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1.  Phenylephrine versus ephedrine on cerebral perfusion during carotid endarterectomy (PEPPER): study protocol for a randomized controlled trial 
Trials  2013;14:43.
Background
Intraoperative arterial hypotension can lead to severe complications in patients undergoing carotid endarterectomy, in particular if cerebral auto-regulation is impaired. Short-acting agents, such as phenylephrine or ephedrine, commonly used to correct intra-operative hypotension, have different hemodynamic effects. Recently, it was reported that, in healthy anesthetized subjects with intact cerebral auto-regulation, frontal lobe cerebral tissue oxygenation declined after phenylephrine bolus administration, while it was preserved after ephedrine use (Br J Anaesth 107:209–217, 2011; Neurocrit Care 12:17–23, 2010). However, the effect of both agents in patients undergoing carotid endarterectomy is unknown. The aim of this study is to assess the effect of two routinely used vasopressors (phenylephrine and ephedrine) on the cerebral hemodynamics during carotid endarterectomy.
Methods/design
Patients undergoing carotid endarterectomy will be prospectively included and randomized for correction of intraoperative hypotension with either phenylephrine (50 to 100 μg) or ephedrine (5 to 10 mg). If hypotension persists for more than five minutes after treatment, the patient will be classified as a non-responder and escape medication as preferred by the anesthesiologist will be administered. Changes in cerebral hemodynamics will be quantified by changes in transcranial Doppler-derived middle cerebral artery blood velocity and near infra-red spectroscopy-derived frontal lobe cerebral tissue oxygenation, when intra-operative hypotension is treated with phenylephrine or ephedrine in patients who undergo carotid endarterectomy with or without an adequate functioning cerebral auto-regulation.
To quantify whether the intra-operative cerebral auto-regulation is impaired or not, a decrease in breathing frequency from the normal 12 breaths per minute to 6 breaths per minute for an episode of three minutes will be performed.
Discussion
Phenylephrine and ephedrine are two of the most commonly used short-acting agents to increase blood pressure in clinical anesthesiologic practice. Monitoring of middle cerebral artery blood velocity with transcranial Doppler and frontal lobe cerebral tissue oxygenation with near infra-red spectroscopy are part of the standard of care. Furthermore, there are no reports that the three-minute modification in breathing frequency described in the “intervention”-section is harmful. Therefore, the risks for participating patients are negligible and the burden minimal.
Trial registration
Clinical trials.gov: NCT01451294
doi:10.1186/1745-6215-14-43
PMCID: PMC3598872  PMID: 23410186
Carotid endarterectomy; Cerebral oxygenation; Intraoperative hypotension; Phenylephrine; Ephedrine
2.  Prevention of hypotension associated with the induction dose of propofol: A randomized controlled trial comparing equipotent doses of phenylephrine and ephedrine 
Background and Aims:
Propofol, the most commonly used intravenous (IV) anesthetic agent is associated with hypotension on induction of anesthesia. Different methods have been used to prevent hypotension but with variable results. The objective of this study was to evaluate efficacy of equipotent doses of phenylpehrine and ephedrine in preventing the hypotensive response to the induction dose of propofol.
Material and Methods:
One hundred thirty five adult patients were randomised to one of the study groups: propofol-saline (PS), propofol-phenylephrine (PP) or propofol-ephedrine (PE) by adding study drugs to propofol. Anesthesia was induced with a mixture of propofol and the study drug. Patients were manually mask-ventilated for 5 min using 40% oxygen in nitrous oxide and isoflurane at 1%. A baseline mean arterial pressure (MAP) was recorded prior to induction of anesthesia. Systolic, diastolic and mean blood pressure and heart rate were recorded every minute for up to 5 min after induction. Hypotension was defined as a 20% decrease from the baseline MAP.
Results:
There were no significant demographic differences between the groups. Overall incidence of hypotension in this study was 38.5% (52/135). Rate of hypotension was significantly higher in group PS than group PP (60% vs. 24.4% P = 0.001) and group PE (60% vs. 31.1% P = 0.005). In contrast, a significant difference in rate of hypotension was not observed between groups PP and group PE.
Conclusion:
In equipotent doses, phenylephrine is as good as ephedrine in preventing the hypotensive response to an induction dose of propofol.
doi:10.4103/0970-9185.169083
PMCID: PMC4676245  PMID: 26702213
Ephedrine; hypotension; induction; phenylephrine; propofol
3.  Comparing prophylactic effect of phenylephrine and ephedrine on hypotension during spinal anesthesia for hip fracture surgery 
Background:
Spinal anesthesia is an accepted technique in hip fracture surgery and prevention of this complication by sympathomimetic agents is of potential clinical significance. The aim of this study is to compare the effect of prophylactic phenylephrine versus ephedrine in the prevention of hypotension during spinal anesthesia in hip fracture surgery.
Materials and Methods:
Ninety-two patients undergoing hip fracture surgery with the American Society of Anesthesiologists I and II were randomized to receive prophylaxis with ephedrine or phenylephrine immediately before the spinal anesthesia. Patients in the ephedrine group received an intravenous (IV) bolus of 10 mg ephedrine, and patients in the phenylephrine group received an IV bolus of 50 μg phenylephrine. We recorded mean arterial pressure (MAP), systolic and diastolic blood pressure, heart rate every 3 min in the first 10 min and then every 5 min until 30 min after spinal anesthesia, nausea and vomiting, additional vasopressor, and atropine administration.
Results:
The frequency of hypotension was significantly lower in MAP, systolic and diastolic pressure in group phenylephrine in 3, 6, and 9 min after spinal anesthesia (P = 0.002, P = 0.001). There were no significant differences between two groups in heart rate at different time of study. In the phenylephrine group, lower additional vasopressor was used (8.7% and 23.9%) (P = 0.04). There were no significant differences between two groups in the use of atropine (P = 0.24), nausea and vomiting.
