acute pain post-cesarean section can have far-reaching implications, adversely impacting maternal emotional well-being, daily activities, breastfeeding, and neonatal care. It may also impede maternal organ function recovery, leading to escalated opioid usage, heightened risk of postpartum depression, and the development of chronic postoperative pain[4,5]. Both the Chinese Enhanced Recovery After Surgery (ERAS) guidelines[6] and the American ERAS Society guidelines[7] consistently advocate for the adoption of multimodal analgesia (MMA) protocols in post-cesarean section pain management. These guidelines stress the importance of employing a combination of diverse analgesic modalities and/or medications to effectively alleviate maternal pain while simultaneously minimizing adverse reactions associated with analgesic medications[8].

Esketamine, functioning as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, has been validated for pain management in surgical patients[9,10] and has exhibited effectiveness in depression treatment[11]. Research has suggested that incorporating esketamine into postoperative pain management via pain pumps can lead to improvements in short-term depression and pain outcomes[12]. This study aims to assess the efficacy and safety of administering a single dose of esketamine during cesarean section. Its objective is to offer valuable insights into the clinical application of esketamine for managing post-cesarean section pain and facilitating rapid postoperative recovery.

MATERIALS AND METHODS

Clinical data

This study, sanctioned by the institutional review board under protocol number 20200060, acquired informed consent from expectant mothers. Enrollees comprised individuals slated for elective cesarean delivery under spinal-epidural anesthesia spanning from January 2021 to January 2023. Inclusion criteria stipulated participants falling within the age bracket of 18 to 40, possessing a body mass index (BMI) ranging from 18 to 35 kg/m², American Society of Anesthesiologists classification II, and anticipating surgical procedures not exceeding 2 hours in duration. Exclusion parameters encompassed contra-indications to neuraxial anesthesia, a history of cerebrovascular accidents, cognitive deficits, epileptic conditions, pregnancy-related complications (including malignancies, gestational hypertension, and thyroid dysfunctions), Edinburgh Postnatal Depression Scale (EPDS) scores equal to or exceeding 13, utilization of sedatives, analgesics, or hypnotics within the three months preceding the operation, and anticipated anesthesia durations surpassing 2 hours. Participants were randomly assigned to one of three groups: The low-dose esketamine cohort (low-dose group), the high-dose esketamine cohort (how-dose group), and the control cohort (control group).

Anesthetic procedure

All patients observed an 8-hour fasting period and refrained from drinking liquids for 2 hours prior to the operation. Peripheral intravenous access was established upon admission, with continuous monitoring of electrocardiography, heart rate, blood pressure, and oxygen saturation. Patients were positioned laterally, and lumbar-epidural anesthesia was administered at the L3-4 or L2-3 interspace. A subarachnoid injection of 0.5% ropivacaine (12.5 mg) was administered, followed by advancement of the epidural catheter 3 cm cranially upon successful subarachnoid blockade. After repositioning the patient supinely, the sensory block level was maintained at T4–T6.

Following fetal delivery, low-dose group received intravenous esketamine (0.15 mg/kg, 10 mL), how-dose group received intravenous esketamine (0.25 mg/kg, 10 mL), and control group received 10 mL of normal saline. Ten minutes prior to completion of surgery, 8 mL of 0.125% ropivacaine and 2 mg of morphine were administered through the epidural catheter. Postoperatively, patient-controlled intravenous analgesia (PCIA) was initiated, with the pump containing butorphanol (10 mg) and dexmedetomidine (100 µg) diluted to 100 mL with normal saline. The PCIA settings included a background infusion of 2 mL/h, patient-controlled analgesia of 0.5 mL, and a lockout time of 15 minutes. Anesthesiologists administering esketamine and normal saline were blinded to the low-dose group location.

Outcome measures

Primary outcomes consisted of Visual Analog Scale (VAS) pain scores documented at 6, 12, 24, and 48 hours postoperatively. Acetaminophen tablets were administered for rescue analgesia when VAS scores surpassed 4. Secondary outcomes encompassed EPDS scores on preoperative day 1, and postoperative days 2, 7, and 42, with an EPDS score of ≥ 13 indicating the presence of postpartum depression. Immediate, 5-minute, and 15-minute Ramsay sedation scores following esketamine injection were recorded. Additionally, the time to first bowel movement, time to first urination, and time to ambulation were documented. Adverse events associated with esketamine injection within the timeframes of 0–2 hours and 2.1–48 hours postoperatively, including vomiting, headache, hallucinations, dizziness, drowsiness, and diplopia, were meticulously recorded.

