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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.
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.
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.
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 NCT01451294
PMCID: PMC3598872  PMID: 23410186
Carotid endarterectomy; Cerebral oxygenation; Intraoperative hypotension; Phenylephrine; Ephedrine
2.  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.
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.
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.
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.
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.
PMCID: PMC3102860  PMID: 21613201
3.  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.
PMCID: PMC3940064  PMID: 24624090
cerebral autoregulation; drug effect; heart rate; fetal; near infrared spectroscopy; vasoconstrictor agents
4.  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.
PMCID: PMC4205832  PMID: 25374543
brain; blood pressure; cardiac output; NIRS; cerebral oxygenation; cerebral oximetry
5.  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 
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.
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).
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).
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.
PMCID: PMC4121492  PMID: 25097737
Apgar score; Cesarean section; Ephedrine; Neonatal outcomes; Phenylephrine; Spinal anesthesia
6.  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.
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.
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.
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.
The negative impact of phenylephrine treatment on and CBV is intensified during hypocapnia while blunted during hypercapnia.
PMCID: PMC3325051  PMID: 22391890
carbon dioxide; cerebral blood volume; cerebral tissue oxygen saturation; modulation; phenylephrine
7.  Vasopressor choice for hypotension in elective Cesarean section: ephedrine or phenylephrine? 
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.
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.
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.
PMCID: PMC3281349  PMID: 22371756
ephedrine; phenylephrine; spinal anesthesia; Cesarean section
8.  The dose effect of ephedrine on the onset time and intubating conditions after cisatracurium administration 
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.
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.
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.
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.
PMCID: PMC4121490  PMID: 25097735
Cisatracurium; Ephedrine; Hemodynamics; Intubation
9.  Comparison of Prophylactic Infusion of Phenylephrine with Ephedrine for Prevention of Hypotension in Elective Cesarean Section under Spinal Anesthesi: A Randomized Clinical Trial 
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.
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.
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.
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
10.  Prevention of post-spinal hypotension using crystalloid, colloid and ephedrine with three different combinations: A double blind randomized study 
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.
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.
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.
PMCID: PMC3544136  PMID: 23326767
Cesarean delivery; hypotension; spinal anesthesia
11.  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.
PMCID: PMC2752773  PMID: 19794988
Anesthesia, Spinal; Cesarean Section; Ephedrine; Hypotension
12.  Prophylactic effect of ephedrine to reduce hemodynamic changes associated with anesthesia induction with propofol and remifentanil 
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.
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.
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.
PMCID: PMC4009643  PMID: 24803761
Adverse effects; ephedrine; hemodynamics; propofol; remifentanil
13.  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
14.  A comparison of pharmacologic and spontaneous baroreflex methods in aging and hypertension 
Journal of hypertension  2009;27(6):1243-1251.
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.
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.
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).
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.
PMCID: PMC2745725  PMID: 19365284
aging; baroreflex sensitivity; heart rate variability; hypertension; phenylephrine technique
15.  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
16.  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.
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.
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).
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.
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.
PMCID: PMC3249864  PMID: 22223901
Bradycardia; elective caesarean section; hypotension; spinal anaesthesia; vasopressors
17.  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
18.  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.
PMCID: PMC2104562  PMID: 17676524
Cardiotoxicity; Ma Huang; ephedra; ephedrine; caffeine
19.  Comparison of phenylephrine and norepinephrine in the management of dopamine-resistant septic shock 
This study aims to compare two vasoconstrictors: – norepinephrine and phenylephrine – in the management of dopamine–resistant septic shock.
Materials and Methods:
We performed a randomized, prospective, controlled trial in 54 septic shock patients, with persistent hypotension despite adequate volume resuscitation and continued dopamine infusion ~25μg/kg/h. Patients were randomly allocated into two groups to receive either norepinephrine or phenylephrine infusion (n = 27 each) titrated to achieve a target of SBP > 90mm Hg, MAP > 75 mm Hg, SVRI > 1100 dynes.s/cm5m2, CI > 2.8 L/min/m2, DO2I > 550 ml/min/m2, and VO2I > 150 ml/min/m2 for continuous 6 h. All the parameters were recorded every 30 min and increment in dose of studied drug was done in the specified dose range if targets were not achieved. Data from pulmonary arterial and hepatic vein catheterization, thermodilution catheter, blood gas analysis, blood lactate levels, invasive blood pressure, and oxygen transport variables were compared with baseline values after achieving the targets of therapy. Differences within and between groups were analyzed using a one-way analysis of variance test and Fischer's exact test.
