The Median Effective Dose of Intrathecal Hyperbaric Bupivacaine for Cesarean Section at Moderately High-Altitude

Introduction

Pregnant women undergo specific physiological changes, including increased intra-abdominal pressure with advancing gestational weeks and reduced CSF volume in the lumbar region.¹ The study identified ED₅₀ estimates for motor block with intrathecal bupivacaine to be 6.9 mg in men and 5.2 mg in women undergoing limb surgery, and 3.4 mg in pregnant women undergoing cesarean delivery under combined spinal epidural block.² These conclusions were all derived from data collected at low altitude.

The population residing in high-altitude regions experiences significant changes in respiratory, circulatory, and hematological systems due to variations in oxygen intake and delivery capacity.³ Long-term chronic hypoxia leads to increased cardiac output and cerebral blood flow, resulting in an elevated cerebrospinal fluid (CSF) volume. Additionally, excessive ventilation alters the acid-base balance of CSF, leading to lower pH values compared to individuals living at low- altitude.^4,5 Study has shown that patients at high-altitude require longer onset time and achieve a lower maximum blockade level with spinal anesthesia compared to patients at low- altitude. Furthermore, they exhibit a higher demand for local anesthetics.⁶

Unfortunately, there is an absence of studies addressing cesarean deliveries in parturients at high-altitude. Insufficient local anesthetic dosage increases the risk of intraoperative pain, while excessive dosage significantly increases the incidence of spinal-induced hypotension (SIH).⁷ Therefore, a quantitative analysis of local anesthetic requirements for spinal anesthesia in high-altitude parturients undergoing cesarean section, along with further comparison to established low-altitude dosage data, is of significant clinical importance for the refinement of anesthetic protocols.

Consequently, we conducted a prospective sequential study to investigate the ED₅₀ dose of bupivacaine for combined spinal epidural anesthesia in elective cesarean section at moderately high- altitude.

Materials and Methods

Study Design

This study was approved by the Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University(IRB2023-131) and People’s Hospital of Yongping County, Yunnan Province (ypxrmyy1120230001), registered in the Clinical Trial Registry Center (ChiCTR2300076935), and conducted at Yongping County People’s Hospital in Yunnan Province from October to December 2023, after obtaining informed consent from parturients. The study recruited singleton parturients undergoing elective cesarean section under Combined spinal- epidural anesthesia. The inclusion criteria were: age between 20 and 40 years, body mass index between 18–28 kg/m², and living locally(altitude of 2000m). Exclusion criteria were: ASA > II, gestational age < 37 weeks, severe pregnancy complications, fetal or placental abnormalities such as premature rupture of membranes, intrauterine growth restriction, and contraindications to spinal anesthesia.

Study Procedure

The parturients including in the study received no preoperative medication. Demographic information, including height, weight, age, gestational weeks, parity, pregnancy complications, etc., was recorded upon entering the operation room. Routine monitoring included non-invasive blood pressure, pulse oximetry, and electrocardiogram monitoring. After the parturient assumed a left lateral position for 5 minutes, the average value of three consecutive measurements of blood pressure (BP) and heart rate (HR) was taken as the baseline value with a 1-minute interval between each measurement. All parturients in the study had an 18G intravenous catheter inserted into the peripheral vein of the upper limb. Combined spinal-epidural anesthesia was performed by a senior anesthesiologist who was not involved in the study, with the parturient in the left lateral position. The L3-L4 intervertebral space was punctured using a needle-in-needle technique, and a pre-determined dose of hyperbaric bupivacaine (3mL) was injected at a uniform speed after confirming the flow of cerebrospinal fluid. After the injection, 0.1 mL of cerebrospinal fluid (CSF) was aspirated back. If the CSF flow is clear, it indicated that the local anesthetic had entered the subarachnoid space, and the aspirated fluid was then injected back into the subarachnoid space. If CSF could not be aspirated smoothly, the parturient was excluded from the study, and the doctor in charge of anesthesia adjusted the medication according to the actual anesthetic effect. A 3–4 cm epidural catheter was inserted into the epidural space in a cephalad direction through the epidural needle. After confirming the absence of blood and cerebrospinal fluid, 3 mL of normal saline was used to rinse the catheter, and no epidural test dose was given. After the anesthesia was completed, the parturient returned to the left lateral by position 15 degrees left tilt of operating table, and oxygen flow at 5L/min was administered through a face mask. Lactated Ringer’s solution was infused intravenously at a dose of 10 mL/kg within 20–30 minutes, followed by a slow infusion to maintain venous patency.