Conclusion:
At the doses of ephedrine and phenylephrine administered in this trial, phenylephrine was better to prevent hypotension during hip fracture surgery with spinal anesthesia. Higher frequency of hypotension was observed in the ephedrine group.
doi:10.4103/2277-9175.190943
PMCID: PMC5137231  PMID: 27995106
Ephedrine; hip fracture; hypotension; phenylephrine; spinal anesthesia
4.  The Effect of Maternal and Fetal β2-Adrenoceptor and Nitric Oxide Synthase Genotype on Vasopressor Requirement and Fetal Acid-Base Status During Spinal Anesthesia For Cesarean Delivery 
Anesthesia and analgesia  2011;112(6):1432-1437.
Background
Previous work demonstrated that maternal haplotypes of the β2-adrenoceptor gene (ADRB2) influence ephedrine requirements during cesarean delivery. The use of ephedrine versus a pure α-adrenergic agonist such as phenylephrine has been associated with lower umbilical artery (UA) pH, thought to be secondary to increased fetal metabolism. There are no data evaluating the effect of fetal/neonatal genotypes on the metabolic response to maternally administered vasopressors. We hypothesized that neonatal ADRB2 genotype would affect the extent of neonatal acidemia. We also examined the effect of maternal ADRB2 and the endothelial nitric oxide synthase gene (NOS3) on ephedrine and phenylephrine requirements for treatment of maternal hypotension.
Methods
The study was performed on 104 Chinese women scheduled for cesarean delivery under spinal anesthesia who were participating in a double-blinded randomized clinical trial evaluating the maternal and neonatal effects of ephedrine versus phenylephrine infusions. Blood samples were drawn from the UA, umbilical vein and maternal radial artery to measure blood gas values, lactate, ephedrine and phenylephrine concentrations, and determine maternal and neonatal genotype at non-synonymous single nucleotide polymorphisms at codons 16 (rs1042713) and 27 (rs1042714) of ADRB2 and codon 298 (rs1799983) of NOS. Clinical variables (UA pH, UA lactate and dose of vasopressors) among genotypes were compared, and regression models were created to assess the effect of genotype on vasopressor dose and fetal acid-base status.
Results
Maternal ADRB2 genotype did not affect the ephedrine dose. Neonatal genotype at codon 16 influenced fetal acid-base status. UA pH was higher in Arg16 homozygous neonates (7.31 ± 0.03 in p.16Arg/Arg vs 7.25 ± 0.11 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.03 ~ 0.09) and UA lactate was lower (2.67 mmol/L ± 0.99 in p.16Arg/Arg vs 4.28 mmol/L ± 2.79 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference −2.40 ~ −0.82). In neonates born to mothers receiving ephedrine, the magnitude of the difference among genotypes was even greater (pH 7.30 ± 0.02 in p.16Arg/Arg vs 7.19 ± 0.10 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.07 ~ 0.14) and UA lactate was lower (3.66 mmol/L ± 1.30 in p.16Arg/Arg vs 5.79 mmol/L ± 2.88 in p.16 Arg/Gly and p.16 Gly/Gly; p = 0.003, 95% C.I of difference −3.48 ~ −0.80). In a multiple linear regression model (R2 = 63.6%; P = 0.03), neonatal ADRB2 genotypes (p.16Arg/Arg and p.27Gln/Glu) and lower neonatal birth weight predicted lower UA lactate concentrations.
Phenylephrine dose was not affected by maternal ADRB2 or NOS3 genotypes, and neonatal NOS3 genotype did not affect UA pH or UA lactate.
Conclusion
In contrast to previous findings in a North American cohort, maternal ADRB2 genotype did not affect ephedrine requirements during elective cesarean delivery in a Chinese cohort. However, our findings suggest that neonatal ADRB2 p.Arg16 homozygosity confers a protective effect against developing ephedrine-induced fetal acidemia.
doi:10.1213/ANE.0b013e3182179424
PMCID: PMC3102860  PMID: 21613201
5.  Effect of phenylephrine vs. ephedrine on frontal lobe oxygenation during caesarean section with spinal anesthesia: an open label randomized controlled trial 
Background: During caesarean section spinal anesthesia may provoke maternal hypotension that we prevent by administration of phenylephrine and/or ephedrine. Phenylephrine is however reported to reduce the near infrared spectroscopy-determined frontal lobe oxygenation (ScO2) but whether that is the case for patients exposed to spinal anesthesia is not known.
Objectives: To evaluate the impact of phenylephrine vs. ephedrine on ScO2during caesarean section with spinal anesthesia in a single center, open-label parallel-group study with balanced randomization of 24 women (1:1). Secondary aims were to compare the effect of the two drugs on maternal hemodynamics and fetal heart rate.
Intervention: Ephedrine (0.8–3.3 mg/min) vs. phenylephrine infusion (0.02–0.07 mg/min).
Results: For the duration of surgery, administration of ephedrine maintained ScO2 (compared to baseline +2.1 ± 2.8%; mean ± SE, while phenylephrine reduced ScO2 (−8.6 ± 2.8%; p = 0.005) with a 10.7% difference in ScO2between groups (p = 0.0106). Also maternal heart rate was maintained with ephedrine (+3 ± 3 bpm) but decreased with phenylephrine (−11 ± 3 bpm); difference 14 bpm (p = 0.0053), but no significant difference in mean arterial pressure (p = 0.1904) or CO (p = 0.0683) was observed between groups. The two drugs also elicited an equal increase in fetal heart rate (by 19 ± 3 vs. 18 ± 3 bpm; p = 0.744).
Conclusion: In the choice between phenylephrine and ephedrine for maintenance of blood pressure during caesarean section with spinal anesthesia, ephedrine maintains frontal lobe oxygenation and maternal heart rate with a similar increase in fetal heart rate as elicited by phenylephrine.