No difference was observed in any of the investigated parameters except for statistically significant reduction of heart rate (HR) (P<0.001) and increase in stroke volume index (SVI) (P<0.001) in phenylephrine group as compared to nonsignificant change in norepinephrine group.
Phenylephrine infusion is comparable to norepinephrine in reversing hemodynamic and metabolic abnormalities of sepsis patients, with an additional benefit of decrease in HR and improvement in SVI.
PMCID: PMC2888327  PMID: 20606906
Dopamine; norepinephrine; phenylephrine
20.  Radiofrequency Ablation:Post-ablation Assessment Using CT Perfusion with Pharmacological Modulation in a Rat Subcutaneous Tumor Model 
Academic Radiology  2009;16(3):321-331.
Rationale and Objectives
Inflammatory reaction surrounding the ablated area is a major confounding factor in the early detection of viable tumor after radiofrequency (RF) ablation. A difference in the responsiveness of normal and tumor blood vessels to vasoactive agents may be used to distinguish these regions in post-ablation follow-up. The goal of this study was to examine longitudinal perfusion changes in untreated viable tumor and the peripheral hyperemic rim of RF-ablated tumor in response to a vasoconstrictor (phenylephrine) or vasodilator (hydralazine) in a subcutaneous rat tumor model.
Materials and Methods
Bilateral subcutaneous shoulder tumors were inoculated in 24 BDIX rats and evenly divided into two groups (phenylephrine and hydralazine groups). One tumor in each animal was completely treated with RF ablation (at 90 ± 2°C for 3 minutes), and the other remained untreated. Computed tomographic perfusion scans before and after phenylephrine (10 μg/kg) or hydralazine (5 mg/kg) administration were performed 2, 7, and 14 days after ablation. Four rats per group were euthanized on each scan day, and pathologic evaluation was performed. The changes of blood flow in the peripheral rim of ablated tumor and untreated viable tumor in response to phenylephrine or hydralazine at each time point were compared. The diagnostic accuracy of viable tumor using the percentage change of blood flow in response to phenylephrine and hydralazine was compared using receiver-operating characteristic analysis.
The peripheral rim of ablated tumor presented with a hyperemic reaction with dilated vessels and congestion on day 2 after ablation, numerous inflammatory vessels on day 7, and granulation tissue formation on day 14. Phenylephrine significantly decreased the blood flow in the peripheral hyperemic rim of ablated tumor on days 2, 7, and 14 by 16.3±9.7% (P = .001), 24.0±22.6% (P = .007), and 31.1±25.4% (P = .045), respectively. In untreated viable tumor, the change in blood flow after phenylephrine was irregular and insignificant. Hydralazine decreased the blood flow in the peripheral rim of both ablated tumor and untreated viable tumor. Receiver-operating characteristic analysis showed that reliable tumor diagnosis using the percentage change of blood flow in response to phenylephrine was noted on days 2 and 7, for which the areas under the curve were 0.82 (95% confidence interval, 0.64–1.00) and 0.81 (95% confidence interval, 0.56–1.00), respectively. However, tumor diagnosis using the blood flow change in response to hydralazine was unreliable.
Phenylephrine markedly decreased blood flow in the peripheral hyperemic rim of ablated tumor but had little effect on the untreated viable tumor. Computed tomographic perfusion with phenylephrine may be useful in the long-term treatment assessment of RF ablation.
PMCID: PMC3309415  PMID: 19201361
Radiofrequency ablation; CT perfusion; vasoactive agents; tumor perfusion; postablation assessment
21.  The effect of phenylephrine on the onset time of rocuronium 
Korean Journal of Anesthesiology  2010;59(4):244-248.
