A comparison of the effect of phenylephrine and norepinephrine on uteroplacental vascular resistance during the treatment of postspinal hypotension in preeclamptic patients

Editor, Although preeclamptic patients have a lower incidence of postspinal hypotension than healthy parturients, the hazards associated with hypotension are more severe.1 Therefore, in preeclamptic patients, it is important to select an appropriate vasopressor to treat the postspinal hypotension. Recently norepinephrine has been suggested as an effective alternative to phenylephrine for treating the postspinal hypotension in normotensive patients.2 However, the effects of norepinephrine or phenylephrine on uteroplacental vessels in preeclamptic patients are still poorly understood. Therefore, we conducted the present study to investigate uteroplacental vascular resistance during the administration of norepinephrine or phenylephrine in preeclamptic patients suffering from postspinal hypotension by using Doppler Ultrasound to measure the resistance index (RI) and pulsatility index (PI).3 Ethical approval for this randomised, controlled study was provided by the Ethical Committee of the Women's Hospital, Zhejiang University School of Medicine on 11 January 2022 (Reference: IRB-20220003-R). The study was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn) with registration number ChiCTR2200056178. The study was conducted from February 1 to April 30 2022. Written informed consent was obtained from all patients before enrolment. We recruited women aged 18 to 40 years with a singleton pregnancy and a diagnosis of preeclampsia scheduled for elective caesarean delivery under combined spinal-epidural anaesthesia. Exclusion criteria included: ASA of III or higher, chronic hypertension, diabetes mellitus, other significant cardiovascular or cerebrovascular disease, known foetal abnormality, foetal growth restriction, obstetric complications, less than 28 weeks gestation, multiple pregnancies, and contraindication to spinal anaesthesia or related drugs. The patients were randomly divided into two groups and received equivalent doses of either phenylephrine 50 μg (Group P) or norepinephrine 4 μg (Group N) for the treatment of spinal-induced hypotension during caesarean section.4 They were fasted for 8 h before surgery and received no premedication. Spinal anaesthesia was induced with 1.5 ml 1% ropivacaine + 1 ml 10% dextrose +0.5 ml ‘0.9% saline (3 ml in total) at a rate of 1 ml per 10 s. The Doppler parameters (RI and PI of uterine arteries and umbilical arteries) were measured before spinal anaesthesia (prevalues) and 5 min after vasopressor administration (postvalues) by a professional sonographer using a KONICA SONIMAGE HS1 with a C5-2 multifrequency curvilinear probe. Maternal cardiac output (CO), systemic vascular resistance (SVR) and stroke output (SV) were also measured using a T-Line 400 monitor. All the haemodynamic data were assessed every minute after spinal injection until delivery of the baby, and then every 5 min until the end of surgery. Hypotension was defined as a decrease in SBP to less than 80% of baseline, or an absolute value less than 100 mmHg. Whenever this happened during caesarean section, the chosen vasopressor bolus was given immediately. The primary outcomes of this study were to compare the changes between the pretreatment and posttreatment values of PI and RI for the uterine artery (ΔUtA–PI and ΔUtA–RI) and umbilical artery (ΔUmA–PI and ΔUmA–RI) during the management of postspinal hypotension. A total of 50 patients finished the study. The mean values of ΔUtA–PI and ΔUtA–RI (Δvalues = valuespost minus valuespre) were significantly lower in Group N compared to Group P (0.05 ± 0.03 vs. 0.08 ± 0.04; 0.04 ± 0.02 vs. 0.06 ± 0.03; Pgroup <0.05); whereas the mean values ofΔUmA-RI and ΔUmA-PI were not significantly different between the two groups (Pgroup >0.05). All the baseline values (preintervention) had no effect on the primary outcomes within the groups (Pbaseline >0.05) (Table 1). Table 1 - The absolute values and the mean Δvalues of ultrasound Doppler parameters for uterine and umbilical arteries (Δvalues = valuespost – valuespre) Group N (n = 25) Group P (n = 25) P value group P value baseline UmA-RIpre 0.74 ± 0.09 0.73 ± 0.07 0.917 UmA-RIpost 0.77 ± 0.09 0.76 ± 0.08 0.831 ΔUmA-RI 0.03 ± 0.02 0.02 ± 0.03 0.655 0.407 UmA-PIpre 0.90 ± 0.09 0.89 ± 0.08 0.947 UmA-PIpost 0.92 ± 0.09 0.93 ± 0.06 0.816 ΔUmA-PI 0.03 ± 0.03 0.03 ± 0.01 0.313 0.231 UtA-RIpre 0.80 ± 0.09 0.78 ± 0.09 0.536 UtA-RIpost 0.84 ± 0.10 0.85 ± 0.09 0.692 ΔUtA-RI 0.04 ± 0.02 0.06 ± 0.03 0.002∗ 0.467 UtA-PIpre 0.95 ± 0.06 0.95 ± 0.07 0.930 UtA-PIpost 1.00 ± 0.06 1.04 ± 0.07 0.068 ΔUtA-PI 0.05 ± 0.03 0.08 ± 0.04 0.003∗ 0.060 Data are presented as mean ± SD. PI, pulsatility index; RI, resistance index; Um A, umbilical artery; Ut A, uterine arteries.∗P < 0.05. Serial changes in heart rate (HR) from the standard monitors and CO from the T-Line 400 monitor for the first 10 min after vasopressor administration are shown in Fig. 1. AUC analysis showed that HR (HR and time) and CO (CO and time) were significantly higher over time in Group N than Group P (865 ± 132 vs. 772 ± 80, P = 0.004), (66 ± 3.6 vs. 63 ± 4.7, P = 0.003). There were no significant differences in other maternal haemodynamic changes, neonatal outcomes, intraoperative adverse events and vasopressor requirements.Fig. 1: Serial changes in systolic cardiac output (a) and heart rate (b).A study by Ngan Kee5 suggested that the estimated dose equivalence of the two drugs in normotensive patients were phenylephrine 100 μg = norepinephrine 8 μg (1/12.5 ratio). According to the commonly used clinical dose of phenylephrine (50 μg bolus) to rescue maternal hypotension in preeclamptic patients, we used a 4 μg bolus of norepinephrine.4 However, the equipotency ratio (1/12.5) of the two vasopressors in preeclamptic patients is uncertain and needs to be further investigated. In our study, after vasopressor administration the significant changes of Doppler parameters were mainly focused on the uterine arteries rather than the umbilical arteries. According to previous studies, the uterine artery is the source of uterine blood during pregnancy and the main site of material exchanges to and from the fetus.6 Although the umbilical artery seems more directly connected to foetus, uterine arteries are also very important for oxygen supply to foetus. Klotz et al.7 found the expression of α1—receptors, which mediate vasoconstriction was significantly greater in uterine arteries than in umbilical arteries, so uterine arteries were more responsive to vasopressors than umbilical arteries. Many factors can modify the effect of the two vasopressors on uteroplacental vascular resistance. The regulation of α-adrenergic and β-adrenergic receptor agonist activity might be an important mechanism.6 As a pure α-agonist drug, phenylephrine may have greater vasoconstriction effects on uterine arteries than norepinephrine. And the mild β-adrenergic receptor agonist activity of norepinephrine may partially weaken its strong α-adrenergic receptor agonist effect. The exact mechanism needs to be confirmed by further laboratory research. In summary, our results showed that when an equivalent dose of phenylephrine and norepinephrine was used to treat spinal-induced hypotension in preeclamptic patients during caesarean section, vascular resistance changes in uterine arteries were less in patients receiving norepinephrine than in those receiving phenylephrine. Furthermore, compared with phenylephrine, norepinephrine can provide a greater maternal HR and CO in preeclamptic patients. Further research is needed to confirm the potential advantages of norepinephrine in preeclamptic patients.