Randomized Double-Blind Study of the Effect of Injectate Temperature on Intrathecal Bupivacaine Dose Requirement in Spinal Anesthesia for Cesarean Delivery

Abstract

BACKGROUND:

Increasing the temperature of intrathecal local anesthetics has been shown to increase the speed of onset and block height of spinal anesthesia. However, how this influences dose requirement has not been fully quantified. The aim of this study was to determine and compare the effective dose for anesthesia for cesarean delivery in 50% of patients (ED₅₀) of intrathecal bupivacaine given at temperatures of 37 °C (body temperature) or 24 °C (room temperature).

METHODS:

Eighty healthy parturients having elective cesarean delivery under combined spinal-epidural anesthesia were randomly assigned to receive intrathecal hyperbaric bupivacaine stored at 37 °C (body temperature group) or 24 °C (room temperature group). The first subject in each group received a bupivacaine dose of 10 mg. The dose for each subsequent subject in each group was varied with an increment or decrement of 1 mg based on the response (effective or noneffective) of the previous subject. Patients for whom the dose was noneffective received epidural supplementation after data collection with lidocaine 2% as required until anesthesia was sufficient for surgery. Values for ED₅₀ were calculated using modified up-down sequential analysis with probit analysis applied as a backup sensitivity analysis. These values were compared and the relative mean potency was calculated.

RESULTS:

The ED₅₀ (mean [95% confidence interval, CI]) of intrathecal hyperbaric bupivacaine was lower in the body temperature group (6.7 [5.7–7.6] mg) compared with the room temperature group (8.1 [7.7–8.6] mg) (P < .05). The relative potency ratio for intrathecal bupivacaine for the room temperature group versus the body temperature group was 0.84 (95% CI, 0.77–0.93).

CONCLUSIONS:

Warming hyperbaric bupivacaine to body temperature reduced the dose requirement for spinal anesthesia for cesarean delivery by approximately 16% (95% CI, 7%–23%).

KEY POINTS.

Question: What is the effect of injectate temperature on the dose requirement of intrathecal bupivacaine when used for spinal anesthesia for cesarean delivery?

Findings: The effective dose in 50% of patients (ED50) was lower when intrathecal bupivacaine was given at body temperature group (mean 6.7 [95% confidence interval, CI, 5.7–7.6] mg) compared with at room temperature (8.1 [7.7–8.6] mg).

Meaning: Warming local anesthetics before intrathecal administration has potential as a simple maneuver to improve effectiveness of spinal anesthesia.

The characteristics of spinal block induced by intrathecal local anesthetics are known to be influenced by several factors including the dose, type, and baricity of drugs given, patient position, and concurrent use of vasopressors.^1–5 Additionally, the temperature of the local anesthetic injectate has also been shown to have an influence. Previous studies have shown that warming intrathecal local anesthetic solutions above room temperature results in more rapid onset of spinal block and/or a higher cephalad level of anesthesia.^6–11 However, this effect has not been fully quantified. In particular, it is not known to what extent the dose requirement of intrathecal local anesthetics may be affected by increasing injectate temperature.

We hypothesized that warming intrathecal hyperbaric bupivacaine to body temperature would reduce the dose requirement for spinal anesthesia. Therefore, we conducted the present study in patients having elective cesarean delivery to determine and compare the effective dose for anesthesia in 50% of patients (ED₅₀) of intrathecal hyperbaric bupivacaine given at body temperature (37 °C) or room temperature (24 °C). We used modified up-down sequential analysis to estimate ED₅₀ values. We compared these values and calculated relative mean potency to quantify the effect of injectate temperature on dose requirement.

METHODS

This randomized, double-blinded, 2-arm parallel, controlled clinical trial was approved by the Ethics Committee of Jiaxing University Affiliated Women and Children Hospital, Jiaxing City, China (protocol number IRB 2021-120), and written, informed consent to participate was obtained from all patients. The trial was registered before patient enrollment at chictr.org.cn (ChiCTR2200059571, principal investigator: F. Xiao, date of registration: May 4, 2022). The study was conducted at Jiaxing University Affiliated Women and Children Hospital, Jiaxing City, China. The first subject was enrolled on June 1, 2022.