Several studies have demonstrated that ephedrine shortens the onset time of muscle relaxants, and it does so probably by increasing the cardiac output. However, elevation of the systemic blood pressure through α adrenergic stimulation via ephedrine may affect the onset of muscle relaxants during the induction of anesthesia. We investigated the effect of phenylephrine, which is a selective α-1 agonist, on the onset time of rocuronium and the intubating conditions in adults after the administration of propofol.
Sixty-four patients were randomly assigned to two groups. Phenylephrine (0.9 µg/kg) (P group) or the same volume of saline (S group) was injected before rocuronium (0.6 mg/kg) administration. Anesthesia was induced with fentanyl 2 µg/kg and propofol 2 mg/kg. The onset time was defined as the time from the end of rocuronium injection to the time when a single twitch height gets to 0% or the minimum level. A well-trained anesthesiologist who was 'blinded' to the treatment groups evaluated the intubating conditions. The mean arterial pressure and heart rate were recorded before induction, before intubation, immediately after intubation and 1 minute and 2 minutes after intubation.
The onset time was 84 ± 18 sec in the P-group and 72 ± 14 sec in the S-group. There was no difference of the intubating conditions, the mean arterial pressure and the heart rate between the two groups.
A small dose of phenylephrine, which has a limited effect on blood pressure, delayed the onset time of rocuronium after the administration of propofol, and the vasoconstriction effect of phenylephrine may affect the prolongation of the rocuronium onset time at the induction of anesthesia with using propofol.
PMCID: PMC2966704  PMID: 21057613
Onset time; Phenylephrine; Rocuronium
22.  The effect of ephedrine on intraoperative hypothermia 
Korean Journal of Anesthesiology  2011;60(4):250-254.
Prevention of intraoperative hypothermia has become a standard of operative care. Since ephedrine has a thermogenic effect and it is frequently used to treat hypotension during anesthesia, this study was designed to determine the effect of ephedrine on intraoperative hypothermia of patients who are undergoing spine surgery.
Twenty-four patients were randomly divided to receive an ephedrine (the ephedrine group, n = 12) or normal saline (the control group, n = 12) infusion for 2 h. The esophageal temperature (the core temperature), the index finger temperature (the peripheral temperature) and the hemodynamic variables such as the mean blood pressure and heart rate were measured every 15 minutes after the intubation.
At the end of the study period, the esophageal temperature and hemodynamic variables were significantly decreased in the control group, whereas those in the ephedrine group were stably maintained. The index finger temperature was significantly lower in the ephedrine group compared to that in the control group, suggesting the prevention of core-to-peripheral redistribution of the heat as the cause of temperature maintenance.
An intraoperative infusion of ephedrine minimized the decrease of the core temperature and it stably maintained the hemodynamic variables during spine surgery with the patient under general anesthesia.
PMCID: PMC3092959  PMID: 21602974
Anesthesia; General; Hypothermia; Temperature
23.  Dose fentanyl injection for blunting the hemodynamic response to intubation increase the risk of reflex bradycardia during major abdominal surgery? 
Korean Journal of Anesthesiology  2012;63(5):402-408.
Although supplemental fentanyl has been widely used to blunt the hemodynamic responses to laryngoscopic intubation, its residual vagotonic effect may increase the risk of reflex bradycardia. We compared the incidence and severity of significant reflex bradycardia after a bolus injection of equivalent doses of fentanyl and remifentanil (control drug).
In this prospective, randomized, double-blind study, 220 adult patients undergoing major abdominal surgery were randomly assigned to receive fentanyl (1.5 µg/kg) or remifentanil (1.5 µg/kg). No anticholinergic prophylaxis was administered. Symptomatic reflex bradycardia was defined as a sudden decrease in heart rate to < 50 beats per minute (bpm) or to 50-59 bpm associated with a systolic arterial pressure < 70 mmHg in connection with surgical maneuvers. If bradycardia or hypotension developed, atropine or ephedrine was administered following a predefined treatment protocol.
In total, 188 subjects (remifentanil, 95; fentanyl, 93) were included. The proportion of subjects with symptomatic reflex bradycardia in the fentanyl group was similar to that in the remifentanil group (30.1% vs. 28.4%, respectively). Atropine and/or ephedrine were needed similarly in both groups. The differences between the group of 55 patients who presented with symptomatic reflex bradycardia were not statistically significant with respect to the lowest heart rate, anesthetic depth-related data (bispectral index and end-tidal sevoflurane concentration), or the proportion of causative surgical maneuvers.
