Esketamine Prevent Carboprost-Induced Adverse Reactions During Cesarean Section Under Combined Spinal-Epidural Anesthesia: a double-blind, randomized trial

doi:10.21203/rs.3.rs-5166355/v1

Objectives

To investigate reduce adverse reactions to carboprost of intravenous esketamine administered after childbirth via cesarean delivery with the patient under combined spinal-epidural anesthesia.

Methods

The study involved women within the age bracket of 20 and 40 years, with American Society of Anesthesiologists (ASA) class II or III, and a gestational age of 37 weeks or more. These women had a scheduled cesarean section procedure with the administration of combined spinal-epidural anesthesia. Patients were randomized to receive esketamine 0.5 mg/kg (Group E) or volume-matched normal saline (Group C) after delivery of the fetus, before carboprost administered. The primary outcome was the incidence of vomiting during surgery. The secondary outcomes were the incidence of adverse reactions (vomiting, nausea, chest rigidity, flushed face, tachycardia, cough, shivering), vital signs (HR, RR, MAP, SPO₂) and blood gas analysis of intraoperative, as well as VAS score for postoperative pain.

Results

Eighty-one pregnancy women completed the study. The incidence of vomiting (22.5% versus 56.1%, p < 0.001) and the incidence of nausea, chest rigidity, flushed face, and hypertension were significantly lower in group E than in group C (all p < 0.01), but the incidence of tachycardia was higher in group E (45% vs 19.5%, p < 0.001). Furthermore, the patients’ arterial partial pressure of oxygen was significantly higher in group E than in group C (91.90 ± 5.14 vs. 79.76 ± 3.96, p < 0.001). Significant reduction in VAS-incision pain scores 6 hours after surgery in group E, but no significant difference was found at the VAS-uterine pain scores.

Conclusion

For women undergoing cesarean delivery under combined spinal-epidural anesthesia, intravenous esketamine after delivery of the fetus, before carboprost administered not only reduced the incidence of adverse reactions caused by carboprost, but also relieve postoperative uterine contractions pain.

Trial registration:

Chinese Clinical Trial Registry (Registration number# ChiCTR2100054985); Date of Registration: 30/12/2021

esketamine

carboprost

cesarean section

combined spinal and epidural anesthesia

Postpartum hemorrhage (PPH) is the leading cause of maternal mortality, with uterine atony, a common condition characterized by the inability of the uterus to contract after delivery, being the most common contributing factor^1,2. Carboprost, a medication consisting of prostaglandin F2α and tromethamine, was introduced in the late 1990 s ³. The drug has a potent effect on uterine smooth muscle, promoting hemostasis through uterine muscle contraction⁴. Carboprost has been widely used to manage PPH due to uterine atony with clinically positive outcomes. However, the drug is associated with several side effects, such as vomiting, nausea, headache, chest tightness, facial flushing, and high blood pressure⁵. While these effects are usually mild and non-fatal, they can reduce patient comfort during labor and cause discomfort during cesarean section under combined spinal-epidural anesthesia. Currently, there is no specific therapy for carboprost-induced adverse reactions, and only symptomatic treatment is available.

Intravenous administration of esketamine, the pure d-enantiomer of ketamine, induces anesthesia within 30 seconds, provides 30 minutes of analgesia and sedation⁶. Additionally, esketamine has mild respiratory depressive effects, and peripheral contraction of the uterus making it a popular choice for obstetric anesthesia.⁷. Clinical experience suggests that a single bolus of esketamine given as a rescue medication during Cesarean section under combined spinal-epidural anesthesia not only can it inhibit the adverse reactions caused by carboprost, but it will not affect the contractile ability of the uterus. Furthermore, the use of esketamine reduced the need for other medications that have the potential to harm the baby through breastfeeding ⁸. In this study, we conducted a prospective, randomized controlled trial to investigate the effect of a single bolus of esketamine on carboprost-induced adverse reactions during the Cesarean section procedure under combined spinal-epidural anesthesia.

Study design and setting

This was a prospective, double-blind, randomized controlled study conducted from January 2021 to June 2021 in accordance with the principles of the Declaration of Helsinki.

Ethical Approval and Consent to Participate

The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100054985) in 12/30/2021 and was approved by the Ethics Committee of the Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University (Jinan, China; 2021-1-050). Written informed consent was obtained from all participants. This manuscript adheres to the applicable EQUATOR guidelines.

