Comparison of Phenylephrine and Ephedrine in Treatment of Spinal-Induced Hypotension in High-Risk Pregnancies: A Narrative Review

To compare maternal and fetal effects of intravenous phenylephrine and ephedrine administration during spinal anesthesia for cesarean delivery in high-risk pregnancies. Source An extensive literature search was conducted using the US National Library of Medicine, MEDLINE search engine, Cochrane review, and Google Scholar using search terms “ephedrine and phenylephrine,” “preterm and term and spinal hypotension,” “preeclampsia and healthy parturients,” or “multiple and singleton gestation and vasopressor.” Society of Obstetric Anesthesia and Perinatology meeting abstracts for the past 4 years were also searched for relevant studies. Principle findings Both phenylephrine and ephedrine can be safely used to counteract hypotension after spinal anesthesia in patients with uteroplacental insufficiency, pregnancy-induced hypertension, and in non-elective cesarean deliveries. Vasopressor requirements before delivery in high-risk cesarean sections are reduced compared to healthy parturients. Among the articles reviewed, there were no statistically significant differences in umbilical arterial pH, umbilical venous pH, incidence of fetal acidosis, Apgar scores, or maternal hypotension when comparing maternal phenylephrine and ephedrine use.  From the limited existing data, phenylephrine and ephedrine are both appropriate selections for treating or preventing hypotension induced by neuraxial blockade in high-risk pregnancies. There is no clear evidence that either medication is more effective at maintaining maternal blood pressure or has a superior safety profile in this setting. Further investigations are required to determine the efficacy, ideal dosing regimens, and overall safety of phenylephrine and ephedrine administration in high-risk obstetric patients, especially in the presence uteroplacental insufficiency.

Related papers:

title: A Quantitative, Systematic Review of Randomized Controlled Trials of Ephedrine Versus Phenylephrine for the Management of Hypotension During Spinal Anesthesia for Cesarean Delivery
abstract: This quantitative systematic review compared the efficacy and safety of ephedrine with phenylephrine for the prevention and treatment of hypotension during spinal anesthesia for cesarean delivery. Seven randomized controlled trials (n = 292) were identified after a systematic search of electronic databases (MEDLINE, EMBASE, The Cochrane Controlled Trials Registry), published articles, and contact with authors. Outcomes assessed were maternal hypotension, hypertension and bradycardia, and neonatal umbilical cord blood pH values and Apgar scores. For the management (prevention and treatment) of maternal hypotension, there was no difference between phenylephrine and ephedrine (relative risk [RR] of 1.00; 95% confidence interval [CI], 0.96–1.06). Maternal bradycardia was more likely to occur with phenylephrine than with ephedrine (RR of 4.79; 95% CI, 1.47–15.60). Women given phenylephrine had neonates with higher umbilical arterial pH values than those given ephedrine (weighted mean difference of 0.03; 95% CI, 0.02–0.04). There was no difference between the two vasopressors in the incidence of true fetal acidosis (umbilical arterial pH value of <7.2; RR of 0.78; 95% CI, 0.16–3.92) or Apgar score of <7 at 1 and 5 min. This systematic review does not support the traditional idea that ephedrine is the preferred choice for the management of maternal hypotension during spinal anesthesia for elective cesarean delivery in healthy, nonlaboring women.

title: Effects of Equipotent Ephedrine, Metaraminol, Mephentermine, and Methoxamine on Uterine Blood Flow in the Pregnant Ewe
abstract: To evaluate the safety of prophylactic vasopressor administration prior to obstetric conduction anesthesia, equipotent doses of ephedrine, metaraminol, mephentermine, and methoxamine were administered to 16 nonanesthetized pregnant ewes near term. When the maternal blood pressure was increased by 50 per cent, uterine blood flow was unchanged with ephedrine and was reduced 20 per cent with mephentermine (P gt; 0.05); 45 per cent with metaraminol (P lt; 0.005) and 62 per cent with methoxamine (P lt; 0.05). Metaraminol and methoxamine consistently decreased uterine blood flow at all levels of maternal blood pressure elevation. No significant change in fetal blood gas and acid-base variables was demonstrated.

title: Fetal and Maternal Effects of Phenylephrine and Ephedrine during Spinal Anesthesia for Cesarean Delivery
abstract: In our routine practice, we observed a reduced incidence of fetal acidosis (umbilical artery p H < 7.20) at cesarean delivery during spinal anesthesia when a combination of phenylephrine and ephedrine was used as first line vasopressor therapy, compared with using ephedrine alone.  The study was randomized and double blind. It compared phenylephrine 100 &mgr;g/ml (phenylephrine group), ephedrine 3 mg/ml (ephedrine group), and phenylephrine 50 &mgr;g/ml combined with ephedrine 1.5 mg/ml (combination group), given by infusion, to maintain maternal systolic arterial pressure at baseline during spinal anesthesia for elective cesarean delivery.  Fetal acidosis was less frequent in the phenylephrine group (1 of 48) (P = 0.004) and less frequent in the combination group (1 of 47) (P = 0.005) than in the ephedrine group (10 of 48). The mean systolic arterial pressure was similar for the three groups: Phenylephrine group median 98% (IQR 94–103) of baseline, ephedrine group 100% (96–106) and combination group 101% (97–108) (P = 0.11). The mean heart rate was higher in the ephedrine group (median 107% [IQR 99–118] of baseline) than in the phenylephrine group (88% [82–98]) (P < 0.0001), or the combination group (96% [86–102]) (P < 0.0001). Nausea and vomiting were less frequent in the phenylephrine group (nausea 17%, vomiting 0%) than in the ephedrine group (nausea 66%, vomiting 36%) (P < 0.0001), or the combination group (nausea 55%, vomiting 18%) (P < 0.0001).  Giving phenylephrine alone by infusion at cesarean delivery was associated with a lower incidence of fetal acidosis and maternal nausea and vomiting than giving ephe-drine alone. There was no advantage to combining phenylephrine and ephedrine because it increased nausea and vomiting, and it did not further improve fetal blood gas values, compared with giving phenylephrine alone.

