Article Text

Comparative dose–response study of intrathecal hyperbaric ropivacaine for cesarean delivery in preterm singleton versus twin pregnancies
  1. Miao Zhu,
  2. Ju-Jun Liu,
  3. Yan-Ping Shen,
  4. Zheng-Bin Pan,
  5. Chang-Cheng Lv,
  6. Wen-Din Chen and
  7. Xiaowei Qian
  1. Department of Anesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Xiaowei Qian, Department of Anesthesiology, Women's Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, China; qianxw{at}


Introduction Previously, we demonstrated that patients with full-term singletons and preterm twins require similar dose of intrathecal hyperbaric ropivacaine. However, these findings may be attributable to enrolled patients with preterm twin pregnancies. In this study, we aimed to determine the intrathecal dose requirements of hyperbaric ropivacaine for twins and singletons at equal gestational ages.

Methods We enrolled 75 patients with preterm singletons and 75 patients with preterm twins scheduled for cesarean delivery under combined spinal-epidural anesthesia in this two-arm parallel, randomized, double-blind, dose–response study. Patients with singletons and twins were randomly assigned to receive one of five different doses of hyperbaric ropivacaine: 10, 12, 14, 16, or 18 mg. A probit regression model was used to determine the dose effective in 50% of patients (ED50) and dose effective in 90% of patients (ED90) values. The relative median potency was calculated to compare the ED50 between patients with twins and singletons.

Results Intrathecal ropivacaine ED50 and ED90 (with 95% CI) in patients with preterm singletons were 9.9 (7.2 to 11.5) mg and 16.8 (14.5 to 22.9) mg, respectively. In patients with preterm twins, these values were 9.2 (95% CI 6.4 to 10.8) mg and 15.6 (95% CI 13.6 to 20.6) mg. Between patients with preterm twins and preterm singletons, the relative potency (ED50 ratios) was 0.933 (95% CI 0.72 to 1.15).

Conclusions During preterm gestation, intrathecal hyperbaric ropivacaine dose requirements for scheduled cesarean delivery were not different between patients with twins and singletons.

Trial registration number ChiCTR2100051382.

  • injections, spinal
  • pharmacology
  • anesthesia, local

Data availability statement

Data are available on reasonable request.

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  • Our prior study suggested that patients with full-term singletons and preterm twins require similar dose of intrathecal hyperbaric ropivacaine.

  • The criteria for both groups were different in terms of gestational age and might impact the generalizability of the results.


  • Compare to later gestational age, lower gestational age might decrease body weight and abdominal girth which might further increase the intrathecal local anesthetic requirement, we therefore, recruited patients with similar gestational age at preterm birth between the two groups in the present trial.


  • At preterm gestation, the dose requirements of intrathecal ropivacaine were not different between patients with twin and singleton pregnancies for scheduled cesarean delivery.

  • This reinforced our decision to choose standard intrathecal local anesthetic doses in patients with twin pregnancies.


Local anesthetic spread is primarily determined by lumbosacral cerebrospinal fluid (CSF) volume,1–3 which has been shown to be highly correlated with abdominal girth.4 Especially in isobaric intrathecal anesthetic solution, patients with larger abdominal girth tend to have a higher spinal block level.5 However, most studies concerning hyperbaric solution did not find a significant correlation between intrathecal local anesthetic requirements and abdominal girth.6 7 Similarly, our previous study demonstrated that the intrathecal hyperbaric ropivacaine requirements were not different between patients with twin and singleton pregnancies.8

Our previous study results must be interpreted cautiously. The previous study employed inclusion criteria for gestation age that were lower for twin pregnancies compared with singleton pregnancies. This is due to clinical practice, where patients with twin pregnancies commonly present for cesarean delivery with preterm gestation. Low gestational age significantly decreases body weight, abdominal girth, birth weight, and placental weight, and possibly further increases the intrathecal local anesthetic requirement.9 10

Consequently, the current study aimed to evaluate the intrathecal hyperbaric ropivacaine dose requirement for cesarean delivery in patients with preterm singleton pregnancies versus preterm twin pregnancies. We postulated that the intrathecal dose requirement of hyperbaric ropivacaine was lower in the twin group than in the singleton group.