Trial registration: Clinical trials NCT 01509521 and EudraCT 2001 006103 35.
doi:10.3389/fphys.2014.00081
PMCID: PMC3940064  PMID: 24624090
cerebral autoregulation; drug effect; heart rate; fetal; near infrared spectroscopy; vasoconstrictor agents
6.  Preserved frontal lobe oxygenation following calcium chloride for treatment of anesthesia-induced hypotension 
Vasopressor agents may affect cerebral oxygenation (rScO2) as determined by near-infrared spectroscopy on the forehead. This case series evaluated the effect of calcium chloride vs. α and β-adrenergic receptor agonists on rScO2 in patients (n = 47) undergoing surgery during i.v. anesthesia. Mean arterial pressure (MAP) and cardiac output (CO) were assessed by Model-flow® and ephedrine (55 ± 3 vs. 74 ± 9 mmHg; 10 mg, n = 9), phenylephrine (51 ± 5 vs. 78 ± 9 mmHg, 0.1 mg, n = 11), adrenaline (53 ± 3 vs. 72 ± 11 mmHg; 1–2 μg, n = 6), noradrenaline (53 ± 5 vs. 72 ± 12 mmHg; 2–4 μg, n = 11), and calcium chloride (49 ± 7 vs. 57 ± 16 mmHg; 5 mmol, n = 10) increased MAP (all P < 0.05). CO increased with ephedrine (4.3 ± 0.9 vs. 5.3 ± 1.2, P < 0.05) and adrenaline (4.7 ± 1.2 vs. 5.9 ± 1.1 l/min; P = 0.07) but was not significantly affected by phenylephrine (3.9 ± 0.7 vs. 3.6 ± 1.0 l/min), noradrenaline (3.8 ± 1.2 vs. 3.7 ± 0.7 l/min), or calcium chloride (4.0 ± 1.4 vs. 4.1 ± 1.5 l/min). Following administration of β-adrenergic agents and calcium chloride rScO2 was preserved while after administration of α-adrenergic drugs rScO2 was reduced by app. 2% (P < 0.05). Following α-adrenergic drugs to treat anesthesia-induced hypotension tissue oxygenation is reduced while the use of β-adrenergic agonists and calcium chloride preserve tissue oxygenation.
doi:10.3389/fphys.2014.00407
PMCID: PMC4205832  PMID: 25374543
brain; blood pressure; cardiac output; NIRS; cerebral oxygenation; cerebral oximetry
7.  Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects 
Aim
The combination of ephedrine and caffeine has been used in herbal products for weight loss and athletic performance-enhancement, but the pharmacokinetic profiles of these compounds have not been well characterized. This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects.
Methods
The pharmacokinetic model was developed based on the simultaneous modelling using plasma samples gathered from two clinical trials. The treatments consisted of single-doses of pharmaceutical caffeine and ephedrine, given alone or together, and an herbal formulation containing both caffeine and ephedrine. We used a mixed-effect statistical model and the program NONMEM to take account of intersubject variability.
Results
Three hundred and seventy-nine ephedrine, 352 norephedrine, 417 caffeine plasma concentrations and 40 ephedrine urine concentrations were obtained from 24 subjects. A one-compartment model with first-order absorption described the caffeine data. Caffeine clearance was 0.083 l min−1 (CV 38%) and decreased to 0.038 l min−1 in presence of oral contraceptive therapy, its volume of distribution was 38.6 l (CV 20%) and its absorption rate constant was 0.064 l min−1 (CV 50%). A four-compartment model described the pharmocokinetics of ephedrine and norephedrine. Ephedrine was eliminated mostly renally, with a clearance of 0.34 l min−1 (CV 11%), and a volume of distribution of 181 l (CV 19%). Nonlinearity in the conversion of ephedrine to norephedrine was observed. Different models showed that the simultaneous administration of caffeine, or the amount of caffeine in the absorption compartment, was associated with a slower rate of absorption of ephedrine. A 32% greater relative bioavailability of herbal compared with pharmaceutical ephedrine administration was observed.
Conclusions
We describe a mechanistic model for ephedrine, norephedrine and caffeine pharmacokinetics and their interactions. The relative bioavailability of ephedrine differed between the herbal supplement compared with the pharmaceutical formulation. Concomitant ingestion of caffeine slowed the absorption rate of ephedrine, which is mainly related to the amount of the former in the absorption compartment. A saturable process appears to be involved in the metabolism of ephedrine to norephedrine.
doi:10.1111/j.1365-2125.2005.02254.x
PMCID: PMC1884794  PMID: 15752380
pharmacokinetics; caffeine; ephedra alcaloids; interaction
8.  The effects on Apgar scores and neonatal outcomes of switching from a combination of phenylephrine and ephedrine to phenylephrine alone as a prophylactic vasopressor during spinal anesthesia for cesarean section 
Background
Ephedrine, unlike phenylephrine, has a dose-related propensity to depress fetal pH during spinal anesthesia during cesarean section. A low arterial umbilical cord pH has a strong association with neonatal mortality and morbidity. The purpose of this retrospective study was to investigate influences of vasopressor change on Apgar scores and adverse neonatal outcomes in cesarean section.
Methods
In obstetric anesthesia, we changed the prophylactic vasopressor from a combination of phenylephrine and ephedrine to phenylephrine alone in 2000. We evaluated the impact of vasopressor change on Apgar scores (1 and 5 min), incidence of Apgar score < 7 (1 and 5 min), neonatal seizure, continuous positive airway pressure (CPAP), intermittent positive pressure ventilation (IPPV), intraventricular hemorrhage (IVH), periventricular leucomalacia (PVL), and hypoxic ischemic encephalopathy (HIE) in low-risk elective cesarean sections during a period when the combination of phenylephrine and ephedrine was used (2008-2009, two years) and the period of phenylephrine use alone (2011-2012, two years).
Results
There were no differences in Apgar scores (1 and 5 min), the incidence of 5 min Apgar score < 7, neonatal seizure, CPAP, IPPV, IVH, PVL, and HIE between the two time periods. However, the incidence of 1 min Apgar < 7 was decreased during the period of phenylephrine use compared with the period of phenylephrine and ephedrine use (P = 0.002).
Conclusions
Conversion from a combination of phenylephrine and ephedrine to phenylephrine alone as a prophylactic anti-hypotensive drug during spinal anesthesia for cesarean section in low-risk pregnancy may be associated with a significant decrease in the incidence of 1 min Apgar < 7.
doi:10.4097/kjae.2014.67.1.38
PMCID: PMC4121492  PMID: 25097737
Apgar score; Cesarean section; Ephedrine; Neonatal outcomes; Phenylephrine; Spinal anesthesia
9.  The dose effect of ephedrine on the onset time and intubating conditions after cisatracurium administration 
Background
The aim of this randomized, double-blind, placebo-controlled study was to evaluate dose effects of ephedrine pretreatment on the onset time and intubating conditions after cisatracurium administration.