title: Multivariate analysis of factors associated with umbilical arterial pH and standard base excess after Caesarean section under spinal anaesthesia.
abstract: We have investigated the factors predicting umbilical arterial pH (UA pH) and standard base excess (UA BE) in 337 consecutive elective Caesarean sections performed under spinal anaesthesia. Multiple linear regression analysis was performed with UA pH and UA BE as the dependent factors. We found that the significant factors predicting UA pH were: use of ephedrine, uterine incision-to-delivery time, maximum decrease in systolic arterial pressure and the interaction between ephedrine use and duration of hypotension (adjusted R2 = 0.39, F15,321 = 15.4, p < 0.0001). The significant factors predicting UA BE were: use of ephedrine and the interaction between ephedrine use and duration of hypotension (adjusted R2 = 0.52, F15,321 = 25.0, p < 0.0001). We conclude that, in order to minimise the risk of fetal acidosis, ephedrine should not be used before delivery, uterine incision-to-delivery time should be as short as possible, and alpha-agonists such as metaraminol or phenylephrine should be used to minimise both the magnitude and duration of hypotension.

title: Placental Transfer and Fetal Metabolic Effects of Phenylephrine and Ephedrine During Spinal Anesthesia for Cesarean Delivery
abstract: reported by a hospital remarkably similar to those for physicians. What was once considered incentive pay to report outcomes is threatening to become whether or not to pay at all if the identified outcomes do not meet a baseline performance or better, with future improvement expected. This has become known in the United States as Pay-for-Performance. There is now a PQRI measure called Perioperative Temperature Management (#193). In summary, it states that for procedures over 60 minutes, the patient’s recorded temperature at 30 minutes before or 15 minutes after the end of anesthesia (general or neuraxial) should be equal to or greater than 361C. Mind you, performance definitions can and have changed from year to year. TheAmerican Society of Anesthesiologists has acknowledged that intraoperative normothermia is a performance measure under our control. Likewise, the authors of this study refer to a similar United Kingdom-based document on thermal management from the National Institute for Health and Clinical Excellence. All this makes me believe that we will soon be asked to document how well we keep our surgical obstetric patients warmduring procedures, regardless of procedure time. How we go about that makes this a very timely study indeed.

title: Effect of intravenous vasopressor on spread of spinal anaesthesia and fetal acid-base equilibrium.
abstract: We previously found rostral spread of spinal plain levobupivacaine to be less with prophylactic i.v. phenylephrine than with ephedrine during Caesarean delivery. This study investigated whether rostral spread of spinal hyperbaric bupivacaine is also less with phenylephrine than with ephedrine.



The study was randomized and double blind. It compared phenylephrine 100 microg ml-1 (phenylephrine group, n=27), and ephedrine 4.5 mg ml-1 (ephedrine group, n=27), given by infusion during spinal anaesthesia for Caesarean delivery. Block height was assessed to cold and light touch sensation at 15, 30, 60, and 90-min after the spinal injection of 2.8 ml of hyperbaric 0.5% w/v bupivacaine, combined with 0.4 ml diamorphine (1 mg ml-1). Umbilical blood gas values were monitored during the study.



Block height was similar for both groups at all of the assessment times. Umbilical artery pH was higher with phenylephrine [median 7.32 (IQR 7.28-7.34)] than with ephedrine [7.20 (7.10-7.28)] (P<0.0001). There was a strong negative correlation between umbilical artery pH and spinal-delivery interval, but only with ephedrine: phenylephrine group, r2=0.09 (P=0.17), and ephedrine group, r2=0.53 (P<0.0001). Five-minute Apgar scores were higher with phenylephrine [10 (9-10)] than ephedrine [9 (9-9)] (P=0.009).



In contrast to its effect on spinal plain levobupivacaine, we did not find rostral spread of spinal hyperbaric bupivacaine to be less with prophylactic phenylephrine than with ephedrine. We observed an unexpectedly high incidence of fetal acidosis with ephedrine and found evidence that longer spinal-delivery intervals increase the risk of fetal acidosis developing with ephedrine, but not phenylephrine.

