Abstract
Background and Aims:
Vasopressor usage can affect the rostral spread of intrathecal drug and, hence, its requirement during cesarean delivery. Although a decreased spread is evidenced with phenylephrine, there is no data for norepinephrine usage. The present study aimed to evaluate the minimum effective dose of intrathecal hyperbaric bupivacaine for cesarean section with and without prophylactic norepinephrine infusion.
Material and Methods:
Patients scheduled for elective cesarean section under combined spinal–epidural block were randomized to receive intravenous infusion of norepinephrine (0.05 μg/kg/min) or normal saline (placebo), initiated immediately after intrathecal injection. Postspinal hypotension in either group (systolic arterial pressure ≤0.8 baseline) was treated with norepinephrine 4 μg rescue. Dose of intrathecal hyperbaric bupivacaine (0.5%) was decided for individual patients using up-and-down sequential allocation method. Primary outcome measure was the minimum effective dose of intrathecal hyperbaric bupivacaine (0.5%) defined as ED50, while secondary observations included spinal block characteristics and neonatal outcomes.
Results:
Demographic parameters were statistically similar between both groups (P > 0.05). ED50 of intrathecal hyperbaric bupivacaine was 7.8 mg (95% confidence interval [CI]: 6.7–8.8) and 7.4 mg (95% CI: 6.1–8.7) for normal saline and norepinephrine group respectively (P = 0.810). Block characteristics were similar between both groups as was neonatal APGAR score, but umbilical artery base excess was greater for norepinephrine versus normal saline group (−4.4 ± 3.6 vs. −6.5 ± 2.4, P = 0.038).
Conclusion:
Use of prophylactic norepinephrine (0.05 μg/kg/min) during cesarean delivery does not require adjustment of intrathecal hyperbaric bupivacaine.
Keywords: Cesarean section, ED50, intrathecal dose, norepinephrine, vasopressor
Introduction
Postspinal hypotension remains a common adverse effect during cesarean section and is associated with undesirable maternal and fetal consequences.[1,2] Various methods are employed to prevent as well as treat postspinal hypotension, and vasopressors continue to be a mainstay of therapy. Commonly used vasopressors for managing postspinal hypotension include ephedrine and phenylephrine, while more recently, norepinephrine has also been investigated.[2] Norepinephrine acts as a vasopressor by virtue of strong α-adrenergic receptor effect and it has relatively weak β-adrenergic agonist action. While phenylephrine is the preferred agent due to supporting data, several studies have demonstrated the efficacy of norepinephrine infusion as a vasopressor during cesarean section.[3,4,5,6,7,8,9,10] Norepinephrine has been noted to be an alternative to phenylephrine, although the concerns about its use in a nonintensive care setting such as the labor ward is discouraged and warned against.[2]
Vasopressor therapy during cesarean section may affect the spread of intrathecal local anesthetic.[11,12] In earlier studies, phenylephrine infusion showed a decreased rostral spread of plain as well as hyperbaric local anesthetic.[11,12] The reason was postulated to be a constriction of the epidural venous plexus, thereby increasing the compliance of epidural space, lowering the intrathecal pressure, and thus reducing the spread of intrathecal injection. Consequent to the decreased rostral spread of intrathecal local anesthetic with phenylephrine infusion, the effect on dose requirement of the intrathecal local anesthetic for cesarean section was also investigated.[13,14,15,16,17,18] An increased intrathecal dose requirement was noted in these studies.There is, however, no data regarding the effect of norepinephrine infusion on the intrathecal drug spread or dose requirement.
Thus, we aimed to evaluate the effect of norepinephrine infusion on dose requirement of intrathecal hyperbaric bupivacaine for elective cesarean section. Herein, the dose requirement of hyperbaric bupivacaine is defined as the minimum effective dose and assessed as ED50 (dose expected to be effective in 50% of the target population), with and without an intravenous norepinephrine infusion titrated to maintain blood pressure.