The study followed the guidelines of the Consolidated Standards of Reporting Trials and was registered at (identifier: ChiCTR2100051382; principal investigator: Miao. Zhu; date of registration: September 22, 2021).

Subjects and setting

We planned to recruit 150 patients to undergo cesarean delivery under spinal anesthesia at Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. Inclusion criteria were as follows: American Society of Anesthesiologists physical status II, 18–40 years of age, pregnancy involving twins or a singleton with a gestational age less than 37 weeks, height ≥150 cm, and weight ≤110 kg. Exclusion criteria were as follows: unable or refused to provide informed consent, active labor, pre-eclampsia, severe heart disease, thrombocytopenia, known allergy to norepinephrine, and undergoing urgent cesarean delivery.

Patients were divided into two groups: group S contained 75 patients with singleton pregnancies; group T contained 75 patients with twin pregnancies. A random number table was generated by IBM SPSS Statistics for Windows V.25.0 (IBM). According to the table, each group’s subjects were randomly allocated into five equal-sized subgroups (15 patients per group); patients in the subgroup were randomly allocated to receive one of five doses: 10, 12, 14, 16, or 18 mg ropivacaine (Naropin; AstraZeneca; 10 mg/ mL). One hundred and fifty sealed opaque, sequentially numbered envelopes were used to secure drug information and were opened before intrathecal injection. All the randomization and drug preparation were performed by the researcher (Z-BP) who was not involved in data collection or patient management. The dosages were based on our previous published descriptions and clinical experience.8 All doses were mixed with 1 mL of 10% glucose and normal saline to 3 mL to facilitate blinding.

Study protocol

Patients fasted for 10 hours and had no premedication. After entering the operating room, peripheral intravenous access was obtained with a 16-gage catheter in an upper limb for administering fluid. The Ringer’s lactate solution was administered as a rapid peripheral intravenous preload of 10 mL/kg and then at a maintenance rate throughout the procedure. Standard non-invasive monitoring was applied, including non-invasive blood pressure, pulse oximetry, and electrocardiography. Patients were placed on a horizontal operating table, and the investigator (MZ) used a tape measure to measure the abdominal girth at the level of the umbilicus at the end of expiration. Patients were placed in the left decubitus position prior to spinal anesthesia. The vertebral column length was measured with their backs flexed as the distance from the C7 vertebra to the sacral hiatus. After a brief calm period, the mean of three consecutive readings taken 1 min apart was taken as a baseline non-invasive blood pressure and heart rate.

A two-space combined spinal epidural technique was performed with patients positioned in the left decubitus position. After skin disinfection and skin infiltration with lidocaine 1% w/ v, epidural puncture was performed at the estimated L1–L2 vertebral interspace with an 18-gage Tuohy needle using the loss of resistance to air. A multiple orifice epidural catheter was inserted 2–3 cm into the epidural space. The epidural catheter was not injected with any drug or saline solution at the time of this procedure. At the estimated L3–L4 vertebral interspace, a 27-gage pencil-point spinal needle was inserted with its orifice facing the ceiling. After confirmation of CSF, the intrathecal solution was injected over approximately 30 s. All intrathecal injections were performed by an experienced anesthesiologist (W-DC) blinded to ropivacaine dose. As soon as spinal anesthesia was completed, the patient was turned supine and a hard pad measuring 15° was placed under the right hip, thus creating a left lateral displacement of the uterus until the skin incision could be made.