Statistical analysis

Data analysis was conducted using SPSS 20.0 software. Normally distributed continuous data were expressed as mean ± SD and compared using ANOVA between groups and repeated measures analysis of variance at different time points. Count data were presented as cases (percentage, %) and compared using the χ² test between groups. A significance level of P < 0.05 was applied to determine statistical significance.

RESULTS

Comparison of general information

Initially, 315 patients were enrolled in this study, with 8 lost to follow-up in Low-dose group and high-dose group, and 7 in control group. The final analysis comprised 292 patients, distributed as follows: 97 in low-dose group, 97 in how-dose group, and 98 in control group. Noteworthy, no statistically significant differences were discerned among the three groups concerning age, BMI, preoperative hemoglobin levels, parity ratio, and educational attainment. Intraoperative blood loss and surgical duration exhibited no significant discrepancies between groups (P > 0.05). For further details, refer to Table 1.

Table 1 Comparison of general and surgical characteristics among the three groups of pregnant women.

Indicator	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	F/χ2	P value
Age (years, mean ± SD)	32 ± 4	33 ± 8	33 ± 4	0.988	0.374
BMI (kg/m2, mean ± SD)	28.8 ± 3.3	28.9 ± 2.9	29.0 ± 2.8	0.159	0.853
Preoperative Hb (g/L, mean ± SD)	115 ± 8	115 ± 8	114 ± 7	0.055	0.946
Parity, n (%)				1.317	0.859
Primipara	25 (25.8)	29 (29.9)	28 (28.6)
Multipara	62 (63.9)	61 (62.9)	59 (60.2)
Grand multipara	10 (10.3)	7 (7.2)	11 (11.2)
Education level, n (%)				1.712	0.789
Below college	21 (21.6)	21 (21.6)	24 (24.5)
College and undergraduate	64 (66.0)	67 (69.1)	67 (68.4)
Master and above	12 (12.4)	9 (9.3)	7 (7.1)
Blood loss (mL, mean ± SD)	372 ± 59	373 ± 59	361 ± 58	1.234	0.293
Operative time (min, mean ± SD)	37 ± 8	37 ± 8	36 ± 8	0.222	0.801

Hb: Haemoglobin.

Comparison of postoperative analgesia

In comparison to control group, VAS scores in low-dose group and high-dose group exhibited significant reductions at 6, 12, and 24 hours postoperatively (P < 0.05). Furthermore, clinical satisfaction with analgesia was achieved as VAS scores remained below 3. Additionally, the rate of rescue analgesia within the first 2 days postoperatively was notably lower in low-dose group and high-dose group compared to control group (P < 0.05). For detailed information, please refer to Table 2.

Table 2 Comparison of Visual Analog Scale scores at different time points post-cesarean section among the three groups of pregnant women (scores, mean ± SD).

Time point	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	F/χ2	P value
Postoperative 6 hours	1.8 ± 0.4a	1.9 ± 0.8a	2.3 ± 0.6b	22.358	< 0.001
Postoperative 12 hours	2.7 ± 0.7a	2.6 ± 0.7a	3.3 ± 1.2b	15.599	< 0.001
Postoperative 24 hours	3.1 ± 1.0a	2.7 ± 0.8a,b	3.5 ± 1.2b	17.220	< 0.001
Postoperative 48 hours	2.1 ± 0.6	2.1 ± 0.7a	2.4 ± 1.1	4.498	0.012
Rescue rate, n (%)	15 (15.5)	14 (14.4)	27 (27.6)	6.705	0.035

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

Comparison of postpartum depression

No statistically significant differences were observed in EPDS scores on preoperative day 1 among the three groups (P > 0.05). However, compared to control group, EPDS scores on postoperative days 2 and 7 were significantly lower in low-dose group and high-dose group (P < 0.05), with no significant differences noted on postoperative day 42 (P > 0.05). Please refer to Table 3 for detailed information.