Methods
A total of 140 adult patients were randomized into 4 groups to receive either 30 µg/kg ephedrine (Group 30, n = 35), 70 µg/kg ephedrine (Group 70, n = 35), 110 µg/kg ephedrine (Group 110, n = 35), 3 ml normal saline (Group C, n = 35) as pretreatment given 30 s before anesthetic induction. Neuromuscular block was achieved with 0.15 mg/kg cisatracurium, evaluated accelomyographically with train-of-four stimulation. An anesthesiologist blinded to patient grouping assessed the intubating conditions 1.5 min after cisatracurium administration.
Results
An onset time of 70 s was obtained in the ephedrine groups (Group 30: 155.4 ± 44.7 s, Group 70: 152.6 ± 40.3 s, Group 110: 151.2 ± 51.6 s) compared to Group C (224.6 ± 56.9 s) after 0.15 mg/kg of cisatracurium (P < 0.001). Ephedrine doses of either 70 or 110 µg/kg for pretreatment significantly improved intubating conditions (P < 0.05). Systolic and diastolic blood pressure and heart rate at 1 min after tracheal intubation were significantly increased than other times in all groups (P < 0.001), with no differences among the groups. However, 5 patients in Group 110 experienced marked hypertension (systolic/diastolic blood pressure: > 200/100 mmHg) 1 min after tracheal intubation with no patients in other groups.
Conclusions
We conclude that pre-treatment with ephedrine 70 µg/kg improved intubating conditions 1.5 min after cisatracurium administration and facilitated the onset of neuromuscular block (70 s) without adverse hemodynamic effects.
doi:10.4097/kjae.2014.67.1.26
PMCID: PMC4121490  PMID: 25097735
Cisatracurium; Ephedrine; Hemodynamics; Intubation
10.  Vasopressor choice for hypotension in elective Cesarean section: ephedrine or phenylephrine? 
Introduction
Hypotensive episodes are a common complication of spinal anesthesia during Cesarean section. The purpose of this study was to compare the effectiveness and the side effects of vasopressors, ephedrine and phenylephrine, administered for hypotension during elective Cesarean section under spinal anesthesia.
Material and methods
The study consisted of 100 selected ASA I/II females scheduled for elective Cesarean section under spinal anesthesia. Each patient was randomly assigned to one of the two double-blind study groups. Group E received 1 ml ephedrine (5 mg/ml) with normal saline if hypotension was present (n=50). Group P received 1 ml phenylephrine (100 µg/ml) with normal saline if hypotension developed (n=50). Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) were compared within and between groups to basal levels at time increments of 0, 2, 4, 6, 8, 10, 15, 20, 25, 30, 45, and 60 min from start of surgery. Incidence of side effects and neonatal outcomes were studied between groups.
Results
All patients required vasopressor therapy for hypotension. Administration of phenylephrine was associated with significant drop in HR. Changes in SBP, DBP, and MAP were similar in both groups for most observed times. The incidences of nausea/vomiting and tachycardia were significantly higher in the ephedrine group.
Conclusions
Phenylephrine and ephedrine are acceptable choices to combat maternal hypotension related to spinal anesthesia in elective Cesarean section. Complications of intra-operative nausea and vomiting, tachycardia and bradycardia should be considered when choosing a vasopressor, suggesting phenylephrine may be more appropriate when considering maternal well-being.
doi:10.5114/aoms.2010.13905
PMCID: PMC3281349  PMID: 22371756
ephedrine; phenylephrine; spinal anesthesia; Cesarean section
11.  Impact of phenylephrine administration on cerebral tissue oxygen saturation and blood volume is modulated by carbon dioxide in anaesthetized patients† 
BJA: British Journal of Anaesthesia  2012;108(5):815-822.
Background
Multiple studies have shown that cerebral tissue oxygen saturation () is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on is affected by arterial blood carbon dioxide partial pressure () because CO2 is a powerful modulator of cerebrovascular tone.
Methods
In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ∼20–30% during hypocapnia, normocapnia, and hypercapnia. and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment.
Results
Phenylephrine caused a significant decrease in during hypocapnia [=−3.4 (1.5)%, P<0.001], normocapnia [=−2.4 (1.5)%, P<0.001], and hypercapnia [=−1.4 (1.5)%, P<0.01]. Decreases in were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia.
Conclusion
The negative impact of phenylephrine treatment on and CBV is intensified during hypocapnia while blunted during hypercapnia.
doi:10.1093/bja/aes023
PMCID: PMC3325051  PMID: 22391890
carbon dioxide; cerebral blood volume; cerebral tissue oxygen saturation; modulation; phenylephrine
12.  Prevention of post-spinal hypotension using crystalloid, colloid and ephedrine with three different combinations: A double blind randomized study 
Background:
The benefit of prophylactic combination therapy using crystalloid and colloid preload with ephedrine has not been cleared to prevent maternal hypotension after spinal anesthesia at cesarean delivery. This study evaluated the efficacy of three combinational methods to prevent hypotension following spinal anesthesia.
Materials and Methods:
In this prospective double blind trial, 150 candidates of elective cesarean delivery under spinal anesthesia were randomly allocated to three treatment groups; 1---Ringer's Lactate (RL) solution (15 ml/kg) plus Hemaxel (7 ml/kg) preload, 2---RL solution (15 ml/kg) preload plus ephedrine (15 mg, IV, bolus), 3---Hemaxel (7 ml/kg) preload plus ephedrine (15 mg, IV, bolus). Maternal hemodynamic changes during 60 min after spinal injection, nausea/vomiting, and neonatal condition were compared among the groups.
Results:
The cumulative incidence of hypotension was 44%, 40%, and 46% in groups 1 to 3, respectively. There were not significant differences in supplementary ephedrine requirement among groups which received or among groups which did not receive prophylactic ephedrine. Groups were not different in the incidence of hypertension and nausea or vomiting. There were no significant differences among groups in Apgar scores at 1 or 5 min and umbilical artery PH.