We recruited 80 American Society of Anesthesiologists physical status II women with singleton pregnancies who were scheduled for elective cesarean delivery at term. Exclusion criteria included: body mass index (BMI) >35 kg/m², any contraindication to neuraxial anesthesia, and allergy to the drugs studied. Patients were fasted for 8 hours for solid food and 2 hours for clear fluids. No premedication was given. On arrival at the operating room, standard monitoring, including noninvasive blood pressure measurement, electrocardiogram, and pulse oximetry were applied. Baseline blood pressure was determined by calculating the mean of 3 consecutive measurements at 3-minute intervals after a short resting period. We inserted an 18-gauge intravenous cannula into a forearm vein but gave no prehydration.

We randomly allocated patients in a 1:1 ratio to one of 2 groups to receive intrathecal hyperbaric bupivacaine at body temperature (37 °C), or room temperature (24 °C). In the body temperature group, the bupivacaine ampoules (bupivacaine 0.75% Shangdong Husky Pharmaceutical Co, Ltd), all additives (dextrose, saline) and syringes were stored for at least 12 hours before administration in a heated incubator (MIR-H163L, PHC Corporation) in the operating room that was maintained at a thermostatically controlled internal temperature of 37 °C (product-specified accuracy ±0.2 °C). In the room temperature group, the same items were stored for at least 12 hours before administration in the anesthesia drug cart kept in the obstetric operating room that was maintained at a thermostatically controlled room temperature of 24 °C according to usual practice. Randomization codes were created using computer-generated random numbers (Microsoft Excel, Microsoft Corporation) and placed into opaque, sealed, sequentially numbered envelopes by an assistant before the commencement of the study.

Combined spinal-epidural (CSE) anesthesia was administered by an attending anesthesiologist (YP-Z) with patients in the left lateral decubitus position under standard aseptic conditions using a needle-through-needle technique. After skin disinfection with povidone iodine, a 17-gauge Tuohy needle (Lvjian Medical) was inserted into the epidural space using the loss-of-resistance-to-saline technique at the estimated L3–L4 vertebral interspace. A 27-gauge Whitacre spinal needle (Lvjian Medical) was then inserted through the Tuohy needle and correct placement of the tip in the intrathecal space was confirmed by observation of free flow of clear cerebrospinal fluid (CSF). The anesthesiologist, who was blinded to the group, then injected the allocated spinal solution intrathecally >15 seconds and removed the spinal needle. A multi-orifice nylon catheter was then inserted 3 to 4 cm into the epidural space and secured and the patient was immediately positioned in the supine position with approximately 15° of left lateral tilt. For cases where no CSF was identified after inserting the spinal needle, a second attempt was made either by removing the spinal needle, reorienting the bevel of the epidural needle and then reinserting the spinal needle, or by removing both needles and repeating the full procedure. If CSF could still not be detected the patient would be withdrawn from the study and the randomization code reused for the next patient.

The study drugs given intrathecally were prepared out of the sight of the anesthesiologists and the patients by an anesthesia nurse who had been given detailed instructions on the protocol. This person opened a randomization envelope for each patient and prepared the study drug under sterile conditions according to the randomization code. Allocated doses of hyperbaric bupivacaine were prepared by measuring 2 mL of plain bupivacaine 0.75% (15 mg) into a 5-mL syringe and adding 1 mL of dextrose 10% which resulted in a bupivacaine concentration of 0.5%. The appropriate volume of this solution (ranging from 1.0 to 2.0 mL for the studied doses of 5–10 mg) was then added to a 5-mL syringe and finally, normal saline was added as required to result in a final volume of 2.5 mL for all patients.

To minimize temperature loss from exposure to ambient temperature for the bupivacaine and additives in the body temperature group, removal from storage and preparation of study drugs was withheld until the anesthesiologist confirmed the correct placement of the spinal needle in the intrathecal space.

After turning the patient supine, the upper dermatomal sensory level of anesthesia was measured by the anesthesiologist by assessing loss of discrimination to pinprick using a 17-gauge Tuohy needle at the anterior axillary line bilaterally. If there was a discrepancy between sides the lower level was used. These assessments were made every 2 minutes for the first 10 minutes, then every 5 minutes.

If the level of sensory block reached the T5 dermatomal level within 10 minutes after intrathecal injection, surgery was allowed to commence. Otherwise, epidural boluses of 5 mL of lidocaine 2% were given as required until the sensory block at the T5 dermatomal level was achieved, and surgery was allowed to commence. For all patients, intraoperative pain was managed with epidural boluses of 5 mL of lidocaine 2% as required. Effective spinal anesthesia was defined as the achievement of sensory block at the T5 dermatomal level within 10 minutes after intrathecal injection and no requirement for intraoperative epidural supplementation.³ The success or failure of the intrathecal dose for each patient was recorded and was made known to the anesthesia nurse responsible for preparing the study drugs who adjusted the dose as necessary for the next patient.