Table 3 Comparison of Edinburgh Postnatal Depression scale scores at different time points among the three groups of pregnant women (scores, mean ± SD).

Time point	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	F value	P value
Prenatal 1 day	7.5 ± 2.2	7.2 ± 2.3	7.3 ± 2.3	0.245	0.783
Postoperative 2 day	7.2 ± 2.2a	7.5 ± 2.6a	8.8 ± 3.4b	8.331	< 0.001
Postoperative 7 day	7.3 ± 3.1a	7.0 ± 2.9a	9.1 ± 3.3b	13.639	< 0.001
Postoperative 42 day	8.3 ± 3.1	8.1 ± 3.0	8.8 ± 3.6	1.158	0.316

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

Similarly, in comparison to control group, the occurrence rates of postpartum depression on postoperative days 2 and 7 were lower in Low-Dose Group and high-dose group (P < 0.05), with no significant differences observed on postoperative day 42 (P > 0.05). Please see Table 4 for further details.

Table 4 Comparison of postpartum depression incidence at different time points among the three groups of pregnant women, n (%).

Time point	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	χ2 value	P value
Postoperative 2 day	5 (5.1)a	6 (6.2)a	14 (14.3)b	6.218	0.045
Postoperative 7 day	8 (8.2)a	5 (5.1)a	16 (16.3)b	7.238	0.027
Postoperative 42 day	11 (11.3)	10 (10.3)	17 (17.3)	2.484	0.289

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

Sedation during surgery

Five minutes following esketamine injection, sedation Ramsay scores in both low-dose group and high-dose group exceeded 3, with low-dose group scores declining to approximately 2 at the 15-minute mark, whereas how-dose group scores remained above 3. In comparison to control group, Ramsay scores exhibited increases at 5 minutes, 15 minutes, and immediately post-procedure upon exiting the operating room following intravenous esketamine administration in low-dose group and high-dose group, with statistically significant differences observed (P < 0.05). Refer to Table 5 for detailed data.

Table 5 Comparison of Ramsay scores after intravenous injection of esketamine among the three groups of pregnant women (scores, mean ± SD).

Time point	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	F value	P value
Mediate injection	1.92 ± 0.28	1.89 ± 0.33	1.83 ± 0.37	1.47	0.23
5 minutes post-injection	3.4 ± 0.6a	4.8 ± 0.4a,b	1.8 ± 0.4b	949.15	< 0.01
15 minutes post-injection	2.2 ± 0.5a	3.6 ± 0.6a,b	1.9 ± 0.3b	355.18	< 0.01
Immediate postoperative	2.04 ± 0.20a	2.08 ± 0.28a	1.85 ± 0.39	17.25	< 0.01

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

Postoperative recovery

In comparison to control group, the time to first flatus and time to first bowel movement exhibited no statistically significant differences (P > 0.05), whereas the time to ambulation was notably shorter in low-dose group and high-dose group (P < 0.05). Detailed data can be found in Table 6.

Table 6 Comparison of post-cesarean section recovery indicators among the three groups of pregnant women (hours, mean ± SD).

Time point	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	F value	P value
Time to first flatus	29 ± 6	28 ± 5	30 ± 5	1.950	0.144
Time to first bowel movement	66 ± 11	65 ± 11	66 ± 10	0.238	0.788
Time to ambulation	23.9 ± 3.1a	23.8 ± 2.5a	25.3 ± 3.0b	8.088	< 0.001

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

Adverse event occurrence

In comparison to the control group, the occurrence rates of hallucinations, drowsiness, and diplopia within 2 hours following esketamine injection were significantly higher in both the low-dose group and the high-dose group (P < 0.05). Specifically, the low-dose group exhibited an increased incidence of these adverse reactions compared to the control group, but the rate was notably lower than that observed in the high-dose group. For instance, patients in the low-dose group experienced fewer episodes of hallucinations, drowsiness, and diplopia than those in the high-dose group, indicating a dose-dependent increase in adverse effects. This suggests that while both doses of esketamine are associated with some degree of neuropsychiatric side effects shortly after administration, the lower dose is better tolerated. However, when examining the occurrence rates of adverse reactions beyond the initial 2-hour period post-injection, no statistically significant differences were observed among the three groups (P > 0.05). This indicates that the adverse reactions induced by esketamine are transient and predominantly occur within the first two hours following administration. After this period, the incidence of adverse effects such as hallucinations, drowsiness, and diplopia diminishes, and the differences between the groups become negligible. These findings highlight the importance of close monitoring during the immediate postoperative period when esketamine is administered, especially at higher doses. The detailed information and specific data on the occurrence rates of these adverse reactions can be found in Table 7.