Material and Methods
The present randomized triple-blinded study was conducted from January 2021 to April 2022 after obtaining approval from the Institutional Ethical Committee (meeting held on 12.19.2020; ref no IECHR/2020/PG/47/14-R1), as well as written informed consent from all patients. It was prospectively registered with the Clinical Trial Registry of India (CTRI/2021/01/030748; registered on 01.25.2021; https://ctri.nic.in).
Patients with uncomplicated, singleton term pregnancy scheduled for elective cesarean section under combined spinal–epidural were included. Those with body mass index >30 kg/m2, preeclampsia, history of diabetes mellitus, cardiovascular or cerebrovascular diseases, or any contraindication to the combined spinal epidural block were excluded.
Randomization to one of the following two groups was done using computer-generated random number table: the norepinephrine group (prophylactic intravenous infusion of the drug) and the control (saline) group (0.9% normal saline infusion at the same rate). Randomization was concealed using sealed opaque envelopes.
In the operating room, monitoring included lead II electrocardiography, oscillometric noninvasive blood pressure measurements, and pulse oximetry. Baseline systolic arterial pressure and heart rate were calculated as an average of two readings taken 5 min apart, with less than 10% variation. Co-loading using 10 ml/kg of Ringer’s lactate was done while the patient received a combined spinal epidural block. For the block, an 18-G Tuohy and 27-G Whitacre spinal needle were used, with the needle-through-needle technique performed at L3–L4 or L4–L5 interspace in a sitting position. The epidural space was identified with loss of resistance to air technique limiting the volume of air to <2 ml and keeping orifice of spinal needle pointed cephalad. Intrathecal solution was injected over 10–15 s, and epidural catheter was threaded through 4 cm into the epidural space, but no injections were made through it at this time. Patient was turned supine with a 15° tilt to the left side and oxygen administered at 4 l/min. Time of completion of intrathecal injection was noted. Blood pressure was recorded every 2 min till delivery of baby, followed by intervals of 5 min.
The up-and-down sequential allocation method was used to determine the dose of intrathecal hyperbaric bupivacaine (0.5%). The first patient in both groups received 8 mg of hyperbaric bupivacaine (0.5%) with 10 μg fentanyl. This starting dose of 8 mg was chosen from a similar methodology adopted in our earlier work evaluating the effect of phenylephrine, albeit on a plain local anesthetic.[14] The dose is also similar to the starting dose for hyperbaric formulation of bupivacaine used in another study in the same area and using up-and-down study design.[16] In subsequent patients, the dose was decreased/increased by 1 mg following an adequate/inadequate block respectively in previous patient of the particular group. Herein, an adequate block was defined as sensory block to T6 level along with a Bromage score of 2 or 3 achieved within 15 min of intrathecal injection. The sensory level of block was assessed by complete loss of sensation to pinprick in the midline, and Bromage score was used to quantify motor block (grade 0 = no motor blockade, 1 = unable to flex hip, 2 = unable to flex knee, and 3 = unable to flex ankle).
Sensory and motor block characteristics were noted every 3 min until three identical sensory block readings were obtained, or 15 min after supine position, whichever was later. After this time, block (sensory and motor) assessment was continued every 15 min intraoperatively, followed by every 30 min postoperatively till the sensory block receded by two or more dermatomes. All assessments were done by an anesthesiologist unaware of the intrathecal dose administered, and were performed till the time before epidural supplementation (for adequate as well as inadequate blocks).
In case the intrathecal block was inadequate, or if intraoperative pain occurred (visual analog scale [VAS] >3), epidural injections of bupivacaine (0.5%) were used in increments of 3–5 ml. The anesthesiologist, obstetrician, as well as patient were blinded to the nature of the intravenous infusion, that is, test (norepinephrine) or control (normal s aline), and the infusion was titrated according to patient’s blood pressure as per the following protocol. The intravenous infusion was initiated at 50 ml/h in both groups using a syringe infusion pump (for norepinephrine group, the 50 ml contained entire hourly dose calculated at 0.05 μg/kg/min). The rate of infusion was doubled or halved to maintain the systolic arterial pressure near patient’s baseline value. Whenever the pressure increased above 1.2 times the baseline value the infusion was stopped, and it was restarted at half the rate when the pressure decreased below 1.2 times of baseline value. Fall in systolic arterial pressure to ≤0.8 times of baseline value or <100 mmHg was treated using rescue bolus of intravenous norepinephrine 4 μg (prepared as 4 μg/ml). Bradycardia was defined as a heart rate <60/min with hypotension or <50/min and was treated with 0.2 mg glycopyrrolate given intravenously.