In each group, the first patient received intrathecal bupivacaine10 mg. The dose of bupivacaine for the next patient was determined by the response (effective or ineffective spinal anesthesia) of the previous patient. If a dose was effective, the dose of bupivacaine for the next patient was decreased by 1 mg whereas if a dose was ineffective, the dose for the next patient was increased by 1 mg.

Hypotension (defined as a decrease in systolic blood pressure to ≤80% of the baseline value or to <90 mm Hg) was treated according to standard institutional practice with intravenous boluses of 100 µg phenylephrine. Bradycardia (defined as a heart rate <50 beats/min) accompanied by hypotension was treated with intravenous boluses of 0.5 mg atropine.

The primary outcome measurement was effective or ineffective spinal anesthesia. We also recorded patient demographics, surgical times, anesthesia characteristics (sensory level, motor block), the incidence of side effects (hypotension, bradycardia, shivering, nausea, and vomiting), and neonatal outcome (1- and 5-minute Apgar scores and umbilical arterial pH).

Statistical Analysis

The sample size of 40 subjects per group was determined based on recommendations that 20 to 40 subjects per group will provide a stable estimate of the ED₅₀ calculated by the modified Dixon up-down method.^12–14 Additionally, calculations using data from our previous study³ that investigated the ED₅₀ of bupivacaine for spinal anesthesia for cesarean delivery showed that ≥16 subjects per group would have ≥90% power to detect a 15% difference in ED₅₀ values for bupivacaine between groups with alpha 0.05.

We estimated values for ED₅₀ with confidence intervals (CIs) for each group using the method described by Choi.¹³ To determine the statistical difference between the estimated values of ED₅₀ in the 2 groups we used overlapping CI methodology, in which differences in group means were considered statistically significant (P < .05) when the 83% CIs did not overlap.^15,16 We used probit regression as a backup sensitivity analysis and calculated the relative median potency ratio using Fieller’s method.¹⁷

For other intergroup comparisons, we used the Kolmogorov-Smirnov test to check the normality of the distribution of continuous variables. Normally distributed data were expressed as mean and standard deviation (SD) and were analyzed with Student t test. Nonnormally distributed data were expressed as median and interquartile range (IQR) and were analyzed using the Mann-Whitney U test. Categorical data were expressed as number (%) and were analyzed using the χ² test or Fisher exact test as appropriate.

Statistical analyses were performed using GraphPad Prism version 8.0 (GraphPad Software Inc), IBM SPSS Statistics for Windows version 22.0 (IBM Corp), and R Package (ED50simulation, Version 0.1.1; https://www.r-project.org/). Values of P < .05 were considered statistically significant.

RESULTS

Patient recruitment and flow are shown in Figure 1. We assessed 86 patients for eligibility. We excluded 2 patients because a low platelet count (<80 × 10⁹/L) precluded neuraxial anesthesia, and 4 patients who declined to participate. No patient was withdrawn because of failure to locate the intrathecal space. A total of 80 patients completed the study and had data analyzed. A total of 18 patients in the body temperature group and 19 patients in the room temperature group required epidural top-ups to achieve adequate block for surgery. Patient characteristics and surgical time are shown in Table 1.

Figure 1.

CONSORT diagram of patient recruitment. CONSORT indicates Consolidated Standards of Reporting Trials.

Table 1.

Patient Characteristics and Surgical Time

	Body temperature group (n = 40)	Room temperature group (n = 40)	P-value
Age (y)	30.2 (4.6)	31.4 (4.2)	0.22
Height (cm)	160.8 (4.2)	160.7 (4.8)	0.92
Weight (kg)	72.5 (8.3)	70.5 (7.2)	0.27
Gestational age (wk)	39.2 (0.8)	39.4 (0.9)	0.44
Surgery time (min)	45.0 (13.3)	45.8 (12.6)	0.082

Data are mean (SD).

Abbreviation: SD, standard deviation.