Conclusion:
Combination of preventive methods decreased the occurrence of hypotension following spinal anesthesia to an acceptable level. Overall, the most effective method was a combination of crystalloid preload with ephedrine.
doi:10.4103/2277-9175.100129
PMCID: PMC3544136  PMID: 23326767
Cesarean delivery; hypotension; spinal anesthesia
13.  Comparison of Prophylactic Infusion of Phenylephrine with Ephedrine for Prevention of Hypotension in Elective Cesarean Section under Spinal Anesthesi: A Randomized Clinical Trial 
Background
Spinal anesthesia is an accepted technique in elective cesarean sections. However, hypotension, resulted from sympathectomy is a common problem, especially in pregnant women. Prevention of this complication by sympathomimetic agents is of potential clinical significance. The aim of this study is to compare the effect of prophylactic infusion of Phenylephrine versus Ephedrine in the prevention of hypotension during spinal anesthesia in elective cesarean section.
Methods
Eighty-three patients were enrolled in this study and randomly divided into three groups. Group Ph received phenylephrine infusion, group E received ephedrine infusion while group P were delivered placebo. Vital signs (blood pressure, heart rate, and arterial oxygen saturation) were recorded throughout the surgery. Maternal and neonatal perioperative complications were also controlled and recorded.
Results
There was an insignificant difference in demographic data between the groups. Systolic and diastolic blood pressures were higher in the phenylephrine group than control, but not higher than the ephedrine group. Maternal dysrhythmias were more common in ephedrine and phenylephrine groups than the control group. Vomiting was more common in ephedrine group (P<0.05). In addition, the fifth-minute Apgar score of neonates was higher in phenylephrine and ephedrine groups than the control group (P<0.05). Neonates of phenylephrine group had less acidosis than the other groups.
Conclusion
Prophylactic infusion of phenylephrine can effectively decrease spinal anesthesia related hypotension without any significant complication for mother or her fetus.
Trial Registration Number: IRCT2012120911700N1
PMCID: PMC4300475  PMID: 25649721
Phenylephrine; Ephedrine; Spinal anesthesia; Cesarean section; Hypotension
14.  Hemodynamic effects of ephedrine and phenylephrine bolus injection in patients in the prone position under general anesthesia for lumbar spinal surgery 
Ephedrine and phenylephrine (PE) are vasoconstrictors commonly used to restore the blood pressure (BP) to normal values. The aim of the present study was to investigate the effects of ephedrine and PE bolus administration on intra-arterial systolic BP (ISBP), intra-arterial diastolic BP (IDBP) and cardiac output (CO) in patients undergoing lumbar spine surgery in the prone position under general anesthesia (GA). In this prospective, randomized, and double-blind study, a total of 60 patients aged 20–60 years and undergoing elective lumbar spine surgery were administered either a single dose of ephedrine (0.1 mg/kg) or PE (1 µg/kg) through a central venous catheter as a bolus injection following the achievement of a stable hemodynamic status for ≥10 min. Following bolus injection of ephedrine or PE, a significant increase in ISBP was observed in the two experimental groups compared with pre-ephedrine and pre-PE values. The duration of the increment in ISBP however was significantly longer in the ephedrine group compared with the PE group. A similar response was observed in IDBP. A significant increase in CO began 1 min following ephedrine injection and lasted for the entire observation period, whereas the increase was only sustained for 3 min following bolus injection in the PE group. The results of the present study demonstrated that bolus ephedrine produces a more persistent pressor response and durable increase in CO and CI compared with PE when patients are in the prone position with GA for spine surgery.
doi:10.3892/etm.2016.3432
PMCID: PMC4950852  PMID: 27446334
ephedrine; phenylephrine; prone position; general anesthesia; hemodynamic
15.  The Effects of Intravenous Ephedrine During Spinal Anesthesia for Cesarean Delivery: A Randomized Controlled Trial 
Journal of Korean Medical Science  2009;24(5):883-888.
We designed a randomized, double-blinded study to determine the efficacy and safety of 0.5 mg/kg intravenous ephedrine for the prevention of hypotension during spinal anesthesia for cesarean delivery. Patients were randomly allocated into two groups: ephedrine group (n=21) and control group (n=21). Intravenous preload of 15 mL/kg lactated Ringer's solution was given. Shortly after the spinal injection, ephedrine 0.5 mg/kg or saline was injected intravenous for 60 sec. The mean of highest and lowest heart rate in the ephedrine group was higher than those of control group (P<0.05). There were significant lower incidences of hypotension and nausea and vomiting in the ephedrine group compared with the control group (8 [38.1%] vs. 18 [85.7%]); (4 [19%] vs. 12 [57.1%], respectively) (P<0.05). The first rescue ephedrine time in the ephedrine group was significantly longer (14.9±7.1 min vs. 7.9±5.4 min) than that of the control group (P<0.05). Neonatal outcome were similar between the study groups. These findings suggest, the prophylactic bolus dose of 0.5 mg/kg intravenous ephedrine given at the time of intrathecal block after a crystalloid fluid preload, plus rescue boluses reduce the incidence of hypotension.
doi:10.3346/jkms.2009.24.5.883
PMCID: PMC2752773  PMID: 19794988
Anesthesia, Spinal; Cesarean Section; Ephedrine; Hypotension
16.  Prophylactic effect of ephedrine to reduce hemodynamic changes associated with anesthesia induction with propofol and remifentanil 
Background:
One of the complications of anesthesia induction with propofol is a substantial decrease in arterial blood pressure and heart rate (HR), which can be intensified by adding remifentanil. This study aimed to assess the prophylactic effects of two doses of ephedrine to control the hypotension and bradycardia caused by anesthesia induced with propofol and remifentanil.
Materials and Methods:
A total of 150 patients candidate for short-term minor elective orthopedic and ophthalmic surgery under general anesthesia were randomized to three groups receiving normal saline, low dose ephedrine (0.07 mg/kg) or high dose ephedrine (0.15 mg/kg). Anesthesia was induced in all groups with propofol 2.5 mg/kg and remifentanil 3 μg/kg. No neuromuscular blocking agent was used. Patients’ hemodynamic status was assessed in the following four steps: Immediately before, 2 min after induction of anesthesia, as well as 1 and 5 min after intubation.