title: A Dose-Response Study of Prophylactic Intravenous Ephedrine for the Prevention of Hypotension During Spinal Anesthesia for Cesarean Delivery
abstract: We performed a randomized, double-blinded dose-finding study of IV ephedrine for prophylaxis for hypotension in 80 women who received an IV crystalloid preload and spinal anesthesia for elective cesarean delivery. One minute after the intrathecal injection, patients were given saline control or ephedrine 10, 20, or 30 mg IV for 30 s. Systolic arterial pressure (SAP) in the first 12 min after the spinal injection was greater in the 30-mg group compared with other groups (P < 0.05). Hypotension occurred in 7 patients (35%) in the 30-mg group compared with 19 (95%), 17 (85%), and 16 (80%) patients in the control and 10- and 20-mg groups, respectively (P < 0.0001). Maximum decrease in SAP was smaller in the 30-mg group (mean lowest SAP 87% of baseline, range 58%–105%) compared with other groups (P < 0.01). Reactive hypertension occurred in 9 patients (45%) in the 30-mg group (mean highest SAP 120% of baseline, range 104%–143%) compared with 2 (10%), 1 (5%), and 5 (25%) patients in the other groups (P = 0.009). Heart rate changes, total ephedrine requirement, incidence of nausea and vomiting, and neonatal outcome were similar among groups. The proportion of patients with umbilical arterial pH < 7.2 was 10.5%, 25%, 42%, and 22% in the control, 10-, 20-, and 30-mg groups, respectively (P = 0.12). We conclude that the smallest effective dose of ephedrine to reduce the incidence of hypotension was 30 mg. However, this dose did not completely eliminate hypotension, nausea and vomiting, and fetal acidosis, and it caused reactive hypertension in some patients.  We investigated different doses of IV ephedrine as prophylaxis for hypotension during spinal anesthesia for cesarean delivery and found that the smallest effective dose was 30 mg. However, this dose did not completely eliminate hypotension, caused reactive hypertension in some patients, and did not improve neonatal outcome.

title: Normal and abnormal transformation of the spiral arteries during pregnancy
abstract: This article reviews the anatomy and physiology of the uterine circulation, with emphasis on the remodeling of spiral arteries during normal pregnancy, and the timing and anatomical pathways of trophoblast invasion of the spiral arteries. We review the definitions of the placental bed and basal plate of the placenta, their relevance to the study of the physiologic transformation of the spiral arteries, as well as the methods to obtain and examine placental bed biopsy specimens. We also examine the role of the extravillous trophoblast in normal and abnormal pregnancies, and the criteria used to diagnose failure of physiologic transformation of the spiral arteries. Finally, we comment on the use of uterine artery Doppler velocimetry as a surrogate marker of chronic uteroplacental ischemia.

title: Preeclampsia, a Disease of the Maternal Endothelium: The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease
abstract: Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic.

Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop.

Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of …

title: Doppler velocimetry in the evaluation of fetal hypoxia
abstract: Knowledge of fetal hemodynamic physiology has developed enormously during the last two decades due to Doppler ultrasound. Some of this knowledge has been utilized for routine surveillance of high-risk pregnancies. The prediction of fetal hypoxia before the development of life lasting sequel is of major importance, especially in the very premature case with absent end-diastolic blood flow in the umbilical artery before lung maturity. This review gives an overview of the present knowledge in this field.

title: Evidence-based Approach to Umbilical Artery Doppler Fetal Surveillance in High-risk Pregnancies: An Update
abstract: Antepartum fetal surveillance with Doppler ultrasound of umbilical artery has shown significant diagnostic efficacy in identifying fetal compromise in pregnancies complicated with fetal growth restriction and preeclampsia. Moreover, randomized clinical trials and their meta-analyses have shown its effectiveness in decreasing perinatal mortality (level I evidence). This is the only antepartum fetal test that has shown this level of effectiveness. There is no evidence that routine Doppler in low-risk pregnancies improves the outcome. It is recommended that umbilical artery Doppler should be the standard of practice in managing high-risk pregnancies complicated with fetal growth restriction and preeclampsia (level A recommendation). However, its use should be integrated with other current fetal monitoring tests (levels B and C recommendation). The overall management should also be guided by additional clinical considerations such as the gestational age, fetal and maternal status, and obstetrical conditions.

title: How useful is uterine artery Doppler flow velocimetry in the prediction of pre‐eclampsia, intrauterine growth retardation and perinatal death? An overview
abstract: To evaluate the clinical usefulness of Doppler analysis of the uterine artery velocity waveform in the prediction of pre‐eclampsia and its associated complications of intrauterine growth retardation and perinatal death.

title: Evaluation of third trimester uterine artery flow velocity indices in relationship to perinatal complications
abstract: Uterine artery Doppler is becoming a routine part of pregnancy surveillance in high-risk pregnancies. Which blood flow velocity waveform index to measure is debated and the ‘notch’ in early diastole is not widely accepted, as it is a subjective measure. The aim of the present study was to evaluate the different indices in the prediction of adverse outcome of pregnancies suspected for intrauterine fetal growth restriction (IUGR). Uterine artery blood flow was recorded in 217 pregnancies admitted for Doppler ultrasound surveillance due to suspected IUGR. The median gestational age at examination was 38 weeks (range 25–42 weeks). Only cases having bilateral uterine artery notching were included in the evaluation. The uterine artery Doppler spectrum was analyzed for different indices, including evaluation of notch and end-diastolic velocities. Umbilical artery Doppler velocimetry was also performed. The outcome variables chosen were: a small-for-gestational-age (SGA) newborn, preterm birth, and abdominal delivery. ROC-curve calculations were used to compare the different indices. The uterine artery blood velocity pulsatility index (PI) and resistance indices (RI) were the best predictors of adverse outcome of pregnancy. Apart from premature birth, the systolic/end-diastolic ratio was less predictive of adverse outcome. The indices including only diastolic blood velocities were the least predictive of adverse outcome. The group with notch velocity above end-diastolic velocity was compared with those having notch velocity below the end-diastolic velocity. No difference in outcome was seen between the two groups.  RI and PI as measures of third trimester utero-placental vascular impedance are the best predictors of adverse outcome of IUGR-suspected pregnancies.

title: Effects of ephedrine and phenylephrine on uterine and placental circulations and fetal outcome following fetal hypoxaemia and epidural-induced hypotension in a sheep model.
abstract: Recent studies support the use of alpha-agonists during regional anaesthesia in uncomplicated term pregnancies. We hypothesized that ephedrine and phenylephrine, administered for maternal hypotension following fetal hypoxaemia, are equal in respect of fetal outcome.