Participants

Obstetrical patients aged 20–40 years with ASA physical status II or III and with a gestational age of ≥ 37 weeks scheduled for cesarean section under combined spinal-epidural anesthesia were enrolled. Patients were excluded for the following reasons: (1) individuals with mental illness; (2) contraindication to prostaglandin, such as asthma or glaucoma; (3) history of allergy to carboprost, esketamine, or ropivacaine; (4) severe pulmonary infection; (5) concomitant disease known to cause nausea, vomiting-like Meniere’s syndrome, vestibular neuritis, or acute gastroenteritis; (6) those who could not cooperate with the study due to disease or language barrier. Furthermore, patients with significant obstetric hemorrhage were also excluded from the study.

Randomization and masking

Subjects were randomly assigned to receive esketamine (Group E) or saline (Group C) in a 1:1 ratio. A random sequence was generated using a computer-generated randomization program and kept within sealed opaque envelopes by an anesthesia nurse not involved in data collection. On the morning of the surgery, the anesthesia nurse opened a sealed envelope and prepared the drugs in identical syringes according to the group allocation. The anesthesiologist who administered the injections, the outcome assessor, and the patients were blinded to the allocation and study drugs.

Anesthesia and intervention

The individuals were fasted for eight hours prior to surgery. Upon entering the operating room, peripheral venous access was established and 500 ml of balanced saline solution was intravenously administered before the start of anesthesia. Standard ASA monitoring was conducted, including measurements of blood pressure,mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation (SpO2), and respiratory rate (RR).

The anesthesia specialist used a midline approach to administer combined spinal-epidural anesthesia at the L2/3 space, with the pregnant patient in a right-side lying position. Confirmed by loss of resistance and free flow of cerebrospinal fluid, the epidural and spinal taps were conducted. After administering 2.6-3.0 ml of 0.5% ropivacaine (1% ropivacaine in 0.9% saline) into the subarachnoid space for 10 seconds, the epidural catheter was maneuvered and positioned cephalad beyond the epidural space 4 cm. After these procedures, the patient was promptly placed in the left-side lying position to facilitate left-sided uterine displacement. If the anesthesia level is not ideal, give 2% lidocaine through the epidural space to deepen the anesthesia level.The surgical procedure was begun when the level of anesthesia diffusion reached T4 or a higher level. Following delivery, 10 units of oxytocin was administered via myometrial injection, and a continuous intravenous infusion of oxytocin (10 units) diluted in 500 ml of balanced saline solution was started at a rate of approximately 250 ml/h. Uterine contractions were evaluated by the attending obstetrician. When the obstetrician needs to inject carboprost into the myometrium to assess uterine inertia Patients in group E received 0.5mg/kg esketamine (Aisi, hengrui Pharmaceutical Co., Ltd, China) before 1 min carboprost was injected, while patients in group C received an equivalent injection of normal saline in addition to comparable carboprost. After the surgical procedure, pregnant patients were transferred to the post-anesthesia care unit (PACU) to undergo bilateral transversus abdominis plane block, conducted by the same anesthesia specialist. If vomiting occurred, 8 mg intravenous Ondansetron was administered. If the patient feels pain during surgery, use chloroprocaine (100mg) through epidural to deepen anesthesia.We defined hypotension as systolic pressure below 90 mmHg or a decline in systolic pressure beyond 30%, and we treated this with intravenous neosynephrine (100 µg) as needed. We treated bradycardia, defined as heart rate below 50 beats /min, with intravenous atropine (0.5 mg). We treated hypoxemia, defined as SpO2 less than 95%, with oxygen. In order to avoid affecting the results of blood gas analysis, oxygen should be administered to the mother as needed after the second blood gas collection is completed. Patients who experienced shivering received heating devices.

Observed parameters

The demographic information of all pregnant patients, including age, height, weight, pregnancy-related data was documented. The researchers documented and analyzed the frequency of adverse reactions related to carboprost, including vomiting, nausea, chest rigidity, facial flushing, hypertension, tachycardia, cough, and shivering during surgery and after the surgery in the PACU. The RR, HR, SpO2 and MAP were monitored before anesthesia, at 1 minute before carboprost injection, 5 minutes after carboprost injection, 15 minutes after carboprost injection, and 30 minutes after carboprost injection. Minimum SpO2 and Minimum RR were recorded during surgery. Blood gases were drawn from arterial samples taken before anesthesia and 15 minutes after carboprost injection. VAS scores for incision pain and uterine contraction pain were collected at 1 hour, 6 hours, 12 hours, and 24 hours after surgery.