Table 7 Comparison of the incidence of adverse reactions after intravenous injection of ketamine in three groups, n (%).

Adverse reaction	Administration time	Low-dose group (n = 97)	How-dose group (n = 97)	Control group (n = 98)	χ2 value	P value
Nausea & vomiting	0-2 h	2 (2.1)	2 (2.1)	3 (3.1)	0.278	0.870
Headache	0-2 h	0 (0)	2 (2.1)	0 (0)	4.048	0.132
Hallucination	0-2 h	2 (7.2)a	9 (9.3)a,b	0 (0)	8.949	0.011
Dizziness	0-2 h	7 (7.2)	7 (7.2)	2 (2.0)	3.368	0.186
Drowsiness	0-2 h	6 (10.3)a	17 (17.5)a,b	0 (0)	18.039	< 0.001
Diplopia	0-2 h	2 (8)a	9 (9.3)a,b	0 (0)	9.213	0.010
Shivering	0-2 h	5 (5.2)	3 (3.1)	6 (6.1)	1.022	0.600
Itching	0-2 h	0 (0)	3 (3.1)	2 (2.0)	2.851	0.240
Reaction delay	0-2 h	3 (3.1)	3 (3.1)	0 (0)	3.095	0.213

^aP < 0.05 compared with control group.

^bP < 0.05 compared with low-dose group.

DISCUSSION

With the rising prevalence of cesarean sections, there is a growing interest in selecting appropriate anesthesia and analgesia modalities. Lumbar-epidural anesthesia has emerged as an effective approach with minimal impact on neonates and breastfeeding[13], thus becoming widely utilized in cesarean deliveries. Research by Ao et al[14] has indicated that adjunctive intravenous sedative and analgesic agents alongside lumbar-epidural anesthesia can enhance intraoperative analgesia, extend postoperative analgesia, and reduce opioid consumption. Current clinical investigations have highlighted the efficacy of small doses of ketamine administered intravenously during surgery in pain alleviation and reducing postoperative opioid requirements[15]. A meta-analysis involving 1737 patients demonstrated that intraoperative ketamine supplementation significantly relieves perioperative pain, prolongs the time to first analgesic request, and reduces overall morphine consumption[16]. Compared to racemic ketamine, esketamine, a ketamine derivative, offers greater safety with fewer adverse reactions and twice the analgesic efficacy[17]. Expert consensus on esketamine suggests that for patients undergoing neuraxial anesthesia, intravenous administration of 0.15 mg/kg esketamine can reduce the requirement for neuraxial local anesthetics, extend the duration of analgesia, and alleviate visceral traction pain. However, the optimal dose of esketamine for parturients remains undefined. This study explores whether intraoperative injections of 0.15 mg/kg and 0.25 mg/kg esketamine can enhance post-cesarean section analgesia.

Esketamine, being a derivative of ketamine, is well-recognized for its rapid and potent antidepressant effects. Recent research[18] has unveiled its analgesic efficacy as well. Esketamine induces analgesia by binding to NMDA receptors on presynaptic and postsynaptic neurons within the pain pathway. Additionally, it exerts analgesic actions by directly binding to central opioid receptors. Furthermore, the combination of NMDA receptor inhibitors with opioid drugs has been found to produce a synergistic effect, augmenting the analgesic effects of opioids and enhancing overall pain relief[19]. In this study, postoperative pain scores at 6, 12, and 24 hours were diminished in the esketamine group, and the rescue analgesia rate within 2 days was significantly lower. This indicates that esketamine, as part of MMA (comprising epidural administration of 2 mg morphine before surgery completion and postoperative utilization of intravenous analgesia pump), effectively mitigates post-cesarean section pain. This observation is consistent with findings from a study by Yao et al[20], which reported lower incisional and uterine pain scores 2 days post-cesarean section in the group receiving a single low-dose ketamine injection during cesarean section compared to the control group.