The infusion was administered from completion of intrathecal injection till fetal delivery. It was prepared by an uninvolved anesthesiologist.
The choice of norepinephrine infusion dose was based on published literature at the time of conceptualization of the study. Several studies have evaluated the optimal dose and efficacy of prophylactic norepinephrine infusion during cesarean section.[3,4,5,6,7,8,9,10] Among these, 0.07 μg/kg/min was noted as an optimal dose.[8] On closer scrutiny, however, 0.05 μg/kg/min appeared to be more commonly used,[4,7] with an incidence of hypotension similar to the increased dose of 0.07 μg/kg/min.[7] Thus, we had decided to use norepinephrine infusion in the dose of 0.05 μg/kg/min, titrated to maintain the baseline blood pressure of the patient.
Baseline characteristics, uterine incision to baby delivery time, time of epidural supplementation, need of norepinephrine bolus or glycopyrrolate, total dose of norepinephrine infusion, the Appearance, Pulse, Grimace, Activity and Respiration (APGAR) scores at 1 and 5 min, umbilical artery pH/base excess, and neonatal birth weight were also noted. Maximum level of sensory and motor block, time from completion of intrathecal injection to positioning the patient supine, attaining an adequate block, maximum sensory and motor block, and two-segment sensory block regression were recorded as well.
Statistical analysis and sample size calculation
ED50 (95% confidence interval [CI]) was calculated using the formula of Dixon and Massey and compared between both groups using t-test.[19] The Kolmogorov-S mirnov test was used to analyze quantitative data for normal distribution. Intergroup comparison of normally distributed quantitative data was done using the unpaired t-test, and non-normal data were compared between groups using the Mann–Whitney test. Intergroup comparison of qualitative/discrete data was done using the Chi-square or Fischer’s exact test as appropriate. For intergroup comparison of repeated variables (heart rate and systolic blood pressure), the general linear model was used. P-value <0.05 was considered significant.
Using the up-and-down methodology, six pairs of reversal constitute an adequate sample size.[19] Therefore, the recruitment had to continue till six such pairs were met in both groups. As a backup measure, a minimum of 40 patients were to be randomized to both groups (n = 20 in each).
Results
A total of 52 patients were evaluated for possible inclusion, and 40 of these were finally enrolled [Figure 1]. The sequences of doses for adequate and inadequate blocks in both groups are shown in Figure 2.
Figure 1.
CONSORT flow chart. BMI = body mass index
Figure 2.
Sequence for doses of hyperbaric bupivacaine in (a) normal saline and (b) norepinephrine group (with ED50). ◊Inadequate block; ♦Adequate block
ED50 of intrathecal hyperbaric bupivacaine was 7.8 (95% CI: 6.7–8.8) for the normal saline group and 7.4 (95% CI: 6.1–8.7) for the norepinephrine group (P = 0.810).
The baseline characteristics were statistically similar between both groups (P > 0.05) [Table 1].
Table 1.
