Bolus administration of ephedrine and etilefrine induces transient vasodilation just after injection in combined epidural and general anesthesia patients: A randomized clinical study.

Hypotension commonly accompanies combined epidural and general anesthesia, and intravenous bolus ephedrine and etilefrine are widely used to correct hypotension. We have noticed that systemic vascular resistance (SVR) transiently decreases just after intravenous bolus administration of these drugs. The goal of the present study was to investigate whether bolus administration of these drugs decrease SVR just after intravenous administration in combined epidural and general anesthesia patients. We investigated 40 patients who were scheduled for elective abdominal surgery. Patients were chosen as subjects if their systolic arterial pressure decreased by 20% or to <100 mmHg at 30 min after the induction of general anesthesia. Baseline hemodynamic values were recorded, and after ephedrine 10 mg injection or etilefrine 2 mg injection (equipotent), the parameters were recorded again at 0.5 min and once each min for the next 5 min thereafter. The 40 patients were enrolled into the ephedrine (n = 20) or etilefrine (n = 20) treatment groups. Patient characteristics were comparable in both groups. After ephedrine injection, SVR decreased significantly at the 1-min time point, whereas after etilefrine injection, SVR decreased significantly at the 0.5- to 2-min time points compared with baseline values. SVR at the 0.5- to 1-min time points was lower in the etilefrine versus the ephedrine group. Both drugs transiently decreased SVR after intravenous injection, but etilefrine decreased SVR much more than ephedrine, indicating that more vasodilation occurred after the injection of etilefrine than after ephedrine. It is thus important to recognize the different characteristics of these drugs.

Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).

INTRODUCTION: Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics. METHODS: Jacketed external telemetry with an implanted miniature blood pressure transmitter (JET-BP) was used to characterize the tolerability, functionality, and sensitivity of this study design in dogs. Thirty-six male or female beagles (n=6 dogs/sex/group) were administered vehicle control (reverse osmosis water) or etilefrine (1, 10mg/kg), sotalol (3, 30mg/kg), and hydralazine (1, 10mg/kg) on separate days. Telemetry data were evaluated for positive control article-related changes and retrospective power analysis was also completed. Animals were evaluated for instrumentation-related changes in clinical and anatomic pathology endpoints. RESULTS: All three positive controls elicited the expected pharmacologic responses that were statistically different at high and low doses. Retrospective power analysis confirmed this study design was able to statistically differentiate minor (approximately 5 to 15%) changes in electrocardiography and blood pressure values. This study also demonstrated the potential advantages of combining cardiovascular data across sex when the test article exposure and pharmacodynamics were consistent. Data collection using miniature telemetry blood pressure transmitters did not result in anatomic or clinical pathology findings that would prevent their use in general toxicology studies. DISCUSSION: This characterization study indicates that JET-BP in dogs offers a scientifically-robust method to evaluate novel therapeutics for potential cardiovascular liabilities.

Effect of systemic blood pressure on microcollateral circulation evaluated by real-time contrast echocardiography.

BACKGROUND: In acute myocardial infarction, residual collateral-derived myocardial blood flow (CBF) within the ischemic area is one of the major determinants of infarct size. Management of systemic blood pressure (sBP) related to maintain collateral circulation is still difficult. The aim of this study was to reveal the influence of sBP on the rescue of area at risk by collateral circulation. METHODS: Real-time myocardial contrast echocardiography just after the onset of complete occlusion of the left circumflex coronary artery was performed in collateral-rich open-chest dogs. The video intensity of the ischemic area was evaluated during the occlusion and the CBF (A x beta) was calculated from a replenishment curve: y = A (1 - e(-beta t)). To analyze the effect of sBP on the collateral circulation, sBP was altered by infusion of nitroglycerin or etilefrine hydrochloride. To evaluate the defect size (%DS), every end-systolic myocardial contrast echocardiography image after left circumflex coronary artery occlusion was converted into binary images using custom offline software. RESULTS: The %DS increased and CBF slightly decreased at low sBP. The %DS decreased and CBF increased at high sBP. At excessively high sBP, %DS increased and CBF decreased again. CONCLUSION: Real-time myocardial contrast echocardiography, which is a useful noninvasive method to evaluate the collateral perfusion quantitatively, has a crucial role in the decision of patient treatment and management strategy of acute myocardial infarction.

Effects of cafedrine/theodrenaline, etilefrine and ephedrine on uterine blood flow during epidural-induced hypotension in pregnant sheep.

INTRODUCTION: Maternal hypotension is a major concern in obstetric anesthesia, and concerns have been raised about standard vasopressor therapy with ephedrine. Therefore, we evaluated the maternal and fetal hemodynamic effects of two potential alternatives to ephedrine. METHODS: Hypotension was induced by epidural administration of lidocaine in 6 chronically instrumented pregnant ewes (at 118-122 days of gestation, term 145 days). Three treatments were studied: 25 mg ephedrine, 5 mg etilefrine and 100 mg cafedrine/5 mg theodrenaline (C/T) intravenously. Mean fetal and maternal blood pressure and heart rate, uterine blood flow, as well as fetal and maternal arterial blood gases were recorded for 60 min. RESULTS: All three vasopressors increased maternal blood pressure, accompanied by a significant increase in uterine blood flow. C/T caused marked maternal tachycardia, whereas ephedrine decreased maternal heart rate. Maternal and fetal blood gases did not change during any of the three treatment regimens. CONCLUSION: All three vasopressors restored maternal blood pressure and uterine blood flow after epidurally induced maternal hypotension. However, restoration of uterine perfusion was delayed and less pronounced with C/T.

Effect of ephedrine on auditory-evoked potentials during light general anaesthesia.

