Objective: This study aimed to determine the ED50 and ED95 of 10 mg of
0.5% ropivacaine combined with different doses of sufentanil in lumbar
anesthesia for cesarean sections in patients with severe preeclampsia by the
sequential method. Methods: A total of 47 patients with severe
preeclampsia, who underwent cesarean section, were enrolled in
the present study. The first patient was given a subarachnoid
injection of 10 mg of isobaric 0.5% ropivacaine plus 2.5
Preeclampsia typically occurs in the third trimester and is characterized by hypertension, edema, and proteinuria. Preeclampsia can affect both the mother and the unborn baby and is estimated to affect between 5% and 8% of healthy pregnancies . It is responsible for about 76,000 maternal deaths and 500,000 infant deaths per year worldwide . Preeclampsia is subdivided into mild and severe forms, with 50% of preeclamptic women experiencing the latter.
Elective cesarean delivery (CD) is the most frequently adopted delivery mode to terminate pregnancy in women suffering from preeclampsia. The currently preferred anesthesia modality for women with preeclampsia undergoing CD is spinal anesthesia . Intrathecal ropivacaine for spinal anesthesia is a widely accepted technique for cesarean sections. It has the following advantages: rapid onset of effect, satisfactory analgesic effect, reliable sacrococcygeal anesthesia, lower intensity motor block with a shorter duration, and high satisfaction of pregnant women and surgeons during the operation [3,4]. However, in order to achieve a good anesthetic effect, it is often necessary to control the anesthetic level above the T6 vertebrae. This usually causes a large drop in blood pressure, resulting in maternal nausea, vomiting, and other discomforts.
Adding opioids to local anesthetics for spinal anesthesia can improve the
quality of anesthesia, prolong the action time, reduce the dosage of local
anesthetic, and shorten the onset time of local anesthesia [5,6]. Sufentanil is a
lipophilic opioid that has less headward diffusion and a stronger analgesic
effect when compared with fentanyl . It is
a common drug used in cesarean sections in combination with the local anesthetic
ropivacaine and has a good clinical effect
and little hemodynamic frustration. The combined use of sufentanil with local
anesthesia for spinal anesthesia in women having cesarean sections who suffer
from severe preeclampsia has
been occasionally reported. In these cases, the doses of sufentanil
range between 2.5-7.5
Our hospital carried out combined spinal-epidural anesthesia (CSE) for cesarean sections in patients with severe preeclampsia. The present study aimed to determine the effective dose 50% (ED50), effective dose 95% (ED95), and 95% confidence interval (CI) of lumbar anesthesia with 10 mg of 0.5% ropivacaine and sufentanil for cesarean sections in patients with severe preeclampsia using the sequential method, in order to provide a reference for clinical treatment.
We recruited pregnant women with severe preeclampsia at term who were due to undergo an elective cesarean section, from December 1, 2017, to February 28, 2018. All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Fujian Maternity and Child Health Hospital (No. 2018-190).
Inclusion criteria were as follows: (1) pregnant woman scheduled for
elective cesarean delivery under spinal anesthesia with a
diagnosis of severe preeclampsia; (2) the pregnant woman was over 18 years old;
(3) healthy singleton pregnancy was beyond 36 weeks’ gestation;
(4) American Society of Anesthesiologists (ASA) physical status of the woman was
grade II/III; (5) platelet count (PLT) was
All the pregnant women would receive antihypertensive drugs before the operation, in order to control blood pressure between 150-180/90-105 mmHg.
After entering the operating room, the pregnant women were routinely monitored
using a multifunctional monitor for noninvasive systolic blood pressure (SBP),
diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR),
pulse oxygen saturation (SpO
The sequential method was designed in the up-to-down order. The first patient
received lumbar spinal anesthesia with 10 mg of isobaric 0.5% ropivacaine
Successful anesthesia was defined as when the bilateral sensory block level of acupuncture reached the T6 level within ten minutes of the intrathecal drug injection. Failure of anesthesia was defined as when the anesthetic level did not reach the T6 level, or the patient required additional analgesia, and the completion of surgery required adjuvant epidural analgesia, at ten minutes after intrathecal administration . In cases of failure, the pregnant woman could request supplemental anesthesia to complete the surgery. The 100-mm VAS was used to evaluate the analgesic effect, in which 0 points represent no pain, and 100 points represent “the most severe pain”. Successful anesthesia and failed anesthesia were regarded as the final endpoint for calculating the ED50 of spinal ropivacaine.
The time for the bilateral sensory block to reach the T6 level was detected by
acupuncture and recorded. Hypotension was defined as an SBP lower than 80% of
basal blood pressure. In this case, the anesthesiologist in charge would perform
an intravenous injection of 50-100
The adverse events during and after the operation, such as hypotension, bradycardia, sedation, nausea, vomiting, shivering, and itching, were recorded.
The bilateral sensory level detected by acupuncture was evaluated by the Hollmen
scale : 0
Sedation was assessed on the 5-point scale: (1) fully awake and oriented patient; (2) drowsy; (3) eyes closed and arousable on command; (4) eyes closed and arousable to physical stimuli; (5) eyes closed, but the patient was not arousable to physical stimuli .
Data were statistically analyzed using the software SPSS 24.0. Normally
distributed measurement data were expressed as mean
Fifty women with a diagnosis of preeclampsia presenting for an elective cesarean section under spinal anesthesia were assessed for eligibility. Of these, three pregnant women failed to complete the study (one woman experienced a wrong dosage setting, and two women were injected with opiates before anesthesia). In these cases, the expected dose was used for the next patient. Therefore, 47 patients were included in the final data analysis.