Results:
A total of 143 patients consisting of 46 patients in the low dose ephedrine (0.07 mg/kg) group, 49 patients in the high dose ephedrine (0.15 mg/kg) group and 48 controls completed the trial. In all three groups, after induction of anesthesia, significant decreases occurred in the mean systolic, diastolic and mean arterial pressures, as well as in the mean HR. This decline was highest in the control group and lowest in the high dose ephedrine (0.15 mg/kg) group.
Conclusion:
Our findings suggest that the administration of high dose ephedrine (0.15 mg/kg) may have a significant effect in preventing hypotension and bradycardia after anesthesia induction with propofol and remifentanil.
doi:10.4103/0970-9185.130024
PMCID: PMC4009643  PMID: 24803761
Adverse effects; ephedrine; hemodynamics; propofol; remifentanil
17.  Effect of phenylephrine infusion on atrial electrophysiological properties. 
Heart  1997;78(2):166-170.
OBJECTIVE: To determine the effect of changes in autonomic tone induced by phenylephrine infusion on atrial refractoriness and conduction. DESIGN: Left and right atrial electrophysiological properties were measured before and after a constant phenylephrine infusion designed to increase sinus cycle length by 25%. SUBJECTS: 20 patients, aged 53 (SD 6) years, undergoing electrophysiological study for investigation of idiopathic paroxysmal atrial fibrillation (seven patients) or for routine follow up after successful catheter ablation of supraventricular tachycardia (13 patients). MAIN OUTCOME MEASURES: Changes in left and right atrial effective refractory periods, atrial activation times, and frequency of induction of atrial fibrillation. RESULTS: Phenylephrine (mean dose 69 (SD 18) mg/min) increased mean blood pressure by 22 (12) mm Hg (range 7 to 44) and lengthened sinus cycle length by 223 (94) ms (20 to 430). Left atrial effective refractory period lengthened following phenylephrine infusion from 250 (25) to 264 (21) ms (P < 0.001) but there was no significant change in right atrial effective refractory period: 200 (20) v 206 (29), P = 0.11. There was a significant relation between the effect of phenylephrine on sinus cycle length and on right atrial refractoriness (r = 0.6, P = 0.005) with shortening of right atrial refractoriness in patients with the greatest prolongation in sinus cycle length. During phenylephrine infusion, the right atrial stimulus to left atrial activation time at the basic pacing cycle length of 600 ms was unchanged, at 130 (18) v 131 (17) ms, but activation delay with a premature extrastimulus increased: 212 (28) v 227 (38) ms, P = 0.002. Atrial fibrillation was induced by two of 58 refractory period measurements at baseline and by 12 of 61 measurements during phenylephrine infusion (P < 0.01). Phenylephrine increased the difference between left and right atrial refractory periods by 22.8 (19.4) ms in the five patients with induced atrial fibrillation after phenylephrine compared to 0.9 (16.2) ms in the 13 patients without induced atrial fibrillation after phenylephrine infusion (P = 0.02). CONCLUSIONS: Phenylephrine infusion increased left atrial refractoriness and intra-atrial conduction delay following a premature right atrial extrastimulus. Induction of atrial fibrillation during phenylephrine infusion was associated with non-uniform changes in atrial refractoriness. These data support the concept that changes in autonomic tone may precipitate atrial fibrillation in susceptible individuals.
PMCID: PMC484898  PMID: 9326992
18.  Efficacy of preanesthetic intramuscular administration of ephedrine for prevention of anesthesia-induced hypotension in cats and dogs 
The Canadian Veterinary Journal  2009;50(2):179-184.
To determine if the preanesthetic administration of ephedrine would prevent anesthesia-induced hypotension in dogs and cats, 10 cats were anesthetized with acepromazine, butorphanol, ketamine, and isoflurane, and 8 dogs were anesthetized with acepromazine, morphine, propofol, and halothane. Cats received ephedrine or saline 10 minutes after premedication. Dogs received ephedrine or saline at the time of premedication. Systolic arterial blood pressure, respiratory rate, heart rate, end-tidal CO2, O2 saturation, cardiac rhythm, and rectal temperature were recorded.
The systolic arterial pressure in cats receiving saline was significantly lower than baseline at 10 minutes after premedication, and systolic arterial pressure was < 80 mmHg for the duration of anesthesia. In cats receiving ephedrine, the systolic arterial pressure was significantly lower than baseline for the duration of anesthesia, but systolic arterial pressure was not < 80 mmHg until 25 min after induction. In dogs, systolic arterial pressure was significantly lower than baseline by 5 and 40 min after pre-medication in dogs receiving saline and ephedrine, respectively. There was no difference in heart rate, respiratory rate, end-tidal CO2, rectal temperature, O2 saturation, or cardiac rhythm among treatment groups. Prophylactic ephedrine delayed, but did not prevent, the onset of hypotension.
PMCID: PMC2629422  PMID: 19412398
19.  Distribution and types of adrenoceptors in the guinea-pig ileum: the action of α-and β-adrenoceptor agonists 
British Journal of Pharmacology  1981;72(2):201-210.
1 Segments of guinea-pig ileum and the myenteric plexus-longitudinal smooth muscle preparation were used for a study of the actions of adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine on the responses of coaxially stimulated ileum at different distances from the ileocaecal valve.
2 The responses of the ileum to electrical stimulation were suppressed by adrenaline, nonadrenaline and ephedrine, while phenylephrine and isoprenaline inhibited them only partially.
3 The twitch inhibition elicited by these adrenoceptor agonists was the same at all distances from the ileocaecal valve. There was no significant difference between their cumulative and non-cumulative concentration-response curves.
4 Smooth muscle relaxation was induced only by isoprenaline and contraction only by phenylephrine at all distances from the ileocaecal junction. Adrenaline and noradrenaline evoked smooth muscle contraction in the terminal (0 to 20 cm), a concentration-dependent, biphasic response in the intermediate part (21 to 50 cm) and a relaxation in the proximal ileum (> 50 cm from the ilecocaecal valve). Ephedrine did not change significantly the smooth muscle tension in the terminal and the intermediate segments and induced smooth muscle relaxation in the proximal ones.
5 Ouabain and a potassium-free solution did not appear to influence the prejunctional action of noradrenaline nor the amplitude of smooth muscle relaxation in the proximal ileum, whereas the concentration-contractor response curves were significantly depressed and shifted to the right by ouabain and in a potassium-free solution.