The sensory block was bilaterally tested in each dermatomal level for loss to pinprick sensation every minute after spinal anesthesia. Surgery started when the sensory block level reached T6. If the sensory block level did not reach T6 after 15 minutes of spinal anesthesia or the parturient complained of pain despite reaching the T6 sensory block level before fetal delivery, additional lidocaine was administered epidurally to deepen and extend the sensory block level. Subsequent anesthesia management was carried out at the discretion of the anesthesiologist. The study continued from the time of drug administration into the subarachnoid space until fetal delivery.

During the study, the parturient’s blood pressure, heart rate, and blood oxygen saturation were recorded every 5 minutes, and adverse reactions such as nausea, vomiting, chills were noted. Hypotension was defined as a decrease in SBP of ≥20% from baseline or <90mmHg. Once hypotension occurred, intravenous injection of 50µg of ephedrine was administered for treatment. Bradycardia was defined as <50 beats/min, and intravenous injection of 0.5mg of atropine was given. Ondansetron (3mg) was administered intravenously for nausea and vomiting, and dexmedetomidine (10µg) was administered by drip for chills.

The up-and-down sequential method was used to find the ED₅₀ of bupivacaine. Based on a previous review on dose of 0.75% hyperbaric bupivacaine for spinal anesthesia during cesarean section,⁸ the estimated ED₅₀ dose ranged from 4.7 mg to 9.8 mg. Considering the higher dose estimation and the set dose change gradient of 0.75mg at high-altitude, the initial dose was set at 12mg (1.6mL) of 0.75% bupivacaine (H31022839, Shanghai Hefeng Pharmaceutical Co., Ltd.,) 0.5mL of 10% glucose solution, and diluted with preservative-free normal saline to 3mL. Effective anesthesia was defined as bilateral sensory block level at or above T6 within 15 minutes after spinal anesthesia, and no additional epidural anesthesia was required before fetal delivery. The dose of local anesthetic for the next parturient was determined based on whether the previous case was effective. If the local anesthetic dose was effective in the previous case, the dose for the next case was reduced by a gradient of 0.75mg. If it was ineffective, the dose for the next case increases by a gradient. If a parturient was excluded from the study, the dose for the next case remained unchanged.

The main outcome of the study was the ED₅₀ of hyperbaric bupivacaine for spinal anesthesia. Secondary outcomes included the incidence of bradycardia, hypertension, hypotension, nausea, vomiting, and chills in parturients during the study period.

Statistical Analysis

The sample size of 30 parturients in each group was determined according to a previously published method, which indicated that 20–40 individuals were required to provide a stabilized estimation of the ED₅₀ using the up-down allocation method.⁹ Additionally, according to prior studies, the sample size was regarded as sufficient when six pairs of reversals of sequence were obtained when the up-down allocation method was applied to evaluate the ED₅₀.¹⁰ After 30 parturients were allocated, we also obtained more than six pairs of reversals of sequence. Thus, the sample size in the current study was sufficient to calculate the ED₅₀.

Data analysis was performed using SPSS 22.0 (SPSS, Inc., Chicago, IL, USA) software. Data was presented as number (percentage), median (range), or mean ± SD, where appropriate. According to the statistical rules of the up-and-down sequential experiment, the cases before the first crossover point was excluded from the final statistical analysis. The Dixon up-and-down method and isotonic regression were used to calculate the ED₅₀ and 95% confidence interval(CI). The Dixon up-and-down method is simple and intuitive, and its conclusion is the main result.¹¹ Isotonic regression has the advantages of reducing bias and mean squared error, and is used to validate the accuracy and sensitivity of the main result.¹² P<0.05 indicates statistical significance.