Statistical Analysis

The primary objective for this study was to minimize the incidence of vomiting. Based on preliminary research results, the vomiting incidence was identified as 22.2% and 55.6% in groups E and C, respectively. With these findings, we estimated the requirement for 40 parturient patients in each group to achieve 90% in vomiting incidence at a significance level of 5% (two-tailed, α = 0.05, β = 0.90). Additionally, we aimed to recruit 43 parturient patients in each group, considering possible dropouts. Data was presented as means ± standard deviations, numbers (%) as appropriate. The IBM SPSS Statistics for Windows 22.0 software (IBM Corp, Armonk, NY, USA) was used for analyzing the data, we used repeated measured analysis of variance to identify differences in vital signs within groups at each time point, and pairwise comparisons were conducted using the LSD method. Categorical variables were analyzed using either the Pearson Chi-square test or Fisher exact test. A two-sided p-value of less than 0.05 was considered statistically significant.

A total of 374 patients were approached for study consideration, 83 met one or more exclusion criteria, the control group (group C) consisted of 41 patients, while the esketamine group (group E) had 40 patients (Fig. 1). There was no observable statistically significant difference between maternal, neonatal baseline variables, and intraoperative variables for both groups, with p > 0.05 (see Table 1).

Table 1

Maternal and newborn characteristics.
	Group C (n = 41)	Group E (n = 40)	P value
Age, years	30.5 ± 4.0	31.4 ± 5.2	0.39
Height, cm	162.8 ± 4.5	162.1 ± 4.9	0.51
Weight, kg	75.1 ± 10.9	73.4 ± 8.5	0.43
BMI	28.3 ± 3.7	27.9 ± 2.9	0.61
Gestational age, weeks	38.6 ± 0.8	39.0 ± 0.7	0.06
Gestation,n Pregnancy,n	1.9 ± 0.9 1.4 ± 0.5	2.0 ± 0.8 1.5 ± 0.5	0.99 0.59
Apgar	10.0 ± 0	9.9 ± 0.3	0.08
Kinetosis,n (%)	6 (14.6%)	7 (17.5%)	0.73
Post-operative nausea and vomiting history, n (%)	19 (46.3%)	21 (52.5%)	0.58

Results on group E showed a substantially lower occurrence of vomiting (22.5%) compared to group C (56.1%) with a p < 0.001. Additionally, the incidence of nausea and chest rigidity was significantly higher in group C compared to group E, with a p < 0.001. For both groups, there was no significant difference for cough and shivering, all having p > 0.05. However, group E experienced higher rates of tachycardia compared to group C, with a p < 0.001. Exact values and observations for these variables relevant to the study can be found on Table 2.

Table 2

Incidence of carboprost-related adverse reactions.
	Group C (n = 41)	Group E (n = 40)	P value
Vomiting, n (%) Nausea, n (%) Chest rigidity, n (%) Flushed face, n (%) Tachycardia, n (%) Cough, n (%) Shivering, n (%)	23 (56.1%) 29 (70.7%) 25 (60.9%) 13 (31.7%) 8 (19.5%) 3 (7.5%) 4 (9.7%)	9 (22.5%) 13 (32.5%) 7 (17.5%) 3 (7.5%) 18 (45.0%) 3 (7.5%) 2 (5.0%)	0.01 0.02 < 0.01 0.06 0.01 0.98 0.41

In group C, the use of ondansetron after carboprost administration was much higher (57.1%) than group E (8.1%), with a p < 0.01. Additionally, the need for Chloroprocaine for rescue analgesia was higher in group C (34.3%) compared to group E (16.2%), with a p < 0.01. However, no significant differences were observed between the surgical aspects of the two groups. It includes the duration of surgery, intraoperative infusion volume, urine volume, intra-operative blood loss, and minimum respiratory rate (RR), all having p > 0.05. Refer to Table 3 for comprehensive values relevant to the study.

Table 3

Maternal and newborn surgical details.
	Group C (n = 41)	Group E (n = 40)	P value
Duration of surgery, min Intraoperative infusion vilume,ml Intraoperative urine vilume,ml Blood loss during surgery, ml Rescue analgesia with Chloroprocaine, n (%) Es-ketamine dosage, µg Use of Ondansetron, n (%) Administration time,min Minimum RR, bpm Minimum SpO2, (%)	51.9 ± 5.1 1102.4 ± 64.2 107.3 ± 26.4 298.8 ± 59.7 12 (34.3%) 0 20 (57.1%) 8.6 ± 2.0 14.4 ± 1.1 96.1 ± 1.5	52.3 ± 3.7 1106.3 ± 48.3 106.3 ± 28.1 305.0 ± 63.9 6 (16.2%) 36.3 ± 4.0 3 (8.1%) 8.2 ± 1.6 14.6 ± 1.2 98.3 ± 1.6	0.64 0.76 0.86 0.65 0.05 < 0.01 < 0.01 0.25 0.36 < 0.01