The sequences of cases are shown in Figure 2. The estimated values for ED₅₀ with CIs are shown in Table 2; absence of overlap of the 83% CIs for the estimates indicates that the mean value for ED₅₀ was significantly lower in the body temperature group (6.7 mg) compared with the room temperature group (8.1 mg). The ED₅₀ values calculated by probit regression were 6.6 (95% CI, 5.0–8.1) mg in the body temperature group and 8.1 (95% CI, 6.4–9.8) mg in the room temperature group. The relative potency ratio for the estimated values of ED₅₀ for the room temperature group versus the body temperature group was 0.84:1 (95% CI, 0.77:1 to 0.93:1). Warming hyperbaric bupivacaine to body temperature reduced the dose requirement for spinal anesthesia for cesarean delivery by approximately 16% (95% CI, 7% 23%).

Figure 2.

Individual responses to intrathecal bupivacaine at corresponding dose in the body temperature group (37 °C) and the room temperature group (24 °C). The effective dose for anesthesia for cesarean delivery in 50% of patients (ED₅₀) of intrathecal bupivacaine estimated using up-down analysis was 6.7 (95% CI, 5.7–7.6) mg in the body temperature group, and 8.1 (95% CI, 7.7–8.6) mg in the room temperature group. The solid horizontal lines show the ED₅₀ values and the dashed horizontal lines show the 95% confidence limits. CI indicates confidence interval; ED_50, effective dose in 50% of patients.

Table 2.

Effective Dose for Anesthesia for Cesarean Delivery in 50% of Patients (ED₅₀) of Intrathecal Bupivacaine

ED50	Body temperature group (n = 4)	Room temperature group (n = 40)
Mean	6.7 mg	8.1 mg
95% confidence interval	5.7–7.6 mg	7.7–8.6 mg
83% confidence interval	6.1–7.2 mg	7.9–8.4 mg

Absence of overlap of the 83% confidence intervals indicates a significant difference between mean values at the 0.05 alpha level.

Abbreviation: ED_50, effective dose in 50% of patients.

There were no significant differences in the incidences of maternal side effects (hypotension, bradycardia, shivering, nausea, or vomiting) or neonatal outcome between groups.

DISCUSSION

Our results showed that the dose requirement of hyperbaric bupivacaine for spinal anesthesia for cesarean delivery was significantly reduced when given at body temperature (37 °C) compared with room temperature (24 °C). The relative potency ratio for the values of ED₅₀ under the study condition was 0.84:1. No significant differences were found in side effects and neonatal outcomes.

Previous studies have shown that increasing the temperature of local anesthetics enhances the speed of onset and/or the maximum cephalic spread of spinal anesthesia.^6–11 Warming local anesthetics has also been shown to enhance the onset of epidural labor analgesia.¹⁸ However, the clinical relevance of these findings is uncertain because no previous study has quantified this effect in terms of dose requirement. Our results showing an estimated relative potency ratio of 0.84:1 suggest that warming the injectate reduced the dose requirement of bupivacaine by approximately 16%. This finding has potential clinical significance as a simple method for enhancing the efficacy of spinal anesthesia.

The mechanism by which warming increases the effectiveness of intrathecal local anesthetics has been suggested to involve several factors. Arai et al⁷ postulated that warming local anesthetics increases the kinetic energy of the local anesthetic molecules resulting in greater molecular motion and spread of anesthesia. The same authors reported that warming hyperbaric bupivacaine decreased its viscosity which may also influence spread.⁷ Heller et al¹⁹ and McLeod²⁰ showed that increasing the temperature of local anesthetics decreased their density, although this was not confirmed by Arai et al⁷ CSF density has been shown to correlate positively with maximum height of spinal block with intrathecal bupivacaine^20,21; the relevant factor is likely the difference in density between bupivacaine and CSF, possibly by an effect on baricity of the local anesthetic.²¹ Additionally, it is likely that the effect of baricity may be influenced by the patient’s position during the block procedure with a greater effect when the block is administered with patients in the sitting position compared with the lateral position. Sanchez et al²² showed that increasing the temperature of lidocaine decreased its pKa. Lower pKa of local anesthetics is associated with a greater unionized drug fraction and a greater amount of lipid-soluble base available to cross neuronal membranes.²³