6 The brief initial (phasic) contraction induced by acetylcholine was not influenced during the sustained increase or decrease in tension induced by catecholamines. On the contrary, the stimulatory catecholamine actions disappeared or were changed to smooth muscle relaxation by acetylcholine pretreatment. Potassium chloride pretreatment did not change the character of the adrenoceptor agonist action of the agonists studied.
7 Since there is a similar prejunctional action at all distances from the ileocaecal valve and a different postjunctional effect of the adrenoceptor agonists at different distances from the ileocaecal junction, it could be suggested that in the guinea-pig ileum there are at least two α-adrenoceptors (inhibitory prejunctional-α2, stimulatory postjunctional-α1), an inhibitory postjunctional β-adrenoceptor and an as yet uncharacterized inhibitory postjunctional receptor.
8 Based on the specific postjunctional action of phenylephrine and the prejunctional action of ephedrine in the guinea-pig ileum, these drugs could be used with success as `specific' α1- and α2-adrenoceptor stimulants.
PMCID: PMC2071517  PMID: 6111369
20.  Maternal and Neonatal Effects of Vasopressors Used for Treating Hypotension after Spinal Anesthesia for Caesarean Section: A Randomized Controlled Study 
AIM:
The aim of the study was to examine whether ephedrine and phenylephrine were different in their efficacy for managing maternal hypotension and their effect of adverse maternal and neonatal outcome.
METHODS:
A double-blind randomized controlled study in healthy pregnant women ASA physical status 2, which underwent elective caesarian delivery under spinal anesthesia. Patients were randomized to receive an intravenous bolus of either phenylephrine (Ph group) or ephedrine (E group) immediately after the episode of hypotension after spinal anesthesia. Maternal and neonatal outcomes were recorded.
RESULTS:
Two hundred and two (202) pregnant women at term were entered in this study. There were no differences between group E and group Ph regarding the incidence of hypotension after vasopressor therapy, and the incidence of nausea and vomiting. There was no significant difference between groups in the first-minute and the 5th minute Apgar score, none of the neonates had the true fetal acidosis.
CONCLUSIONS:
Ephedrine and phenylephrine have the same efficacy in treating hypotension after spinal anesthesia for caesarean section. The use of Phenylephrine was associated with better fetal acid-base status, and there were no differences on Apgar score values and on the incidence of maternal bradycardia and hypotension.
doi:10.3889/oamjms.2016.003
PMCID: PMC4884253  PMID: 27275330
ephedrine; caesarean section; hypotension; maternal; neonatal outcome; phenylephrine
21.  A comparative study of infusions of phenylephrine, ephedrine and phenylephrine plus ephedrine on maternal haemodynamics in elective caesarean section 
Indian Journal of Anaesthesia  2011;55(6):578-583.
Introduction:
This randomized double blind study was started with an objective of management of spinal anaesthesia-induced hypotension in elective caesarean section by combining two commonly used vasopressors – ephedrine and phenylephrine in half of their usual doses with an expectation of reducing their foetomaternal side effects.
Methods:
One hundred and thirty two patients were randomized into three groups to receive either 100 μg/ml phenylephrine (group-P, n=31) or 3 μg/ml ephedrine (group-E, n=33) or 50 mg phenylephrine plus 1.5 mg ephedrine/ml (group-PE, n=29). Immediately after spinal injection the study solution was started prophylactically in every patient at the rate of 40 ml/h. A predefined algorithm was used to adjust the infusion rate according to the systolic blood pressure (SBP).
Results:
Mean fall of SBP was significantly more in group-E than group-P (P=0.009) and group-PE (P=0.013). This was not significantly different when compared between group-P and group-PE (P=0.9). Episodes of hypotension and tachycardia were more in group-E than the other two groups. Statistically significant tachycardia was seen in Group-E than that in other two groups. Incidence of bradycardia and hypertension did not differ significantly among the groups. Maternal nausea and Apgar score were also comparable in three groups.
Conclusion:
Current study claims that prophylactic phenylephrine 100 mg/ml is a better choice than ephedrine (3 mg/ml) or 50 mcg phenylephrine plus 1.5 mg ephedrine/ml in prevention of spinal anaesthesia-induced hypotension in elective caesarean section. Combination of two drugs in half the usual dose has no added advantage over phenylephrine, but this is better than ephedrine alone.
doi:10.4103/0019-5049.90612
PMCID: PMC3249864  PMID: 22223901
Bradycardia; elective caesarean section; hypotension; spinal anaesthesia; vasopressors
22.  A comparison of pharmacologic and spontaneous baroreflex methods in aging and hypertension 
Journal of hypertension  2009;27(6):1243-1251.
Background
Phenylephrine bolus injection is an established technique to measure baroreflex sensitivity (BRS). This study quantified the relationship between the phenylephrine method and noninvasive measures of BRS and examined the effects of aging and hypertension on BRS. We also examined whether heart rate variability (HRV) provides as much information as does BRS.
Methods
BRS was determined by phenylephrine bolus (BRSphe), amyl nitrite inhalation (BRSamyl), Valsalva maneuver (BRSVals) and by time (BRS(+)) and spectral domain analysis (BRSLFα, 004–015Hz) of spontaneous blood pressure and R—R interval changes over the 5-min time period.
Results
The phenylephrine method significantly correlated with other methods (BRSLFα R=0.54, BRS(+) R=0.55, BRSVals R=0.43 and BRSamyl R=0.39; P≤0.001). Each method underestimated the BRSphe by the factors 0.62, 0.64, 0.59 and 0.33, respectively; P value less than 0.001. Only BRSLFα was significantly different between normotensive and hypertensive patients in young [24.3±1.4 (n=40) vs. 12.2±2.3 (n=7)] and middle-aged [16.5±1.1 (n=71) vs. 10.8±1.1 (n=31) groups, respectively]. HRV in the high frequency band (0.15–0.40Hz) was significantly lower in young hypertensive patients than in normal controls (26±6.0 vs. 50±2.4, P<0.05).