Baseline characteristics
| Normal saline group (n=20) | Norepinephrine group (n=20) | P | |
|---|---|---|---|
| Age (years) | 26.9±4.4 | 27.8±4.9 | 0.544 |
| Weight (kg) | 59.1±7.9 | 62.6±9.2 | 0.214 |
| Height (cm) | 152.4±5.346 | 152.8±6.5 | 0.833 |
| Body mass index (kg/m2) | 25.3±3.1 | 26.6±3.0 | 0.197 |
| Gravidity | 2 [2–3] | 2 [2–3] | 0.504 |
| Parity | 1 [1–1] | 1 [1–2] | 0.367 |
| Period of gestation (weeks) | 38.4±1.2 | 38.6±1.2 | 0.494 |
| Baseline systolic blood pressure (mmHg) | 126.9±9.5 | 124.4±7.1 | 0.362 |
| Baseline heart rate (/min) | 93.8±16.3 | 94.3±15.0 | 0.928 |
Values are mean±SD or median [IQR]. IQR=Interquartile range, SD=Standard deviation
Spinal block characteristics among patients with adequate block were also statistically similar between both groups (P > 0.05) [Table 2]. From among those who developed an adequate block, epidural supplementation was required intraoperatively in three patients each in both groups. The time of epidural supplementation that was calculated from intrathecal block completion was 57, 62, and 64 min for norepinephrine group patients and 52, 52, and 33 min for normal saline group patients.
Table 2.
Details related to block characteristics among patients with adequate block
| Normal saline group (n=20) | Norepinephrine group (n=20) | P | |
|---|---|---|---|
| Ts (s) | 155 [126–170] (60–185) | 126 [105–187] (82–240) | 0.910 |
| Time of achieving adequate block (min) | 10.1 [8.0–12.0] (6–14) | 10.0 [8.0–13.7] (8–15) | 0.677 |
| Maximum sensory block level | T5 [3–5] (T3–T6) | T5 [5–5] (T3–T6) | 0.337 |
| Time to maximum sensory level (min) | 12 [8–12] (6–15) | 10.5 [8–12] (6–12) | 0.381 |
| Time to two-segment regression (min) | 60 [45–60] (45–75) | 45 [45–60] (45–75) | 0.515 |
| Maximum motor block (Bromage score) | 3 [3–3] (3–3) | 3 [3–3] (3–3) | 1.000 |
| Time to maximum motor blockade (min) | 3 [3–6] (0–6) | 4.5 [3–6] (0–9) | 0.385 |
Values are median [IQR] (range). IQR: Interquartile range, Ts: Time from completion of intrathecal injection to positioning the patient supine
The duration and volume of the vasopressor/saline infusion were statistically similar between both groups (P > 0.05) [Table 3]. The median amount of norepinephrine used as infusion was 67.1 μg (47.5–93.6) for the norepinephrine group [Table 3]. The number of norepinephrine boluses required to manage severe hypotension (0.8 times or lower of baseline, or <100 mmHg) was significantly greater for the normal saline group compared to norepinephrine group (P = 0.032) [Table 3]. The incidence of bradycardia and dose of glycopyrrolate to treat it were clinically greater for the normal saline group, though they were statistically similar between both groups (P > 0.05) [Table 3].
Table 3.
Details of vasopressor and related management
| Normal saline group (n=20) | Norepinephrine group (n=20) | P | |
|---|---|---|---|
| Duration of infusion (intrathecal injection to baby delivery) (min) | 20.0 [14.0–25.0] (6.0–34.0) | 22.0 [16.5–24.5] (14.0–64.0) | 0.341 |
| Volume of infusion (ml) | 15.0 [12.0–21.0] (4.0–27.0) | 18.0 [12.7–22.0] (6.0–56.0) | 0.343 |
| Total dose of norepinephrine as infusion (µg) | 0 | 67.1 [47.5–93.6] (25.6–201.6) | - |
| Number of norepinephrine boluses | 2 [0–5] (0–9) | 0 [0–2] (0–5) | 0.032 |
| Bradycardia | 5 (25) | 1 (5) | 0.182 |
| Dose of glycopyrrolate (mg) | 0.2 [0.2–0.5] (0.2–0.6) | 0.2 [0.2–0.2] (0.2–0.2) | 0.488 |
Values are mean±SD or median [IQR] (range). IQR=Interquartile range, SD=Standard deviation
The baby weight, APGAR scores at 1 and 5 min, and umbilical artery pH were statistically similar between both groups (P > 0.05) [Table 4]. The base excess was significantly greater for the norepinephrine group compared to the normal saline group (P = 0.038) [Table 4].