Although placing drugs in a warming incubator or cabinet is a simple maneuver to increase the effectiveness of intrathecal local anesthetics, it should be noted that our investigation was performed under controlled research conditions. Arai et al⁷ reported that the temperature of hyperbaric bupivacaine decreased from 36.9 °C to 36.6 °C after 50 seconds when it was removed from warmed storage to room temperature. In our study, to minimize temperature loss of the bupivacaine in the body temperature group after exposure to ambient room temperature, we did not remove drugs, additives, and syringes used to prepare the injectate from the warming incubator until the correct placement of the spinal needle in the intrathecal space was confirmed by the anesthesiologist. In actual clinical practice, such a step may not always be practical. It would be of interest to repeat our study under “real world” conditions to determine the generalizability of our results to normal clinical conditions. Such a study could be performed by removing warmed drugs from the incubator based on convenience and work flow. Further clinical relevance might also be achieved by adopting a pragmatic study design that did not restrict intrathecal drug choice or dose.²⁴

There may be concerns about the stability of local anesthetics that are stored at high temperatures,²⁵ and it is common for pharmaceutical companies to recommend that drugs be stored within a specified temperature range (eg, 20–25 °C).²⁶ However, Huang et al²⁷ reported that there was no degradation of hyperbaric bupivacaine after storage at 65 °C for 72 hours. Nevertheless, we would consider it prudent to limit the exposure time of local anesthetics to high temperatures, for example by placing them in warming incubators only hours or a day before use, and to acknowledge that this practice may be “off label.” Extrapolation of our results would also suggest that it may be advisable to avoid intrathecal administration of local anesthetics that have been stored at cold temperatures without time to equilibrate to ambient temperature as this could potentially reduce their effectiveness.

The method of injectate preparation used in our study resulted in the different dose groups of bupivacaine having varying concentrations of dextrose (ranging from 1.33% to 2.67% for studied bupivacaine doses of 5–10 mg). This would have resulted in varying baricity of the solutions across dose groups which may have affected the relative effect of temperature for each dose group. However, because this effect would have been common across both groups, we do not consider that this would have significantly affected our main findings. It is possible that there may be a difference in the effect of temperature on the effectiveness of commercial preparations of hyperbaric bupivacaine which have higher dextrose concentration, typically in the range of 8.0% to 8.25%, and thus greater baricity compared with our studied doses. However, increasing temperature has also been shown to enhance the effectiveness of plain bupivacaine for spinal anesthesia,¹¹ so it may be unlikely that the enhancing effect of warming intrathecal local anesthetics is significantly dependent on dextrose concentration.

We administered anesthesia to patients in the left lateral decubitus position in keeping with our normal clinical practice. It would be of interest to repeat our study with administration of anesthesia with patients in the sitting position which is common practice in many other centers around the world.²⁸

We conducted this study according to a double-blinded design. However, we cannot exclude the possibility that the patients may have been aware of the temperature of the solution being injected intrathecally or that the anesthesiologist performing CSE anesthesia may have been able to feel the temperature of the syringe containing the local anesthetic through surgical gloves. However, because of the objective nature of the main outcome measure of the study, we do not consider that any deficiencies in blinding would have had a material effect on our results.

In our study, the drugs were warmed in an incubator that was already in the operating room as part of standard equipment for warming other materials (eg, irrigation fluids). Therefore no extra equipment costs were incurred. We expect that around the world most modern operating rooms would have similar warming cabinets; however, if not, it is unlikely to be cost-effective to install warming incubators specifically for warming drugs for spinal anesthesia.

We would emphasize that our study was designed to determine the difference in potency and dose requirement of bupivacaine administered at different temperatures, and was not designed to be a dosing guide. Accordingly, we determined values for ED₅₀ which is the usual reference choice to describe drug potency.²⁹ At this point, the dose-response curves for drugs are steepest and thus the effect of independent factors such as temperature are more readily able to be detected and quantified. Values for doses higher on the dose-response curve (eg, ED₉₅) would be considered a better choice to inform clinical practice; further research on this would be of interest. Finally, we did not add a lipophilic opioid to the bupivacaine dose which is a common practice for spinal anesthesia for cesarean delivery in many centers.²⁸ Although it is possible that temperature may influence the efficacy of intrathecal opioids by an effect on cephalad spread or spinal cord penetration, we are not aware of any studies that have investigated this.

ACKNOWLEDGMENTS

The authors would like to thank the staff in the Department of Operation Room of Jiaxing University Affiliated Women and Children Hospital, Jiaxing, Zhejiang, China, for their help and cooperation with this study and Warwick D. Ngan Kee, Clinical Professor (Honorary), Department of Anaesthesia and Intensive Care, The Chinese University Hong Kong, Hong Kong, China, for assistance with article preparation.

DISCLOSURES

This manuscript was handled by: Jill M. Mhyre, MD.