Conclusion
Although all methods correlated with the phenylephrine technique, none of them could be used interchangeably with that technique. BRSLFα detected the baroreflex loss of hypertension most clearly, and BRSamyl did not differ among groups.
doi:10.1097/HJH.0b013e32832a6e1b
PMCID: PMC2745725  PMID: 19365284
aging; baroreflex sensitivity; heart rate variability; hypertension; phenylephrine technique
23.  Influence of lateral decubitus positioning after combined use of hyperbaric and hypobaric ropivacaine on hemodynamic characteristics in spinal anesthesia for caesarean section 
Purpose: Positioning of the patient during and after surgery can have significant implications on recovery. Therefore, the purpose of the present study was to determine the influence of placing patients in a lateral decubitus position for 15 min after combined use of hyperbaric and hypobaric ropivacaine and assess hemodynamic characteristics during spinal anesthesia for caesarean section. Methods: One hundred-forty patients undergoing elective cesarean delivery with combined use of hyperbaric and hypobaric ropivacaine were included in the present study. Patients meeting inclusion criteria (134) were randomly allocated into Group A: immediately turned to the supine position after induction of spinal anesthesia (n = 67) or Group B: maintained in a lateral decubitus position for 15 min before being turned to the supine position (n = 67). Primary endpoints of the study were to compare hemodynamic characteristics and sensory blockade levels in the two groups, while a secondary endpoint was to observe the incidence of complications. Results: Both groups showed similar effects of the combined anesthetic treatment. Incidence of hypotension (43% vs 18%, P = 0.001), systolic AP < 90 mmHg (36% vs. 16%, P = 0.011), usage of ephedrine (43% vs. 18%, P = 0.001) and the total dose of ephedrine [0 (0-24) vs 0 (0-18), P = 0.001] were significantly higher in Group A compared to Group B. Group A had a higher incidence of nausea compared to Group B (25% vs 7%, P = 0.005). Conclusions: Combined use of hyperbaric and hypobaric ropivacaine had satisfactory anesthetic effects and a more stable hemodynamic characteristic than either drug used alone. Maintaining the patient in a lateral decubitus position for 15 min can significantly decrease the incidence of hypotension.
PMCID: PMC4307535  PMID: 25664088
Spinal anesthesia; hyperbaric ropivacaine; hypobaric ropivacaine; caesarean section; lateral decubitus position
24.  Effects of Ketamine-Propofol Mixture on Intraocular Pressure and Haemodynamics in Elderly Patients: A Randomised Double-Blind Trial 
Objective
The aim of this study was to compare the effects of a ketamine-propofol mixture (ketofol) and propofol on intraocular pressure (IOP) and haemodynamics in elderly patients during anaesthetic management at each repeated measurement times.
Methods
Forty elderly ASA I and II patients were divided into two random groups and received either propofol (1.5 mg kg−1; group P, n=20) or ketofol (1:1 single syringe mixture of 5 mg mL−1 ketamine and 5 mg mL−1 propofol; group KP, n=20). A proseal laryngeal mask airway (PLMA) was inserted 60 seconds after induction of anaesthesia. IOP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) values were recorded at preinduction (t0), immediately following induction (t1), and at 1 (t2), 3 (t3), and 5 (t4) minutes after induction. Haemodynamic complications and the need for ephedrine were also recorded.
Results
Patient characteristics at the beginning of the procedure were similar between the groups. SBP and HR were significantly increased in group KP compared to group P at t1 and t4 (p=0.044). Induction of both anaesthetic agents significantly decreased the IOP values from the t0 (p=0.026). A significant decrease in IOP was found at t1 and t4 in group P compared to group KP (p=0.018). The total dose of ephedrine was statistically different in group P (p=0.034).
Conclusion
Ketofol can be an alternative agent to provide haemodynamic stability with a moderate decrease in IOP during anaesthesia induction in elderly patients.
doi:10.5152/TJAR.2013.56
PMCID: PMC4894100  PMID: 27366382
Intraocular pressure; hemodynamic; ketamine; propofol; elderly patient
25.  Cardiotoxicity of Ma Huang/Caffeine or Ephedrine/Caffeine in a Rodent Model System 
Toxicologic pathology  2007;35(5):657-664.
Ma Huang (equivalent to 0, 12.5, 25, or 50 mg/kg ephedrine) or ephedrine (0, 6.25, 12.5, 25 mg/kg) were administered as one bolus oral dose to male F344 rats with and without caffeine. The herbal medicine Ma Huang (ephedra) in combination with caffeine caused rapid clinical signs of toxicity including salivation, hyperactivity, ataxia, and eventually lethargy, and failure to respond to stimuli. When this syndrome of clinical signs emerged, animals were moribund sacrificed, and a histological analysis for heart lesions performed. Cardiotoxicity included hemorrhage, necrosis, and degeneration in the ventricles or interventricular septum within 2–4 hours after treatment with Ma Huang (ephedra)/caffeine or ephedrine (the principal active component in Ma Huang)/caffeine. There was a steep dose response curve for cardiotoxicity with minimal toxicity seen at levels of Ma Huang (equivalent to 12.5 mg/kg ephedrine) with caffeine. However, cardiotoxic lesions occurred in 28% of animals with Ma Huang dosages equivalent to 25 mg/kg ephedrine with 15 or 30 mg/kg caffeine, and in 90% of animals at Ma Huang exposures equivalent to 50 mg/kg ephedrine with 15 or 30 mg/kg caffeine. Cardiotoxic lesions occurred in 47% of animals in the 25 mg/kg ephedrine groups with caffeine at 7.25, 15, or 30 mg/kg. There was no statistical difference in the occurrence of cardiotoxic lesions when 15 or 30 mg/kg caffeine was combined with Ma Huang equivalent to 25 or 50 mg/kg ephedrine; likewise there was no statistical difference in the occurrence of cardiotoxic lesions when 7.25, 15, or 30 mg/kg caffeine was combined with 25 mg/kg ephedrine. These results show that the cardiotoxic effects of the herbal medicine, Ma Huang, are similar to that of ephedrine, the principal active ingredient in the herbal medicine. The combination of Ma Huang or ephedrine with caffeine enhanced the cardiotoxicity over that with the herbal medicine or the active ingredient alone.
doi:10.1080/01926230701459978
PMCID: PMC2104562  PMID: 17676524
Cardiotoxicity; Ma Huang; ephedra; ephedrine; caffeine

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