Table 4.
Neonatal characteristics
| Normal saline group (n=20) | Norepinephrine group (n=20) | P | |
|---|---|---|---|
| Baby weight (kg) | 2.5±0.4 | 2.7±0.4 | 0.353 |
| APGAR score (1 min) | 9 [9–10] (9–10) | 9 [9–10] (9–10) | 0.513 |
| APGAR score (5 min) | 10 [10–10] (10–10) | 10 [10–10] (10–10) | 1.000 |
| Umbilical artery pH | 7.28±0.06 | 7.30±0.04 | 0.296 |
| Umbilical artery base excess | −6.5±2.4 | −4.4±3.6 | 0.038 |
| Uterine incision–baby delivery (min) | 2 [1–2] (1–4) | 2 [2–2] (1–4) | 0.211 |
Values are mean±SD or median [IQR]. IQR=Interquartile range, SD=Standard deviation
Intergroup comparison for repeated values of heart rate and systolic blood pressure was done for up to 12 min after making the patient supine. There were no differences in heart rate or systolic blood pressure at any of the compared time points (P = 0.326 and P = 0.536, respectively).
Discussion
The present study was designed to evaluate the effect of prophylactic norepinephrine infusion on dose requirement of intrathecal hyperbaric bupivacaine during elective cesarean section. The salient finding included a lack of any significant difference in the dose requirement (ED50) of intrathecal hyperbaric bupivacaine during elective cesarean section when administered with or without intravenous prophylactic norepinephrine infusion. As corroborative evidence, there was no significant difference in the characteristics of sensory and motor blockade as well.
In contrast, previous data evaluating intrathecal dose requirement during cesarean section shows a significant increase in ED50 with prophylactic vasopressor infusion.[14,15,16,17,18] The mechanism of action for the dose-enhancing effect of prophylactic vasopressor is the vasoconstriction of veins in the epidural space, which thereby increases the compliance of epidural space, lowers the intrathecal pressure, and reduces spread of intrathecal injection or, in turn, increases the dose requirement.[11,12,13,14,15,16,17,18]
There could be various reasons for the contrasting results noted in our study.
Firstly, none of the previous studies documenting increased intrathecal dose requirement used norepinephrine as the vasopressor. Rather, all evaluated the effect of phenylephrine, either against normal saline or ephedrine.[11,12,13,14,15,16,17,18] Norepinephrine could have a different effect compared to phenylephrine with regards to epidural venoconstriction. This is similar to an earlier observation that phenylephrine may constrict the engorged lumbar epidural veins to a greater extent than another vasopressor popular at that time, viz., ephedrine.[11,12] A difference in the effects of phenylephrine and ephedrine on intrathecal drug spread and hence the cephalad level of block has been previously noted.[11] It was noted that phenylephrine caused a significantly lesser rostral spread of the intrathecal drug, probably consequent to greater vasoconstriction than ephedrine.[11] Our speculation of a difference in the vasoconstrictive effects of norepinephrine compared to phenylephrine can be answered only by further research comparing the two agents in equipotent doses for their effect on intrathecal dose requirement.
Secondly, the lack of association between norepinephrine infusion and intrathecal dose may be attributed to the amount of vasopressor used by us. We used norepinephrine infusion in a dose of 0.05 μg/kg/min, that was titrated intraoperatively to maintain the systolic maternal blood pressure near baseline value. The doses of norepinephrine evaluated as a prophylactic vasopressor during cesarean section range from 0.05 to 0.24 μg/kg/min.[6,7,8,10,20,21] The optimal dose has been variably noted to be 0.05 μg/kg/min,[7] or 0.07 μg/kg/min,[7,8] or 0.08 μg/kg/min,[21] or 0.09 μg/kg/min,[20] or 0.16 μg/kg/min.[10] Thus, the recommended dose appears to vary from 0.05 to 0.16 μg/kg/min, spanning an almost 10 times increase from the lowest dose. We had chosen 0.05 μg/kg/min since this was most often recommended. It is well known that the vasoconstriction caused by norepinephrine is a dose-dependent phenomenon.[22] Whether doses higher than the amount used by us will produce different results due to greater vasoconstriction of epidural veins will need further evaluation.