Fentanyl (1.5 µg/kg) administered intravenously during anesthetic induction is unlikely to increase the incidence and severity of significant reflex bradycardia in patients undergoing major abdominal surgery.
PMCID: PMC3506848  PMID: 23198032
Bradycardia; Fentanyl; Reflex; Surgical procedures
24.  Sevoflurane versus propofol for interventional neuroradiology: a comparison of the maintenance and recovery profiles at comparable depths of anesthesia 
Korean Journal of Anesthesiology  2014;66(4):290-294.
Sevoflurane and propofol are used widely for interventional neuroradiology (INR). Using the bispectral index (BIS), we compared the clinical properties of sevoflurane and propofol anesthesia in patients undergoing INR at comparable depths of anesthesia.
The patients were allocated randomly into two groups. The sevoflurane group received propofol (1.5 mg/kg), alfentanil (5 µg/kg), and rocuronium (0.6 mg/kg) for induction, and the propofol group was induced with a target effect-site concentration of propofol (4 µg/ml), alfentanil (5 µg/kg), and rocuronium (0.6 mg/kg). After intubation, anesthesia was maintained with sevoflurane or propofol with 67% nitrous oxide in 33% oxygen. Sevoflurane and propofol concentrations were titrated to maintain the BIS at 50-60. Phenylephrine or opioid was used to maintain the mean arterial pressure within 20% of the baseline values. The amounts of phenylephrine or alfentanil used, the number of patients showing movement during the procedure, and the recovery times were recorded.
Compared to the propofol group, the sevoflurane group showed faster recovery in spontaneous ventilation, eye opening, extubation, and orientation (4 vs. 7 min, 7 vs. 9 min, 8 vs. 10 min, 10 vs. 14 min, respectively; P < 0.01). In the propofol group, significantly greater amounts phenylephrine were used (P < 0.05), and more patients moved during the procedure (P < 0.05).
The use of sevoflurane in maintaining anesthesia during INR was associated with faster recovery, less patient movement during the procedure, and a more stable hemodynamic response when compared to propofol.
PMCID: PMC4028556  PMID: 24851164
Bispectral index; Interventional radiology; Propofol; Sevoflurane
25.  The Effects of Adding Various Doses of Clonidine to Ropivacaine in Spinal Anesthesia 
The Eurasian Journal of Medicine  2009;41(3):149-153.
In this study, we compared the clinical effects of combined doses of ropivacaine and clonidine.
Materials and Methods:
Seventy-five patients between ages 18 and 75, in ASA I–III groups who were to undergo elective lower extremity surgery, were included in the study with informed consent. Subjects were randomly assigned to 3 groups. Group I: % 1 ropivacaine 12 mg, group II: % 1 ropivacaine 12 mg + clonidine 15 µg, group III: % 1 ropivacaine 12 mg + clonidine 30 µg. Mean arterial pressure, breathing, heart rate and peripheral oxygen saturation, total amount of ephedrine and atropine used, sensory and motor block levels, level of sedation, pain level and complications were monitored.
The mean arterial pressure recorded in group III decreased significantly at 75, 105 and 120 min compared to groups I and II. In group I, time to two segment regression and time to sensory block to S2 was shorter when compared to the other groups (P<0.0001). The time to voiding and the duration of motor blockade was significantly longer in group I in comparison to the other groups. The need for atropine in group III was significantly higher (P<0.001). The incidence of hypotension and the requirement for ephedrine were significantly higher in groups II and III as compared to group I (P<0.01). Similarly, sedation in group III was significantly higher compared to the other groups (P<0.05).
In summary, our study revealed that clonidine can be added to ropivacaine for spinal anesthesia in surgical interventions to obtain deeper and longer sensory and motor block. However, hypotension, bradycardia and sedation should be monitored closely.
PMCID: PMC4261276  PMID: 25610092
Spinal anesthesia; Clonidine; Ropivacaine

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