Postpartum depression, a debilitating yet manageable mental condition, ranks among the most prevalent complications following childbirth. Early identification and timely intervention for postpartum depression are paramount. Esketamine, investigated for its antidepressant properties, has garnered widespread attention in psychiatry. Studies indicate that esketamine, when used in conjunction with antidepressants, exerts a significant therapeutic impact on treatment-resistant depression, rapidly ameliorating depressive symptoms, enhancing quality of life, and fostering satisfaction[21,22]. In recent years, research has unveiled the potential of incorporating esketamine into postoperative analgesia regimens to mitigate postpartum depressive symptoms[12]. Esketamine functions by inhibiting the NMDA receptor, disrupting the interaction between glutamate and the NMDA receptor, augmenting excitatory glutamate neurotransmitter release, synthesizing BDNF, stimulating dendritic and synaptic growth in the prefrontal cortex and limbic system, and potentially reshaping dopamine neuron structure via various signaling pathways, thereby enhancing dopamine expression and achieving antidepressant effects[23,24]. The EPDS serves as the predominant screening tool for peripartum depression, characterized by its simplicity in scoring and operational convenience, and has been translated into over 50 Languages. This study utilized EPDS scores to evaluate postpartum depression. The findings of this study indicate that intravenous esketamine injection postpartum significantly diminishes the incidence of depression on postoperative days 2 and 7, albeit without impacting the occurrence rate and depression score on postoperative day 42.

Esketamine functions by binding to the NMDA receptor, thereby inhibiting glutamate activation of this receptor, reducing neuronal activity, and eliciting a sedative effect. In this study, Ramsay sedation scores in low-dose group and high-dose group surpassed those in the control group following fetal delivery, suggesting superior sedation effects in clinical practice. Such effects can be beneficial for parturients navigating the tense and anxious surgical process, thereby offering advantages for expediting postoperative recovery. However, Ramsay scores in the esketamine groups at 5–15 minutes post-administration ranged between 3 and 5. In clinical practice, such profound sedation is unnecessary, and even the 0.25 mg/kg group might experience loss of consciousness. Therefore, the suitability of esketamine for all parturients may be questioned, and its usage should be tailored based on individual circumstances.

Although there were no significant differences observed in the time to first flatus and time to first bowel movement among the three groups of parturients, the time to ambulation was notably shorter in the esketamine groups, facilitating postpartum recovery. Common adverse reactions to postoperative analgesics encompass nausea, vomiting, headache, dizziness, drowsiness, shivering, itching, and neurological excitatory symptoms such as delirium, illusions, and hallucinations. In this study, the incidence of hallucinations, drowsiness, and diplopia within 2 hours after esketamine injection increased in the esketamine groups compared to the control group. Notably, the 0.15 mg/kg esketamine group exhibited a lower incidence of adverse reactions than the 0.25 mg/kg group. However, there were no significant differences noted in the incidence of adverse reactions beyond 2 hours among the three groups. Literature reports[25] indicate that esketamine may induce transient hypertension and mental symptoms, peaking approximately 40 minutes after administration and returning to pre-administration levels within 2 hours. Wang et al's meta-analysis revealed that postoperative administration of 0.25 mg/kg esketamine effectively mitigates postoperative pain but may elevate the incidence of mental adverse events[26]. Although clinical studies have reported mild and self-limiting adverse reactions to esketamine, vigilant monitoring and observation are imperative.

In summary, esketamine, as part of a multimodal postoperative analgesia regimen, demonstrates efficacy as a postoperative analgesic, albeit with a potential for increased mental adverse events, particularly at higher doses. The low-dose group experiences fewer adverse reactions. Both doses of esketamine administered during cesarean sections are effective in reducing the incidence of postpartum depression on postoperative days 2 and 7. Considering the incidence of adverse reactions, a single intraoperative injection of 0.15 mg/kg esketamine is more appropriate for parturients undergoing cesarean section. In addition, due to the limited sample size and dimensions of the indicators examined in this study, there is a certain lack of depth in the research of the two groups. We will further improve this in future studies.

CONCLUSION

Esketamine enhances analgesia and postpartum recovery; a 0.15 mg/kg dose is optimal for cesarean sections, balancing efficacy with minimized adverse effects.