The pharmacology of norepinephrine supports our hypothesis that a greater dose may, indeed, produce a different result than the present one. Norepinephrine has potent α-1 and weak β receptor activity.[2] It acts as a vasoconstrictor by its α-1 activity. At low doses (less than 2 μg/min), the β-1 effects of norepinephrine may be more pronounced and increase the cardiac output, while at doses higher than 3 μg/min, the α-1 effects may predominate.[23] The total dose of norepinephrine used by us, that is, 67.1 μg (47.5–93.6), over a duration of 22.0 min (16.5–24.5) translates to a median of 3 μg/min (67.1/22). Thus, it implies that the dose used by us is on the lower end of spectrum as far as vasoconstriction is concerned. This supports the speculation that lack of significant increase of intrathecal dose requirement with norepinephrine infusion could be a result of the dose of the vasopressor used by us.
Although there is no previous data regarding the effect of norepinephrine infusion on intrathecal dose requirement, there are suggestions from studies using phenylephrine that the association may, indeed, be dose dependent. Previous studies evaluating the effect of prophylactic phenylephrine on the intrathecal dose requirement compared it to either a normal saline control group[14,15,16,17,18] or ephedrine.[13] Among these, the ones noting a significantly greater requirement of intrathecal drug with use of phenylephrine had infused it at doses of 0.7 μg/kg/min,[17,18] or 0.8 μg/kg/min,[15,16] or 1.0 μg/kg/min.[14] In contrast, the only study that failed to document a significant effect of phenylephrine infusion on intrathecal dose requirement used it in a much lower amount of approximately 0.2 μg/kg/min.[13] We calculated these doses in equivalents of μg/kg/min from the concentration and rate of infusion as well as the average body weight reported in each study. Thus, even when evaluating phenylephrine infusion for its effect on intrathecal dose requirement, there appears to be a dependence on the amount of the vasopressor used. This further supports that norepinephrine should be evaluated in the various clinically recommended doses, currently documented up to 0.16 μg/kg/min.[10]
As ancillary observations, we noted that the number of rescue blouses of norepinephrine (4 μg i.v.) was significantly lesser and the umbilical artery base excess was better preserved for the group where we used vasopressor infusion (P = 0.032 and 0.038, respectively). It thus appears that use of a prophylactic norepinephrine infusion to prevent postspinal hypotension during cesarean section is more effective than use of therapeutic boluses only. Even though the systolic blood pressure was treated at value of <0.8 of the baseline value in both groups, maintaining it nearer to baseline with norepinephrine infusion proved more efficacious in terms of fetal acid–base equilibrium. Hence, the role of prophylactic vasopressors may be more beneficial than therapeutic doses during cesarean section as previously documented.[2]
Bolus doses of norepinephrine were administered whenever systolic blood pressure dropped to <80% of baseline or <100 mmHg in either group. This implies that the present results may also be interpreted as a comparison of the effect for preventive infusion versus therapeutic bolus regimens of norepinephrine on intrathecal dose requirement.
The present study has certain limitations. Firstly, it evaluated only a single dose of norepinephrine infusion. Since there was no previous data at the time of conceptualization of the study, we used only the lowest and the most commonly recommended dose of norepinephrine for cesarean section. Thus, the results are applicable only to norepinephrine used in a dose of 0.05 μg/kg/min. Secondly, the present study design using the up-and-down sequential allocation method is beneficial for determining ED50. We evaluated ED50 to enable comparison with previous seminal studies on the topic that preferentially used ED50.[13,14,15,16,17,18] In clinical practice, ED90 or ED95 is required, so as to minimize failed responses. Further studies may be based on modifications of the up–down method that are better suited for such extremes of effective doses, for example, the biased allocation design. Lastly, it needs to be pointed out that the intrathecal dose requirement (ED50 or 90 or 95) will be affected by the definition used to describe an adequate block when using a sequential allocation method for dose determination.