Results

A total of 30 parturients were approached for participation in the study(Figure 1). The parturients had a mean age of 29.07±4.15 years, gestational age of 38.25±1.48 weeks, height of 157.83±4.81 cm, and weight of 69.37±7.92 kg, including 12 primiparas and 18 multiparas. According to the rules of the up-and-down sequential trial, the cases before the first crossover were excluded, and the data of 28 parturients were included in the final statistical analysis.

Figure 1 Sequences of effective and ineffective doses. As assessed using the Dixon up-down analysis the ED50 of hyperbaric bupivacaine was 8.23 mg (95% CI, 6.52–9.32 mg).

The ED₅₀ of hyperbaric bupivacaine was calculated as 8.23 mg (95% CI, 6.52–9.32 mg) using the Dixon up-and-down method. Further validation of the ED₅₀ of hyperbaric bupivacaine was performed using isotonic regression, which yielded a value of 8.39 mg (95% CI, 7.48–9.30 mg).

The incidence of adverse reactions in the parturients during surgery was shown in Table 1. Six women experienced hypotension, while no cases of hypertension, bradycardia, nausea, vomiting, or shivering were observed.

Table 1 Incidence of Intraoperative Adverse Reactions in Parturients

Discussion

In the up-and-down sequential trial, we established the ED₅₀ of hyperbaric bupivacaine for spinal anesthesia during cesarean section in parturients residing at moderately high-altitudes was 8.23 mg (95% CI, 6.52–9.32 mg). To our knowledge, this was the first study to investigate the effective dose for spinal anesthesia during cesarean section in parturients at moderately high-altitude.

We found 13 studies on the ED₅₀ of bupivacaine for spinal anesthesia during cesarean section. Three of these studies reported the ED50 of bupivacaine at low altitude without opioids^13–15, which were comparable to our findings. The altitude of the research sites, the intrathecal solution, the puncture segment and position, and the statistical methods used in the three studies were showed in Table 2. The trial sites were all located at low-altitude, and the reported ED₅₀ of bupivacaine in the three studies were lower than that in our study based on intuitive data comparison.

Table 2 Characteristics of Studies Examining ED50 of Intrathecal Bupivacaine for Cesarean Delivery

One of the studies, by Xiao et al¹⁵ had a study design almost identical to ours (the puncture segment, the intrathecal solution, and the injection time were all consistent), and the cases were parturients living at low altitude region of China (Zhejiang Province). The study found that the ED₅₀ of 0.75% hyperbaric bupivacaine for spinal anesthesia during cesarean section was 7.9 mg, which was significantly lower than that in our study. The only difference was 3 mL of saline injected to epidural space in our study. However, the minimum epidural saline volume that affects the level of sensory block under spinal anesthesia is 7.3 mL (95% CI, 5.5–9.9 mL).¹⁶ Therefore, the epidural administration of 3mL of saline does not have a significant effect on the results, and if it does, it is to reduce the dose of ED₅₀,¹⁷ which narrow the difference in dose between the two studies.

The demographic characteristics of the parturients at moderately high -altitude were similar to those at low- altitude in terms of gestational age, weight, and age. The average height of parturients at moderately high-altitude was shorter than those at low-altitude. Height is a factor that affects the dose of local anesthetics, and the shorter the height, the less the dose of local anesthetics required.¹⁸ Therefore, the difference in requirement for anesthesia in parturients at moderately high- altitude of the same height may be more obvious. A randomized controlled trial comparing the outcomes of parturients at high-altitude and low-altitude is a prospective direction for our future research endeavors.