15 minutes after carboprost injection, the mean PaO2 levels in group C were significantly lower than in group E, with a p < 0.01. However, no significant variance was observed in the mean pH and blood sugar levels, whereas the mean lactic acid level was significantly higher for both groups before anesthesia and 15 minutes after carboprost injection, with p-values greater than 0.05. A detailed summary of these values at 15 minutes after carboprost injection can be found in Table 4.

Table 4. Maternal cord blood gas parameters.

Information on the vital signs for both groups can be found in Fig. 2. The HR trends for both groups were similar following carboprost injection, with the exception of Group C, which demonstrated a significant difference in HR only at T3 with a p < 0.05. Additionally, at minutes after carboprost injection, the mean respiratory rate (RR) in Group E was significantly higher with a p < 0.001. The mean arterial pressure (MAP) was also higher in Group E at minutes after carboprost injection and 30 minutes after carboprost injection with a p < 0.001. However, the mean values of MAP for both groups remained within the normal range throughout the study. Moreover, for both groups, the SpO2 levels slightly decreased after carboprost injection, with lower mean values in Group C at 1 minute before carboprost injection, 5 minutes after carboprost injection, and 15 minutes after carboprost injection, with p-values less than 0.001, less than 0.01, and less than 0.05, respectively. These findings were consistent with the blood gas analysis results shown in Fig. 2.

15 minutes after carboprost injection, the mean PaO2 levels in group C were significantly lower than in group E, with a p < 0.01. However, no significant variance was observed in the mean pH and blood sugar levels, whereas the mean lactic acid level was significantly higher for both groups before anesthesia and 15 minutes after carboprost injection, with p-values greater than 0.05. A detailed summary of these values at 15 minutes after carboprost injection can be found in Table 4.

There was an overall statistically significant difference in postoperative pain scores at the incision site measured by VAS between the intervention group and the control group during the first 6 hours after cesarean delivery. Specifically, the intervention group had significantly lower VAS scores. However, there was no statistically significant difference in postoperative pain scores in the uterus measured by VAS between the two groups at other times (see Fig. 3).

After combined spinal and epidural anesthesia, administering a single intravenous dose of esketamine effectively alleviated adverse reactions caused by intramuscular injection of carboprost, decreased postoperative pain, and significantly improved the comfort of pregnant women, without any noticeable complications.

Carboprost, a synthetic derivative of prostaglandin F2α, contracts uterine smooth muscle, increases uterine contractions' frequency and amplitude, constituting its main pharmacological action to prevent and reduce uterine bleeding in pregnant women^9,10. Carboprost also causes a series of adverse reactions, such as hypertension, increased heart rate, decreased oxygen saturation, nausea, vomiting, chest tightness, respiratory distress, and hot flashes, as it has a strong contractile effect on peripheral blood vessels, gastrointestinal, and bronchial smooth muscles^5,9. In this study, administering esketamine after carboprost injection showed a lower incidence of vomiting in mothers than the control group. We also noted a reduction in the incidence of other adverse reactions caused by carboprost, such as nausea and chest tightness; however, the frequency of tachycardia was higher than in the control group. Yet, the mothers did not experience any apparent discomfort since they received anesthesia.

Previous studies have administered opioid drugs during surgery to mitigate unfavorable reactions brought on by carboprost¹¹. Nevertheless, opioids can impede uterine contractions and increase intraoperative bleeding¹². Esketamine is the only anesthetic that does not suppress uterine contractions, therefore can significantly minimize unfavorable reactions and has an excellent anesthetic effect¹³. Esketamine is a pure dextral enantiomer of ketamine, used for clinical analgesia and anesthesia,its primary effect is achieved by noncompetitively inhibiting the N-methyl-D-aspartic acid receptor¹⁴.Esketamine also interacts with opioid, monoamine, and adenosine receptors¹⁵. Its fast onset, lack of respiratory inhibition, and ability to enhance circulatory stability make it a suitable candidate for intravenous administration during spinal anesthesia and cesarean section¹⁶. Moreover, S-ketamine has low milk secretion and is relatively safe for infants and children.¹⁷. In our research, the rate of nausea, vomiting, and chest tightness in mothers who received esketamine was low due to its effective sedative action. In clinical practice, we noted that esketamine was a more potent antiemetic than traditional antiemetic drugs administered during carboprost administration, hence decreased their utilization. Carboprost induces vomiting by exciting gastrointestinal smooth muscle, while ondansetron's antiemetic effect is hindered by its action of inhibiting the release of serotonin (5-HT) from chromaffin cells in the small intestine. Esketamine leads to quick effect, mitigates gastrointestinal smooth muscle stimulation and intraoperative visceral traction reflex, thereby regulating hemodynamic stability and producing a superior antiemetic effect.In addition, esketamine effectively reduces the rate of chloroprocaine supplementation during epidural administration or surgery due to its suitable analgesic effect.