At 117-132 days gestation, chronically instrumented, anaesthetized and mechanically ventilated ewes were randomized to receive boluses of ephedrine (n=9) or phenylephrine (n=8) for maternal epidural-induced hypotension after a period of fetal hypoxaemia. Uterine (QUtA) and placental (QUA) volume blood flows were measured with perivascular transit-time ultrasonic flow probes, and uterine (RUtA) and placental (RUA) vascular resistances were computed from volume blood flows and maternal and fetal mean arterial pressures. Uterine (PIUtA) and umbilical artery (PIUA) pulsatility indices were obtained by Doppler ultrasonography.



Ephedrine increased QUtA and decreased RUtA and PIUtA from a hypotensive to baseline level and had no significant effect on umbilical circulation. With phenylephrine, QUtA remained lower (P=0.011) and RUtA higher (P=0.043) than at baseline, although PIUtA decreased to baseline level. PIUA increased from baseline with phenylephrine (P=0.007), whereas QUA decreased (P=0.050). Maternal volume expansion with hydroxyethyl starch decreased RUtA significantly irrespective of the vasopressor used. There were no significant differences in fetal blood gas values or lactate concentrations between the ephedrine and phenylephrine groups.



Despite the more favourable effects on uterine and placental circulations of ephedrine over phenylephrine, no significant differences in fetal acid-base status or lactate concentrations were observed.

title: Ephedrine and phenylephrine for the treatment of maternal hypotension in a chronic sheep model of increased placental vascular resistance.
abstract: We hypothesized that ephedrine and phenylephrine are equal with respect to uterine and placental haemodynamics and fetal acid-base status after exposure to maternal hypoxaemia and hypotension in a chronic sheep model of increased placental vascular resistance (R(UA)).



At 114-135 days gestation, chronically instrumented fetal sheep underwent placental embolization leading to increased R(UA). Twenty-four hours after embolization, the ewes were anaesthetized and randomized to receive boluses of ephedrine (n=7) or phenylephrine (n=6) for epidural-induced hypotension after maternal hypoxaemia. Uterine (Q(UtA)) and placental (Q(UA)) volume blood flows and uterine vascular resistance (R(UtA)) and R(UA) were recorded. Uterine (PI(UtA)) and umbilical artery (PI(UA)) pulsatility indices were obtained by Doppler ultrasonography. Fetal arterial blood samples were analysed for acid-base values and lactate concentrations.



During hypotension, Q(UtA), fetal pH, BE, and Po(2) decreased whereas R(UtA), PI(UtA), R(UA), and fetal lactate concentration increased. With ephedrine, Q(UtA), R(UtA), PI(UtA), R(UA), and fetal Po(2) returned to baseline. Fetal pH, BE, and lactate concentration did not change from hypotensive values. With phenylephrine, Q(UtA) remained lower (P=0.007) and R(UtA) (P=0.007), PI(UtA) (P=0.013), and R(UA) (P=0.050) higher than at baseline. Fetal Po(2) returned to baseline and fetal pH and BE did not change from hypotensive values. However, fetal lactate concentration increased further (mean difference 1.49, 95% confidence interval 0.72-2.26 mmol litre(-1); P=0.004).



In a chronic sheep model of increased placental vascular resistance, compared with ephedrine administration, phenylephrine administration was associated with impaired uterine and placental haemodynamics and increased fetal lactate concentrations.

title: Placental structure: in a comparative aspect.
abstract: The outstanding structural diversity of the placenta among mammals, i.e. horse, pig, domestic ruminants, cat. Guinea pig and human, has been studied in a comparative manner using terms of classification such as: type of placental membranes, placental shape, placental maternofetal interdigitation, layers of the placental interhemal barrier, trophoblast invasiveness and decidual cell reaction, formation of syncytiotrophoblast, maternofetal blood flow interrelationships, and placental separation at birth. These terms, originating partly from classical acquirements of knowledge and partly from recent research, are presented and new aspects discussed; thus helping towards a better understanding of the structure and function of the different placental types.