The primary outcome was the success rate of the intrathecal block. The definition of success was a bilateral T6 sensory level to pinprick within 10 min after intrathecal injection plus no need for epidural supplementation within 30 min. Failure was defined as the inability to attain a T6 sensory level within 10 min of intrathecal injection or require additional analgesia because the numerical rating scale scores (0–10; 0=no pain and 10=worst pain imaginable) were greater than 3 within 30 min. In failure cases, 1.73% lidocaine bicarbonate (Bailika; Jichuan Pharmaceutica; 17.3 mg/ mL) in a 5 mL bolus was repeated as needed. As the skin was being closed, all women were given 0.5 mg of hydromorphone via an epidural catheter for postoperative analgesia.

Hypotension was defined as a reduction in systolic blood pressure of more than 20% of the baseline value. When hypotension occurred, 8 µg of norepinephrine was injected intravenously once and could be repeated until blood pressure returned to 80% of baseline systolic blood pressure. When nausea and vomiting occurred during surgery (after hypotension had been excluded), 4 mg of ondansetron was injected intravenously.

Systolic blood pressure was recorded every 1 min for the first 10 min after spinal anesthesia and every 5 min after that, and the total dose of norepinephrine administered was recorded. The sensory level was assessed bilaterally by a plastic stylet from the epidural needle every 2 min after spinal anesthesia. The question asked patients was, ‘Tell me when you know something sharp is touching your skin’. Pain scores were determined by a numerical rating scale scores at the following times: skin incision, delivery, uterine exteriorization, and skin closure. Intraoperative nausea and vomiting were reported by the parturient and recorded by the investigator. Height, weight, age, repeat cesarean delivery, gestational age, Apgar scores, neonatal weight, and umbilical arterial blood gases were recorded.

Statistical considerations

The sample size was calculated based on the data from our pilot study, with the incidence of successful spinal anesthesia being 35%, 60%, 80%, 91%, and 96%, respectively, for the five doses of 10, 12,14, 16, and 18 mg. These data were used in the Cochran-Armitage test for trend in proportions with PASS V.11 (NCSS; Kaysville, Utah, USA) to calculate the sample size. Based on the Z test with continuity correction, with a significance level of 0.05 and a power of 0.90, 11 patients per group were required. The number of patients in each group was increased to 15 to attain a narrower CI.

Continuous data were tested for normality using the Shapiro-Wilk test. Normally distributed data were reported as the mean (SD), and differences were evaluated using Student’s t-test. Non-normally distributed data were assessed by the Mann-Whitney U test. Fisher’s exact test, or the χ2 test, was used to analyze the categorical data.

The dose–response relation for intrathecal ropivacaine was determined by probit regression as we have described.8 Dose effective in 50% of patients (ED50) and the dose effective in 95% of patients (ED95) of each group were determined with 95% CI. The relative median potency (ED50 ratios) of the two groups were calculated to confirm that the ED50 values differed between groups.

All statistical analyses were performed by SPSS V.25.0 for Windows statistical package (SPSS) and Microsoft Excel 2010. A p<0.05 was considered statistically significant.


A total of 167 patients were assessed for eligibility between October 2021 and April 2022. The recruitment of patients is summarized in figure 1. In each group, three patients dropped out, and their numbered envelopes were given to the next patient enrolled. The anesthesiologist (W-DC) was blinded to the drug information and only the researcher (Z-BP) was aware of it. One hundred and fifty subjects were enrolled in the study, and 75 patients were studied in each group. Patients’ characteristics are summarized in table 1. The two groups had significant differences in weight, body mass index, repeat cesarean delivery, symphysis pubis-fundus distance, abdominal girth, placental weight, and birth weight (p<0.05).

Figure 1

Consolidated Standards of Reporting Trials diagram showing recruitment and flow of patients in the two groups.