The maternal demographics and operative data are presented in Table 1. The
frequency of maternal adverse events is presented in Table 2. No neonatal
side-effects have been observed. Fig. 1 reveals the up-to-down order. Among
these patients, 24 patients were effective in analgesia, and 23 patients were
ineffective in analgesia. According to the formula of Dixon and Massey , it
was calculated that the ED50 of sufentanil was 1.830
|Age (years)||28.3 |
|Weight (kg)||76.5 |
|Hight (cm)||160.6 |
|Gestational age (weeks)||36.1 |
|Operative time (min)||53.3 |
|Note: SD, standard deviation. Date are expressed as mean |
|Adverse event||n (%)|
|Date are expressed as percentage of group total.|
The dose of sufentanil was used in the up-to-down order. The effective dose was expressed as a square, while the ineffective dose was expressed as a round.
The most important pathophysiological change in severe preeclampsia is systemic vasospasm, which can affect uterine placental perfusion, and it is one of the most serious pregnancy complications of the third trimester . When these patients need a cesarean section, medical staff should strive for the quiet and complete analgesia of puerperants during anesthesia to reduce the stress response. Epidural anesthesia is the most commonly used anesthesia at present. However, approximately 23% of patients will suffer from an incomplete block , which seriously affects the hemodynamic stability of the puerperants. However, in general anesthesia, an abnormal increase in blood pressure will occur during the laryngoscope placement, endotracheal intubation, and extubation, causing hypertension crises and strokes. Patients with severe preeclampsia often have complications with airway edema, which can increase the risk of a difficult airway, resulting in a failure of intubation and ventilation, and difficult airway management is the main cause of morbidity and mortality in patients with preeclampsia . Studies have reported that spinal anesthesia can be used in patients with severe preeclampsia for cesarean sections [16,17], and this has often been used as the anesthesia method for emergency cesarean sections.
The minimum local effective anesthetic dose (MLAD) of sufentanil is equivalent to ED50; that is, the effective dose of analgesics for 50% patients, which has important significance for selecting a suitable dose in clinics. In the present study, the Dixon-Massey method was adopted. Its characteristics are that the sequential trials of subjects were performed one by one, and the dose used for the next subject was determined according to the response of the previous subject. This trial method can concentrate the dosing process close to the most effective reaction rate ED50 to avoid an inefficient reaction rate. The advantage is that it can make full use of the information provided by the data, and it can decrease the number of observation cases by 30%-40% accordingly when compared with other methods . The ED50 value assessed by the up-to-down sequential allocation method represents only a single point along the dose-response curve but does not show the steepness of the curve . In clinical practice, ED95 may be more important.
The dose of ropivacaine was chosen as a reference to the literature . In the
present study, the applied dose of
ropivacaine was 10 mg. Gautier et al. reported that local anesthetic combined
Shivering is a common event during spinal anesthesia for cesarean sections (the incidence occurs in 38%-70.7% of cases) [22,23], and may make the patient feel uncomfortable, increase oxygen consumption, and produce lactic acidosis. The study by De Figueiredo et al.  suggested that the addition of sufentanil to bupivacaine and morphine during spinal anesthesia provided a beneficial effect for the prevention of shivering. Thus, sufentanil could have promising uses as an agent for shivering prevention in parturients. In the present study, the investigators noted that the incidence of shivering was low, and this is consistent with previous studies [5,24].
With the increase in the dose of sufentanil in the subarachnoid space, patients may have a sedative depth significantly correlated to sufentanil dose [25,26]. However, in the present study, the highest level of sedation was level 2, and none of these patients required a strong level of sedation. Although the results of sedation during cesarean sections are controversial, according to the investigators’ experience in clinical practice, the investigators considered that mild to moderate sedation levels can reduce intraoperative anxiety, and that mild sedation below level 2 is beneficial for patients undergoing a cesarean section.
With the increase in the dose of sufentanil, dose-related adverse events, such as pruritus, often occur . Pruritus is a common unwanted side-effect of intrathecal opioid administration that can decrease patient satisfaction with anesthesia. In the present study, the investigators observed that the incidence of pruritus was high (25.5%), which was similar to the results reported by Demiraran et al. . However, its intensity was mild and of short duration. Hence, the treatment was not required.
There were several limitations to the present study. First, the present study was carried out in a single center. Hence, the intraoperative fluid and anesthetic management may differ from those in other institutions. Second, the investigators only analyzed the data from puerperants of the same ethnic group. There may be regional or racial differences in other groups. Hence, similar studies in other countries are needed to confirm this. Third, obstetricians have different surgical experience and skill levels, and these may have an impact on the results. Finally, recent developments in pharmacogenetic research have identified numerous genetic variations that may impact on the analgesic response to opioids . For example, a previous study revealed that women carrying the variant allele of p.118A/G of OPRM1 (G118) had a lower ED50 for sufentanil given for early labor analgesia than women homozygous for the wild-type allele . But in this study, we did not investigate the role of genetic polymorphisms on the ED50 of sufentanil. Future studies in this field are needed.
In summary, in 10 mg of 0.5% isobaric ropivacaine, combined with different
doses of sufentanil in lumbar anesthesia for cesarean sections in patients with
severe preeclampsia, the ED50 of sufentanil was 1.830
Jing Wang and Min Zhou designed the research study. Jing Wang and Li Zhang performed the research. Min Zhou provided help and advice on the experiments. Long-Xin Zhang analyzed the data. Jing Wang, Li Zhang and Min Zhou wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
I would like to express my gratitude to all those who helped me during the writing of this manuscript.
Authors declare that there is no conflict of interest.