title: Isoflurane and the Pulmonary Vascular Pressure‐Flow Relation at Baseline and during Sympathetic alpha‐ and beta‐Adrenoreceptor Activation in Chronically Instrumented Dogs
abstract: The extent to which isoflurane anesthesia alters systemic vascular regulation has received considerable attention. In contrast, the pulmonary vascular effects of isoflurane have not been elucidated. Our initial objective was to investigate the net effect of isoflurane on the baseline left pulmonary vascular pressure‐flow (LPQ with dot with dot) relation compared with values measured in the conscious state. In addition, we assessed the extent to which isoflurane alters the pulmonary vascular responses to sympathetic alpha‐ and beta‐adrenoreceptor activation.  Twelve conditioned mongrel dogs were chronically instrumented to measure the LPQ with dot relation. LPQ with dot plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure left atrial pressure) and left pulmonary blood flow during gradual ([nearly equal] 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. LPQ with dot plots were generated at baseline in the conscious and isoflurane‐anesthetized states (n 12). The pulmonary vascular dose‐response relation to the sympathetic alpha‐adrenoreceptor agonist phenylephrine also was investigated in conscious and isoflurane‐anesthetized dogs (n 6). Finally, after preconstriction with the thromboxane analogue U46619, the dose‐response relation to the sympathetic beta‐adrenoreceptor agonist isoproterenol was assessed in the conscious and isoflurane‐anesthetized states (n 8).  Compared with values measured in the conscious state, isoflurane anesthesia had no net effect on the baseline LPQ with dot relation. The magnitude of the pulmonary vasoconstrictor response to phenylephrine observed in conscious dogs was not altered during isoflurane anesthesia. In contrast, the pulmonary vasodilator response to isoproterenol was markedly potentiated (P < 0.01) during isoflurane anesthesia compared with that in the conscious state.  These results indicate that isoflurane does not exert a net vasodilator influence on the pulmonary circulation at baseline. In contrast to the systemic circulation, the pulmonary vasoconstrictor response to sympathetic alpha‐adrenoreceptor activation is maintained during isoflurane anesthesia. Surprisingly, the pulmonary vasodilator response to sympathetic beta‐adrenoreceptor activation is actually potentiated during isoflurane. Thus, isoflurane anesthesia has differential effects on the canine pulmonary vascular response to sympathetic alpha‐ and beta‐adrenoreceptor activation.

title: Effect of placental resistance, arterial diameter, and blood pressure on the uterine arterial velocity waveform: a computer modeling approach.
abstract: A computer model was used to simulate velocity waveforms that can be visualized in the human uterine artery using Doppler ultrasound. It was found that increasing uteroplacental vascular resistance from normal caused an increase in the systolic/diastolic velocity ratio (S/D) and pulsatility index (PI) of the waveform. Increasing uteroplacental resistance also caused the appearance of a dicrotic notch. Reducing the uterine artery radius increased the S/D and PI and this effect was accentuated at high placental resistance. In contrast, increasing mean arterial pressure in the uterine artery had little effect on S/D and PI. Results suggest that waveform shape abnormalities observed in obstetric patients with pregnancy-induced hypertension are primarily caused by high uteroplacental vascular resistance and a reduced uterine arterial diameter.

title: The Effects of Ephedrine and Phenylephrine on Placental Vascular Resistance During Cesarean Section Under Epidual Anesthesia
abstract: The purpose of this article is to study the effect of ephedrine and phenylephrine on placental vascular resistance during cesarean section under epidural anesthesia via Doppler ultrasonography. Sixty female subjects, scheduled for elective cesarean section and had an intrathecal injection of bupivacaine, were randomly divided into two groups to receive phenylephrine (50 μg/min) or ephedrine (4 mg/min) via titration to maintain systolic blood pressure at baseline. Doppler ultrasonography was used to measure baseline vascular resistance values prior to administration of anesthesia, and resistance index (RI) and systolic peak velocity/diastolic velocity (S/D) values of umbilical artery and uterine artery were measured at each time point within first 20 min following intrathecal injection. Blood samples were collected from umbilical artery and umbilical vein during delivery to assess the blood gas values. No significant differences in RI and S/D values of umbilical artery and uterine artery after intrathecal injection were found between two groups. RI and S/D values of uterine artery slightly increased in both groups at each time point after anesthesia, but remained within the normal range. No significant differences were observed in blood gas values and the total amount of vasoconstriction drugs between two groups. In contrast to previous reports that used animal models, our study did not show increased placental vascular resistance in patients following phenylephrine (50 μg/min) or ephedrine (4 mg/min) infusion, as well as no significant differences in the effect of either of these two. The discrepancy between the results of human and animal studies may be related to species differences and the mechanism of human placental vascular remodeling.

title: Prenatal stress and hemodynamics in pregnancy: a systematic review
abstract: Maternal prenatal stress is associated with preterm birth, intrauterine growth restriction, and developmental delay. However, the impact of prenatal stress on hemodynamics during pregnancy remains unclear. This systematic review was conducted in order to assess the quality of the evidence available to date regarding the relationship between prenatal stress and maternal–fetal hemodynamics. The PubMed/Medline, EMBASE, PsycINFO, Maternity and Infant Care, Trip, Cochrane Library, and CINAHL databases were searched using the search terms pregnancy; stress; fetus; blood; Doppler; ultrasound. Studies were eligible for inclusion if prenatal stress was assessed with standardized measures, hemodynamics was measured with Doppler ultrasound, and methods were adequately described. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-accepted quality appraisal guidelines. Of 2532 studies reviewed, 12 met the criteria for inclusion. Six reported that prenatal stress significantly affects maternal or fetal hemodynamics; six found no significant association between maternal stress and circulation. Significant relationships between prenatal stress and uterine artery resistance (RI) and pulsatility (PI) indices, umbilical artery RI, PI, and systolic/diastolic ratio, fetal middle cerebral artery PI, cerebroplacental ratio, and umbilical vein volume blood flow were found. To date, there is limited evidence that prenatal stress is associated with changes in circulation. More carefully designed studies with larger sample sizes, repeated assessments across gestation, tighter control for confounding factors, and measures of pregnancy-specific stress will clarify this relationship.

title: Phenylephrine infusions for maintaining blood pressure during spinal anesthesia for cesarean delivery: finding the shoe that fits.
abstract: “By three methods we may learn wisdom: first, by reflection, which is noblest; second, by imitation, which is easiest; and third by experience, which is the bitterest.” —Confucius

title: Retrospective study of association between choice of vasopressor given during spinal anaesthesia for high-risk caesarean delivery and fetal pH.
abstract: Phenylephrine given during spinal anaesthesia for low-risk caesarean section is associated with higher fetal pH than ephedrine. However, there is little evidence on the effects of ephedrine and phenylephrine in complicated pregnancies. The aim of this study was to compare umbilical artery pH with phenylephrine and ephedrine given during spinal anaesthesia where caesarean section was performed because of an increased risk of fetal compromise.