Table 1

Characteristics of subjects who completed the study

Figure 2 shows the dose–response curves for hyperbaric ropivacaine for both groups. The R2 values of the probit regression curves were 0.92 and 0.94, respectively. As a result, the model fit the data adequately. The initial goal of the current investigation was to determine ED95 values. Ultimately, we failed to provide the ED95 values because they were higher than the study’s maximal dose (18 mg). The ED50 and ED90 values (with 95% CI) of anesthesia success in preterm singleton pregnancies were, respectively 9.9 (7.2 to 11.5) mg and 16.8 (14.5 to 22.9) mg. In patients with preterm twin pregnancies, these values were 9.2 (95% CI 6.4 to 10.8) mg and 15.6 (95% CI 13.6 to 20.6) mg. The relative median potency (ED50 ratios) between patients with preterm singleton and preterm twin pregnancies was 0.93 (95% CI 0.72 to 1.15).

Figure 2

Dose–response curves of hyperbaric ropivacaine for spinal anesthesia in patients with preterm singleton and twin pregnancies undergoing scheduled cesarean delivery generated by probit regression. Response is shown as the probability of successful spinal anesthesia. Successful spinal anesthesia was defined as a bilateral T6 sensory level to pinprick within 10 min after intrathecal injection plus no need for epidural supplement within 30 min. Filled circle=patients with preterm twin pregnancies (group T); filled square=patients with preterm singleton pregnancies (group S).

The mean level of sensory block 10 min after intrathecal injection was T7 (IQR 6–8) in Group T vs T7 (IQR 6–8) in Group S (p=0.50). There were 35 patients (46.7%) in group T and 42 (56%) in group S who required epidural local anesthetic supplementation (p=0.33). The dose requirement for supplemental epidural lidocaine was 5 (IQR 0–10) mL in group T vs 0 (IQR 0–10) mL in group S (p=0.89).

The results of table 2 indicate that there was no significant difference between the groups in terms of hypotension, nausea, vomiting, and shivering. The neonatal outcome is summarized in table 3. Birth weight and placental weight were heavier in group T than in group S (p<0.001). Base excess and umbilical arterial pH were lower in group T than in group S (p<0.01).

Table 2

Adverse effects of anesthesia

Table 3

Neonatal outcome


According to our study, the 95% CI of relative median potency (ED50 ratios) spans unity, showing no significant difference between the two groups. Therefore, at preterm gestation, patients with twin pregnancies did not have different intrathecal hyperbaric ropivacaine dose requirement compared with those with singletons.

It is controversial whether patients with large abdominal girth require less intrathecal local anesthetic. Studies using isobaric intrathecal local anesthetics generally indicated that patients with a larger abdominal girth had higher spinal block levels.5 11 12 Nevertheless, these findings did not hold true with hyperbaric solutions,6 7 13 including ours.8 In our previous study, due to the fact that patients with twin pregnancies frequently present for scheduled cesarean delivery with preterm gestation, we recruited a substantial number of patients with twin pregnancy with gestational age ≤37 weeks. Consequently, the median gestational age of the twin group was lower compared with that of the singleton group. Assuming that the twin group was of the same gestational age as the singleton group, for example, recruiting patients with preterm singleton pregnancies into the singleton group, there would be greater disparities between the two groups in terms of body weight, abdominal girth, birth weight, and placental weight, which may alter the requirements for intrathecal local anesthesia. Therefore, we conducted the present trial under similar gestation ages to compare the optimal intrathecal local anesthetic between patients with twin and singleton pregnancies.