Based on the present observations, we recommend that when using an intravenous norepinephrine infusion (0.5 μg/kg/min) titrated to maintain blood pressure during elective cesarean section, there is no need to adjust the intrathecal dose of hyperbaric bupivacaine. Further studies evaluating other doses of norepinephrine are required for establishing a dose–response relationship.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
- 1.Ngan Kee WD, Khaw KS, Lee BB, Lau TK, Gin T. A dose response study of prophylactic intravenous ephedrine for the prevention of hypotension during spinal anaesthesia for delivery. Anesth Analg. 2000;90:1390–5. doi: 10.1097/00000539-200006000-00024. [DOI] [PubMed] [Google Scholar]
- 2.Kinsella SM, Carvalho B, Dyer RA, Fernando R, McDonnell N, Mercier FJ, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia. 2018;73:71–92. doi: 10.1111/anae.14080. [DOI] [PubMed] [Google Scholar]
- 3.Ngan Kee WD, Lee SWY, Ng FF, Khaw KS. Prophylactic norepinephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anesth Analg. 2018;126:1989–94. doi: 10.1213/ANE.0000000000002243. [DOI] [PubMed] [Google Scholar]
- 4.Hasanin A, Amin S, Refaat S, Habib S, Zayed M, Abdelwahab Y, et al. Norepinephrine versus phenylephrine infusion for prophylaxis against post-spinal anaesthesia hypotension during elective caesarean delivery: A randomised controlled trial. Anaesth Crit Care Pain Med. 2019;38:601–7. doi: 10.1016/j.accpm.2019.03.005. [DOI] [PubMed] [Google Scholar]
- 5.Ngan Kee WD, Lee SW, Ng FF, Tan PE, Khaw KS. Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery. Anesthesiology. 2015;122:736–45. doi: 10.1097/ALN.0000000000000601. [DOI] [PubMed] [Google Scholar]
- 6.Vallejo MC, Attaallah AF, Elzamzamy OM, Cifarelli DT, Phelps AL, Hobbs GR, et al. An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery. Int J Obstet Anesth. 2017;29:18–25. doi: 10.1016/j.ijoa.2016.08.005. [DOI] [PubMed] [Google Scholar]
- 7.Hasanin AM, Amin SM, Agiza NA, Elsayed MK, Refaat S, Hussein HA, et al. Norepinephrine infusion for preventing postspinal anesthesia hypotension during cesarean delivery: A randomized dose-finding trial. Anesthesiology. 2019;130:55–62. doi: 10.1097/ALN.0000000000002483. [DOI] [PubMed] [Google Scholar]
- 8.Wei C, Qian J, Zhang Y, Chang X, Hu H, Xiao F. Norepinephrine for the prevention of spinal-induced hypotension during caesarean delivery under combined spinal-epidural anaesthesia: Randomised, double-blind, dose-finding study. Eur J Anaesthesiol. 2020;37:309–15. doi: 10.1097/EJA.0000000000001152. [DOI] [PubMed] [Google Scholar]
- 9.Xu S, Mao M, Zhang S, Qian R, Shen X, Shen J, et al. A randomized double-blind study comparing prophylactic norepinephrine and ephedrine infusion for preventing maternal spinal hypotension during elective cesarean section under spinal anesthesia: A CONSORT-compliant article. Medicine (Baltimore) 2019;98:e18311. doi: 10.1097/MD.0000000000018311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Chen D, Qi X, Huang X, Xu Y, Qiu F, Yan Y, et al. Efficacy and safety of different norepinephrine regimens for prevention of spinal hypotension in cesarean section: A randomized trial. Biomed Res Int. 2018;2018:2708175. doi: 10.1155/2018/2708175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cooper DW, Jeyaraj L, Hynd R, Thompson R, Meek T, Ryall DM, et al. Evidence that intravenous vasopressor can affect rostral spread of spinal anesthesia in pregnancy. Anesthesiology. 2004;101:28–33. doi: 10.1097/00000542-200407000-00007. [DOI] [PubMed] [Google Scholar]