We reviewed the case notes of all women at our hospital from 2000-2003 who had undergone high-risk caesarean section under spinal anaesthesia, where umbilical artery and venous pH had been recorded at delivery. Umbilical artery pH was compared by choice of vasopressor and multiple regression analysis was used to investigate the effects of other possible confounding variables.



One hundred and fifteen patients received no vasopressor, 122 ephedrine (group E) and 148 phenylephrine (group P). The median umbilical artery pH was 7.26 (IQR 7.21-7.30) for the no-vasopressor group, 7.27 (7.22-7.30) for group E and 7.28 (7.22-7.32) for group P (P=0.21). Using multiple regression analysis, the only variable associated with altered umbilical artery pH was a non-reassuring fetal heart trace.



Umbilical artery pH was similar whether ephedrine or phenylephrine was used to maintain maternal arterial pressure, which contrasts with studies of low-risk caesarean section.

title: Randomized double-blind comparison of ephedrine and phenylephrine for management of post-spinal hypotension in potential fetal compromise.
abstract: Most studies comparing phenylephrine and ephedrine have been conducted during elective caesarean sections in healthy mothers with no fetal compromise. The effect of vasopressors on fetal outcome may differ between healthy and compromised fetuses. There has been little research into the effect of phenylephrine and ephedrine, when used for management of post-spinal hypotension in the presence of potential fetal compromise.



Healthy women with a singleton pregnancy undergoing emergency caesarean section for fetal compromise under spinal anaesthesia were studied. One-hundred-and-six consecutive subjects, who developed hypotension after spinal anaesthesia, were randomly allocated to two groups of 53 each, to receive either phenylephrine (Group P) or ephedrine (Group E). For every systolic blood pressure reading <100mmHg patients received phenylephrine 100μg or ephedrine 8mg depending on group allocation. Umbilical blood gas parameters and Apgar scores were recorded.



There was no statistically significant difference in umbilical arterial pH (P=0.79), umbilical venous pH (P=0.98), other blood gas parameters, incidence of fetal acidosis (P=1.00) and Apgar scores. The number of hypotensive episodes, vasopressor doses for treatment of the first hypotensive episode and the total number of doses used during the study period were comparable. The median [IQR] total number of doses of phenylephrine and ephedrine used before delivery were 2 [1-2] and 2 [1-2], respectively (P=0.67). More patients receiving ephedrine (24.5%) developed tachycardia than those receiving phenylephrine (3.8%) (P=0.004). Bradycardia was more common with phenylephrine, with 39.6% of patients in Group P as compared to only 1.9% of patients in Group E developing a heart rate <60beats/min after vasopressor administration (P=0.001).



Both phenylephrine 100μg and ephedrine 8mg boluses are equally efficacious when treating post-spinal hypotension in the presence of potential fetal compromise. However, phenylephrine may be a better choice in the presence of maternal tachycardia.

title: A randomized trial comparing prophylactic phenylephrine and ephedrine infusion during spinal anesthesia for emergency cesarean delivery in cases of acute fetal compromise.
abstract: Previous evidence showed that use of phenylephrine was associated with higher umbilical artery pH (UA pH) than ephedrine after elective cesarean delivery (CD). However, the best choice of vasopressor and its effect on funic gases in cases of acute fetal compromise require additional studies.



Ninety parturients showing acute fetal compromise during intrapartum period and taken up for CD (category II) under spinal anesthesia were randomized to receive prophylactic infusion of ephedrine 2.5mg/min or phenylephrine 30μg/min. Systolic blood pressure was targeted between 90% and 110% of baseline. Incidence of fetal acidosis (UA pH <7.2 and/or base deficit >12mmol/L) was recorded. Other parameters of cord gases, Apgar score, need for immediate resuscitation, maternal hemodynamics, and adverse events were also compared.



Number of neonates showing acidosis with ephedrine or phenylephrine was comparable (P=.22). Of these, newborns with base deficit >12mmol had low 1-minute Apgar scores (n=15/23). The ephedrine group had higher oxygen content in UA (P=.03). There was no adverse neonatal outcome during the period of observation. Incidence of maternal nausea and vomiting was higher with ephedrine than with phenylephrine (22.2% vs 4.4%; P=.02). Maternal bradycardia was observed with phenylephrine (P=.02).