While it is generally accepted that spinal anesthesia spread is enhanced in twin pregnancies, there are several factors that may mitigate this effect. First, the extent of inferior vena cava compression by the gravid uterus appears to be similar in patients with twin and singleton pregnancies. The utilization of angiography and MRI has provided direct evidence showing that the inferior vena cava experiences nearly 100% compression from the gravid uterus while the individual is in a supine posture, and the compression is not alleviated when the individual assumes a 15° left-lateral position.14 Furthermore, in one hemodynamic trial, patients with twin and singleton pregnancies undergoing cesarean delivery under spinal anesthesia were assessed for cardiac output, stroke volume, mean arterial pressure, and total peripheral resistance. No differences were found in any hemodynamic parameter, perhaps indirectly reflecting the similar compression of the inferior vena cava.15 Second, besides abdominal girth, vertebral column length has a strong correlation with lumbosacral CSF volume4 and spinal block level.5 Our series of studies found that the vertebral column length was not significantly different between the twin and singleton groups, which may partly explain the similar intrathecal local anesthetic requirements.8 By combining the abdominal girth and vertebral column length, it may be possible to predict the spread of intrathecal local anesthetic more accurately than by using either factor alone.16 Third, the baricity of local anesthetic is believed to significantly influence the outcome of spinal anesthesia.17 According to studies conducted on patients receiving isobaric bupivacaine, there was a positive correlation between body weight, abdominal girth, intra-abdominal pressure, and cephalad spread, as well as an inverse relationship between height, vertebral column length, and cephalad spread in these patients.5 11 12 18 However, in patients receiving hyperbaric bupivacaine, most studies fail to find any relationship between patient characteristics and spinal block level.7 13 19 Because the density of hyperbaric solution is greater than CSF, local anesthetics spread gravitationally, and the level achieved may be more predictable.17 20 Isobaric solution has a gravity close to CSF, and the drug stays closer to where it is injected. Thus, drug spread is largely determined by the volume of lumbosacral CSF, which is highly correlated with the body characteristics of the patient.1 3 5 17

Our present study had several limitations. First, we chose ropivacaine as the intrathecal local anesthetic, whereas bupivacaine is much more commonly used in the USA and Europe.21 Ropivacaine is China’s most commonly used intrathecal local anesthetic and has been safe and widely used for a decade.22 23 There is evidence that intrathecal ropivacaine and bupivacaine have similar dose–response relationships.24 Hence, the conclusions from this study likely can be applied to bupivacaine, which is 30%–40% more potent than ropivacaine.24 25 Second, our intrathecal solutions do not contain opioids, which is not common practice in other medical centers.21 26 Intrathecal opioids can optimize the quality of intraoperative anesthesia and provide post cesarean delivery analgesia.27 In our hospital, we prefer to insert an epidural catheter to manage intraoperative pain and provide post cesarean delivery analgesia. Due to the lack of commercially available hyperbaric ropivacaine, we have to add 10% glucose and normal saline into plain ropivacaine. In this situation, adding another drug certainly has a potential infection risk. Thus, we chose ropivacaine alone as the intrathecal solution. Third, clinically, anesthesiologists usually administer a dose higher than the ED90 for single-shot spinal anesthesia because a 10% failure rate is unacceptable. Our ED95 values were not reported as their calculated values exceeded the upper limit of the dosage range used in the study. A note of caution, however, is that the ED95 value in probit regression was derived from the plateau region of the dose–response curve, making it less certain than the ED50, which was derived from the rapidly ascending region.6


In conclusion, when gestational age was controlled, the dose requirement of intrathecal ropivacaine was not different between patients with twin and singleton pregnancies for scheduled cesarean delivery. This reinforced our decision to choose standard intrathecal local anesthetic doses in patients with twin pregnancies. It is worth noting that these findings were in the setting of combined spinal epidural anesthesia, insertion with patients in the left position, no opioids, low-weight cohort, hyperbaric ropivacaine, and norepinephrine boluses.

Supplemental material

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by Women’s Hospital, Zhejiang University School of Medicine Ethics Committee (IRB-202100248; September 3, 2021) Participants gave informed consent to participate in the study before taking part.


The authors thank the teachers and colleagues in the Department of Anesthesia, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.


Supplementary materials

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  • Contributors C-CL, J-JL, W-DC, Y-PS and Z-BP: Study conducted; MZ: Data collected, statistical analysis and drafting manuscript; XQ: Study design and drafting manuscript. All authors contributed to manuscript revision and read and approved the submitted version. XQ is responsible for the overall content as a guarantor.

  • Funding This work was supported by National Natural Science Foundation of China (Surface project No. 82272183).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.