- 12.Cooper DW, Gibb SC, Meek T, Kokri MS, Malik AT, Koneti KK. Effect of intravenous vasopressor on spread of spinal anesthesia and fetal acid base equilibirium. Br J Anaesth. 2007;98:649–56. doi: 10.1093/bja/aem056. [DOI] [PubMed] [Google Scholar]
- 13.Hennebry MC, Stocks GM, Belavadi P, Barnes J, Wray S, Columb MO, et al. Effect of i.v. phenylephrine or ephedrine on the ED50 of intrathecal bupivacaine with fentanyl for caesarean section. Br J Anaesth. 2009;102:806–11. doi: 10.1093/bja/aep095. [DOI] [PubMed] [Google Scholar]
- 14.Tyagi A, Kakkar A, Niwal N, Mohta M, Sethi AK. Effect of intravenous phenylephrine infusion on dose requirement of intrathecal plain levobupivacaine for cesarean section: A placebo-controlled preliminary study. Saudi J Anaesth. 2017;11:421–6. doi: 10.4103/sja.SJA_269_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zhang W, Wu H. ED50 of intrathecal ropivacaine for cesarean section under prophylactic infusion of phenylephrine: A consort study. Medicine (Baltimore) 2017;96:e8319. doi: 10.1097/MD.0000000000008319. doi:10.1097/MD.0000000000008319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zhang YF, Xiao F, Xu WP, Liu L. Prophylactic infusion of phenylephrine increases the median effective dose of intrathecal hyperbaric bupivacaine in cesarean section: A prospective randomized study. Medicine (Baltimore) 2018;97:e11833. doi: 10.1097/MD.0000000000011833. doi:10.1097/MD.0000000000011833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Xiao F, Drzymalski D, Liu L, Zhang Y, Wang L, Chen X. Comparison of the ED50 and ED95 of intrathecal bupivacaine in parturients undergoing cesarean delivery with or without prophylactic phenylephrine infusion: A prospective, double-blind study. Reg Anesth Pain Med. 2018;43:885–9. doi: 10.1097/AAP.0000000000000850. [DOI] [PubMed] [Google Scholar]
- 18.Xu W, Xiao F, Zhang Y, Liu L, Chang X. ED50 and ED95 of intrathecal hyperbaric ropivacaine for parturients undergoing cesarean section with prophylactic infusion of phenylephrine: A Prospective dose-finding study. Medicine (Baltimore) 2018;97:e13727. doi: 10.1097/MD.0000000000013727. doi:10.1097/MD.0000000000013727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Dixon WJ, Massey FJ. Introduction to Statistical Analysis. 4th ed. New York: McGraw-Hill Book Company; 1983. [Google Scholar]
- 20.Xu W, Drzymalski DM, Ai L, Yao H, Liu L, Xiao F. The ED50 and ED95 of prophylactic norepinephrine for preventing post-spinal hypotension during cesarean delivery under combined spinal-epidural anesthesia: A prospective dose-finding study. Front Pharmacol. 2021;12:691809. doi: 10.3389/fphar.2021.691809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Fu F, Xiao F, Chen W, Yang M, Zhou Y, Ngan Kee WD, et al. A randomised double-blind dose-response study of weight-adjusted infusions of norepinephrine for preventing hypotension during combined spinal-epidural anaesthesia for caesarean delivery. Br J Anaesth. 2020;124:e108–14. doi: 10.1016/j.bja.2019.12.019. [DOI] [PubMed] [Google Scholar]
- 22.Thomas CW, Heather M, Dawid PW. Adrenergic agonist and antagonists. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman's Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill Medical; 2018. pp. 191–223. [Google Scholar]
- 23.Smith MD, Maani CV. Stat Pearls. Treasure Island (FL): Stat Pearls Publishing; 2022. Norepinephrine. [Google Scholar]