In this study, the arterial blood gas levels in mothers were measured before the administration of anesthesia and 15 minutes after the administration of carboprost. Esketamine's respiratory inhibitory effect was alleviated compared to Group C. It effectively mitigated the decrease in blood oxygen pressure brought about by carboprost and increased the average intraoperative oxygen saturation. The use of esketamine also improved the comfort of mothers during the procedure. There was a decrease in lactate production through anaerobic glycolysis, owing to an increase in the oxygen pressure. Additionally, reducing the requirement for supplementary medications to manage adverse reactions brought about by carboprost could decrease the likelihood of adverse reactions in newborns during breastfeeding. Therefore, esketamine can decrease adverse reactions caused by carboprost, improve maternal comfort, and not lead to an increase in adverse reactions experienced by newborns.

Statistically significant differences existed in the hemodynamic and respiratory parameters between the two groups for certain time points, although almost all parameters were at normal levels across all time points. Carboprost attains the highest plasma concentration approximately 30 minutes after intramuscular injection. Hankins et al. reported a decline in SpO2 levels among five patients with PPH who underwent treatment with 15-methylprostaglandin F2 α. Their findings suggested that the injection led to a decrease in arterial oxygen saturation by an average of 10.4% ± 5.4%, primarily within 7 ± 2.5 minutes following administration. The pulmonary shunt also increased by 20.7% ± 5.9%. The authors concluded that the reduced arterial oxygen saturation was a result of the decreased ventilation-to-blood flow ratio as well as an increase in intrapulmonary shunt¹⁸. Our research discovered that esketamine increased the maternal respiratory rate while reducing fluctuations in maternal oxygen saturation, which aligns with the 15-minute arterial blood gas results obtained after carboprost administration. Esketamine increased maternal mean arterial pressure and heart rate during surgery, primarily due to its mild excitatory effect on the cardiovascular center, but these parameters remained within the normal range¹⁹. With regards to postoperative pain scores, esketamine decreased the incision pain score six hours after surgery. However, 24 hours postoperatively, the incision pain score was higher in comparison to the control group, which could be due to breakthrough pain after the metabolism of esketamine had cleared. Meanwhile, the uterine contraction pain score was not significantly different from that of the control group.

This research has certain limitations. Other studies have proven that the postoperative analgesic efficacy of esketamine is uncertain, necessitating the evaluation of more objective indicators and a large sample size. Our study indicates that esketamine has a favorable inhibitory impact on adverse reactions within the initial half-hour of administering carboprost. However, carboprost can lead to uterine contractions that persist for approximately two hours. We did not conduct a post-operative examination to observe the incidence of adverse reactions. Previous studies have reported that ketamine can cause hallucinations and other adverse reactions²⁰. Due to our small sample size, some complications related to esketamine may remain undetected. Furthermore, our experimental results show that both carboprost and esketamine can cause hypertension and tachycardia, despite their normal values. However, further research is necessary to determine if they have any long-term effects on postpartum women.In conclusion, the results of this study indicate that a single intravenous injection of 0.5mg/kg anesthesia dose of esketamine can effectively prevent adverse reactions induced by carboprost during spinal and epidural anesthesia for cesarean section.

Funding

This research was funded by the Jinan Science and Technology Project (Grant/Award Number: 202134071) and the Shandong Medical Health Science and Technology Project (Grant/Award Number: 202318001388).

Conflict of interest

The authors declare that they have no conflict of interest.

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No competing interests reported.

Esketamine Prevent Carboprost-Induced Adverse Reactions During Cesarean Section Under Combined Spinal-Epidural Anesthesia: a double-blind, randomized trial

Status:

Version 1

Abstract

Objectives

Methods

Results

Conclusion

Trial registration:

Figures

Introduction

Materials and methods

Study design and setting

Participants

Randomization and masking

Anesthesia and intervention

Observed parameters

Statistical Analysis

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1