Our data report similar fetal acidosis with either phenylephrine or ephedrine administered during spinal anesthesia for treating maternal hypotension in cases of emergency CD.

title: Placental Cytokines and the Pathogenesis of Preeclampsia
abstract: The authors explore the hypothesis that tumor necrosis factor‐α (TNF‐α) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of “toxic” factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF‐α and in‐terleukin‐1 (IL‐1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF‐α and IL‐1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF‐α and IL‐1 have DNA sequences homologous or nearly homologous to the hypoxia‐responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

title: Patients with Severe Preeclampsia Experience Less Hypotension During Spinal Anesthesia for Elective Cesarean Delivery than Healthy Parturients: A Prospective Cohort Comparison
abstract: In this prospective cohort study, we compared the incidence and severity of spinal anesthesia (SA)-associated hypotension in severely preeclamptic (n = 30) versus healthy (n = 30) parturients undergoing cesarean delivery. After the administration of IV fluids, SA was performed with hyperbaric 0.5% bupivacaine, sufentanil, and morphine. Blood pressure (BP) was recorded before and at 2-min intervals for 30 min after SA. Clinically significant hypotension was defined as the need for ephedrine (systolic BP decrease to <100 mm Hg in healthy parturients or 30% decrease in mean BP in both groups). Despite receiving a smaller fluid volume (1653 ± 331 mL versus 1895 ± 150 mL; P = 0.005) and a larger bupivacaine dose (10.5 ± 0.9 mg versus 10.0 ± 0.7 mg; P = 0.019), the severely preeclamptic patients had a less frequent incidence of clinically significant hypotension (16.6% versus 53.3%; P = 0.006), which was less severe and required less ephedrine. The risk of hypotension was almost six times less in severely preeclamptic patients (odds ratio, 0.17; 95% confidence interval, 0.05–0.58; P = 0.006) than that in healthy patients.

title: Spinal Anesthesia-Induced Hypotension: A Risk Comparison Between Patients with Severe Preeclampsia and Healthy Women Undergoing Preterm Cesarean Delivery
abstract: We previously showed that, in comparison with term healthy parturients, patients with severe preeclampsia had a less frequent incidence of spinal hypotension, which was less severe and required less ephedrine. In the present study, we hypothesized that these findings were attributable to preeclampsia-associated factors rather than to a smaller uterine mass. The incidence and severity of hypotension were compared between severe preeclamptics (n = 65) and parturients with preterm pregnancies (n = 71), undergoing spinal anesthesia for cesarean delivery (0.5% bupivacaine, sufentanil, morphine). Hypotension was defined as the need for ephedrine (systolic blood pressure <100 mm Hg in parturients with preterm fetuses or 30% decrease in mean blood pressure in both groups). Apgar scores and umbilical arterial blood pH were also studied. Neonatal and placental weights were similar between the groups. Hypotension was less frequent in preeclamptic patients than in women with preterm pregnancies (24.6% versus 40.8%, respectively, P = 0.044). Although the magnitude of the decrease in systolic, diastolic, and mean arterial blood pressure was similar between groups, preeclamptic patients required less ephedrine than women in the preterm group to restore blood pressure to baseline levels (9.8 ± 4.6 mg versus 15.8 ± 6.2 mg, respectively, P = 0.031). The risk of hypotension in the preeclamptic group was almost 2 times less than that in the preterm group (relative risk = 0.603; 95% confidence interval, 0.362–1.003; P = 0.044). The impact of Apgar scores was minor, and umbilical arterial blood pH was not affected. We conclude that preeclampsia-associated factors, rather than a smaller uterine mass, account for the infrequent incidence of spinal hypotension in preeclamptic patients.

title: Retrospective comparison of ephedrine and phenylephrine for the treatment of spinal anesthesia induced hypotension in pre-eclamptic patients
abstract: To compare neonatal acid base status in parturients who underwent cesarean delivery and received either ephedrine or phenylephrine boluses for the treatment of spinal anesthesia induced hypotension.  After institutional review board approval, the perioperative database of the University of Iowa Hospitals and Clinics was used to identify all women diagnosed with pre-eclampsia and had cesarean delivery under spinal anesthesia for the period 1 January 2005 to 31 July 2014. Data retrieved included patient demographics, indication for cesarean delivery, severity of pre-eclampsia, dose of vasopressor, neonatal umbilical artery pH and Apgar scores.  Primary outcome was umbilical artery pH.  Data for 146 patients was included in the analysis. Ephedrine was used in 57 patients (group E) and phenylephrine in 89 (group PE) patients. The median umbilical artery pH was 7.30 (IQR 7.20–7.30) and 7.30 (IQR 7.20–7.30) in the ephedrine and phenylephrine groups respectively (P = 0.41). Non-reassuring fetal heart trace was the only factor significantly associated with lower umbilical artery pH on multivariable regression analysis (β = −0.09, P = 0.002).  We found no difference in neonatal umbilical artery pH between ephedrine and phenylephrine when used to treat spinal anesthesia induced hypotension during cesarean delivery in pre-eclamptic patients. Limitations of the study include its retrospective single center design and the fact that the choice of vasopressor was not randomized.