Previous study conducted a comparison of patients undergoing lower limb surgery at high-altitude versus low-altitude regions, employing spinal anesthesia.⁴ The results showed that compared with patients at moderately high-altitude (altitude of 1890 meters), patients at low- altitude (near sea level) had a shorter onset time of sensory and motor block, longer duration of block, and lower highest block level. It was inferred that patients at moderately high-altitude required more local anesthesia. Our conclusion just validated this inference.

The mechanism that patients at high-altitude need more local anesthetics is not yet fully understood. Long-term residence at high altitudes can cause physiological adaptations to sustain tissue oxygenation amid reduced ambient oxygen levels. These adaptive responses encompass augmented ventilation, heightened pulmonary arterial pressure,¹⁹ an accelerated heart rate, and a diminished stroke volume.²⁰ Concomitant with the increase in hemoglobin concentration, there is an augmentation in red blood cell mass,³ a diminution in plasma volume, and a deceleration in blood flow velocity, while cerebral arterial blood flow and CSF volume rise.^21,22 The CSF volume is an important factor affecting the demand for spinal anesthesia drugs. During spinal anesthesia, a larger CSF volume requires a greater dose of local anesthetic to achieve the same blockage level.²³ Investigations have found that the density of cerebrospinal fluid is positively correlated with the peak level of sensory blockage, and the volume of lumbosacral cerebrospinal fluid is positively correlated with the onset time of motor blockage. Both the density and volume of CSF are determinants in the dissemination of spinal anesthesia, with the latter also bearing upon its duration.^24,25 Additionally, acidification of CSF is a compensatory response to chronic respiratory alkalosis following increased ventilation. A lowered pH increases the amount of local anesthesia in the ionized cationic form, which should act as a potent blocker of sodium channels.²⁶

The study found that blood pressure in patients significantly decreased 10 minutes after spinal administration,²⁷ and 55% of patients experienced hypotension when the dose of hyperbaric bupivacaine exceeded 8 mg.²⁸ In our study, the incidence of hypotension in parturient was 20%, and common adverse reactions such as nausea, vomiting, and shivering did not occur. However, in Xiao’s study,¹⁵ 46% parturients experienced hypotension, and the incidence of related adverse reactions such as nausea and vomiting were 36%, and shivering was 14%. Previous studies have reported that patients at moderately high-altitude have higher mean arterial pressure values at baseline and intraoperation compared with patients at low- altitude.²⁹ Chronic hypoxia leads to an increase in systemic arterial pressure, which is due to the significant activation of the sympathetic nervous system and adaptive changes in tissue hypoxia.³⁰ Hypoxia also increases the secretion of renin in the body, activates the renin-angiotensin-aldosterone system, increases intraglomerular pressure, and raises mean arterial pressure.³¹ The higher incidence adverse reactions such as nausea and vomiting may be related to hypotension. Of course, due to the limit number of sequential trial cases, the incidence of adverse reactions may be biased and requires further analysis and comparison with a larger sample size.

There are some limitations in our study: First, there was no control group of women who lived in low- altitude area at the same time, although the comparable dose data of low- altitude area were searched, it was lack of statistical analysis and persuasive. It is necessary to make a further multi-center study on the comparison of local anesthetic dose between low-altitude and moderately high-altitude. Second, the ED₉₀ obtained in the up-down sequential trial design may be biased, so the study only provided the ED₅₀ dose, and exploring the ED₉₀ dose has more clinical guidance significance. Third, due to the routine, there is no combination of opioids for spinal anesthesia in the study. There is no doubt that the ED₅₀ of hyperbaric bupivacaine will be significantly reduced after the addition of opioids.

Conclusion

The ED₅₀ of 0.75% hyperbaric bupivacaine for spinal anesthesia during cesarean section at moderately high-altitude is 8.23 mg, which is higher than the known ED₅₀ required by parturient at low-altitude. Further research will determine the ED₉₅ of spinal anesthesia for cesarean section at moderately high-altitude in order to better guide clinical practice.