title: Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models.
abstract: Normal pregnancy is associated with reductions in total vascular resistance and arterial pressure possibly due to enhanced endothelium-dependent vascular relaxation and decreased vascular reactivity to vasoconstrictor agonists. These beneficial hemodynamic and vascular changes do not occur in women who develop preeclampsia; instead, severe increases in vascular resistance and arterial pressure are observed. Although preeclampsia represents a major cause of maternal and fetal morbidity and mortality, the vascular and cellular mechanisms underlying this disorder have not been clearly identified. Studies in hypertensive pregnant women and experimental animal models suggested that reduction in uteroplacental perfusion pressure and the ensuing placental ischemia/hypoxia during late pregnancy may trigger the release of placental factors that initiate a cascade of cellular and molecular events leading to endothelial and vascular smooth muscle cell dysfunction and thereby increased vascular resistance and arterial pressure. The reduction in uterine perfusion pressure and the ensuing placental ischemia are possibly caused by inadequate cytotrophoblast invasion of the uterine spiral arteries. Placental ischemia may promote the release of a variety of biologically active factors, including cytokines such as tumor necrosis factor-alpha and reactive oxygen species. Threshold increases in the plasma levels of placental factors may lead to endothelial cell dysfunction, alterations in the release of vasodilator substances such as nitric oxide (NO), prostacyclin (PGI(2)), and endothelium-derived hyperpolarizing factor, and thereby reductions of the NO-cGMP, PGI(2)-cAMP, and hyperpolarizing factor vascular relaxation pathways. The placental factors may also increase the release of or the vascular reactivity to endothelium-derived contracting factors such as endothelin, thromboxane, and ANG II. These contracting factors could increase intracellular Ca(2+) concentrations ([Ca(2+)](i)) and stimulate Ca(2+)-dependent contraction pathways in vascular smooth muscle. The contracting factors could also increase the activity of vascular protein kinases such as protein kinase C, leading to increased myofilament force sensitivity to [Ca(2+)](i) and enhancement of smooth muscle contraction. The decreased endothelium-dependent mechanisms of vascular relaxation and the enhanced mechanisms of vascular smooth muscle contraction represent plausible causes of the increased vascular resistance and arterial pressure associated with preeclampsia.

title: Comparing the Hemodynamic Effects of Spinal Anesthesia in Preeclamptic and Healthy Parturients During Cesarean Section
abstract: Despite controversies about the safest anesthetic technique for cesarean delivery in severely preeclamptic women, there is evidence that supports the use of spinal anesthesia in this group of patients.  This prospective randomized clinical trial was designed to determine the hemodynamic effects of low-dose spinal bupivacaine and the incidence of spinal anesthesia-associated hypotension in severely preeclamptic and healthy parturients undergoing cesarean sections.  Spinal anesthesia was performed with 10 mg (= 2 mL) hyperbaric 0.5% bupivacaine plus 2.5 µg sufentanil in two groups of patients after they received 500 mL of IV lactated Ringer’s solution. Heart rate and blood pressure were recorded before spinal anesthesia and at two minutes intervals for 15 minutes after the block, and then every five minutes until the end of the surgery. Hypotension was defined as more than 25% of decline in the mean arterial blood pressure compared to the baseline in both groups (or systolic blood pressure < 100 mmHg in healthy parturients) and was treated with 5 mg IV ephedrine. The total amounts of intravenous administered fluid and the total doses of ephedrine were recorded for each patient as well.  The incidence rate of hypotension among the preeclamptic patients was lower than that of the healthy parturients, despite the former group receiving smaller volumes of intravenous fluids (P < 0.05). The total doses of IV ephedrine for treating hypotension were significantly lower among the preeclamptic patients (3.2 mg in preeclamptic patients versus 7.6 mg in normotensive patients) (P = 0.02). The one-minute Apgar score was significantly lower for the preeclamptic parturients (8.4 ± 0.7 versus 7.2 ± 1.5) (P = 0.001), but there was no significant difference in the five-minute Apgar scores between the two groups.  Our results confirm that low-dose bupivacaine spinal anesthesia is associated with a lower risk of hypotension than previously believed, and it can therefore be safely used in severe preeclamptic women undergoing cesarean delivery.

title: Prevention of maternal hypotension after regional anaesthesia for caesarean section.
abstract: Purpose of reviewHypotension during regional anaesthesia for caesarean section remains a common clinical problem, particularly for spinal anaesthesia. The purpose of this review is to evaluate recent research in this area with a focus on English language papers from the past 1–2 years.

title: Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for Caesarean section.
abstract: During spinal anaesthesia for Caesarean section, the optimal phenylephrine regimen and the optimal blood pressure (BP) to which it should be titrated are undetermined. The ideal regimen would balance efficacy for maintaining uteroplacental perfusion pressure against potential for uteroplacental vasoconstriction, both of which may affect fetal acid-base status. We compared phenylephrine infusion regimens based on three different BP thresholds.



After intrathecal injection, we infused phenylephrine 100 microg min(-1) for 2 min. Then, until delivery, we infused phenylephrine whenever systolic BP (SBP), measured every 1 min, was below a randomly assigned percentage of baseline: 100% (Group 100, n=25), 90% (Group 90, n=25) or 80% (Group 80, n=24). We compared umbilical blood gases, Apgar scores and maternal haemodynamics and symptoms.



Patients in Group 100 had fewer episodes [median 0 (range 0-8)] of hypotension (SBP <80% baseline) compared with Group 80 [5 (0-18)] and Group 90 [2 (0-7)] (P<0.001 in each instance). Total dose of phenylephrine was greater in Group 100 [median 1520 microg (interquartile range 1250-2130 microg)] compared with Group 90 [1070 (890-1360) microg] and Group 80 [790 (590-950) microg]. Umbilical arterial pH was greater in Group 100 [mean 7.32 (95% confidence interval 7.31-7.34)] than in Group 80 [7.30 (7.28-7.31)] (P=0.034). No patient had umbilical arterial pH <7.2. In Group 100, 1/24 (4%) patients had nausea or vomiting compared with 4/25 (16%) in Group 90 and 10/25 (40%) in Group 80 (P=0.006).



For optimal management, phenylephrine should be titrated to maintain maternal BP at near-baseline values.