Ephedrine, a sympathomimetic drug, may stimulate the central nervous system via its amphetamine-like effect under light general anaesthesia. We compared the effect of ephedrine on auditory-evoked potentials with that of etilefrine, a sympathomimetic drug that lacks an amphetamine-like effect, in patients undergoing abdominal surgery under general anaesthesia with 67% nitrous oxide in oxygen and epidural blockade. Ephedrine (0.08 mg x kg-1 intravenously) significantly decreased the latencies of Nb and P1 from 49.5 (4.2) [mean (SD)] and 63.9 (9.1) ms to 45.9 (4.2) and 59.0 (9.9) ms, respectively; whereas etilefrine (0.02 mg x kg-1 intravenously) caused no significant changes in these potentials. In addition, the latencies of Nb and P1 before drug administration were positively correlated with patient age. These findings suggest that ephedrine can cause excitation of the central nervous system during light general anaesthesia, and that auditory-evoked potentials may be a sensitive indicator of the depth of anaesthesia.

Effect of midodrine on chlorpromazine-induced orthostatic hypotension in rabbits: comparison with amezinium, etilefrine and droxidopa.

Orthostatic hypotension was produced in urethane-anesthetized rabbit by a combination of chlorpromazine (0.1 mg/kg, i.v.) and 45 degrees head-up tilt. The effect of midodrine (1 and 3 mg/kg, i.d.) was investigated in comparison with amezinium (10 and 30 mg/kg, i.d.), etilefrine (10 and 30 mg/kg, i.d.) and droxidopa (30 and 100 mg/kg, i.d.). The higher doses of each drug significantly mitigated the chlorpromazine-induced orthostatic hypotension, while none of the lower doses caused a significant effect. The effect of midodrine developed most rapidly; a significant effect was observed 25 min after administration. The order of onset time was midodrine < etilefrine < amezinium < droxidopa. The effect of droxidopa was significant only at 130 to 160 min after administration. The amplitude of effect was in the following order; midodrine = droxidopa > or = etilefrine > amezinium. Midodrine (3 mg/kg, i.d.) mitigated orthostatic hypotension induced by prazosin (0.1 mg/kg, i.v.), but not by pentolinium (0.6 mg/kg, i.v.). It is suggested that midodrine competes with chlorpromazine at alpha1-adrenoceptors and subsequently recovers reflex vasoconstriction. Midodrine may be useful to protect patients with impaired baroreflex activity from accidental orthostatic hypotension during treatment with neuroleptics.

[Intracavernous injections of etilefrin: its efficacy in the treatment of priapism in sickle cell patients]. / Injections intracaverneuses d'étiléfrine: efficacité dans le traitement curatif des épisodes de priapisme chez le drépanocytaire.

OBJECTIVE: To date, the treatment of priapism in sickle-cell patients has relied on measures aimed at lowering blood viscosity and acidosis and reducing the level of circulating hemoglobin S (hyperhydration, alkalinization, or exsanguinotransfusion...) Surgical cavernous-venous shunt may be proposed if conservative treatment fails. We examined the efficacy of intracavernous etilefrin injections. PATIENTS AND METHODS: From January 1996 through October 1997 (20 months) we performed 35 consecutive intracavernous injections of an alphastimulant, etilefrin in 7 sickle-cell patients (6 SS, 1 AS) who had experienced one or several episodes of low-flow priapism lasting 2 to 28 hours. RESULTS: Involution of the tumefaction was rapidly achieved in all cases. Tolerance was satisfactory, although some post-injection undesirable effects were reported by certain patients: moderate transient pain (2-5 min) in the retrosternal area, or intense pain in the penis (more intense than the priapism) which lasted 10 to 30 minutes. This work confirmed the earlier reported efficacy of intracavernous injections of etilefrin and suggests that the autonomous nervous system plays an important role in the genesis of this condition in sickle-cell patients. Patients should be informed about the observed undesirable effects which have not been reported previously in the literature. CONCLUSION: Etilefrin can be proposed as first line treatment for priapism in sickle-cell patients (at least in cases lasting less than 24 h). The pathogenic mechanism could involve neuromuscular dysfunction.

Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study.

BACKGROUND: Etilefrine is an alpha-agonist agent with a potent vasoconstrictor effect, which is potentially useful in preventing vasovagal syncope by reducing venous pooling and/or by counteracting reflex arteriolar vasodilatation. The present multicenter, randomized, placebo-controlled study was designed to evaluate the efficacy of this drug for the long-term management of patients with recurrent vasovagal syncope. METHODS AND RESULTS: In the 20 participating centers, 126 patients with recurrent vasovagal syncope (at least 3 episodes in the last 2 years) and a positive baseline head-up tilt response were randomly assigned to placebo (63 patients) or etilefrine at a dosage of 75 mg/d (63 patients) and were followed up for 1 year or until syncope recurred. The primary end-point of the study was the first recurrence of syncope. There were no differences between the 2 study groups in the patients' baseline characteristics. During follow-up, the group treated with etilefrine had a similar incidence of first syncopal recurrence to that of placebo group both in the intention-to-treat analysis (24% versus 24%) and in on- treatment analysis (26% versus 24%). Moreover, the median time to the first syncopal recurrence did not significantly differ between the 2 study groups (106 days in the etilefrine arm and 112 days in the placebo arm). CONCLUSIONS: Oral etilefrine is not superior to placebo in preventing spontaneous episodes of vasovagal syncope. Randomized controlled studies are essential to assess the real usefulness of any proposed therapy for patients with vasovagal syncope.

Resistance index as a prognostic factor for prolonged erection after penile dynamic colour Doppler ultrasonography.

OBJECTIVE: To identify an objective and reliable prognostic factor for prolonged erection after penile dynamic colour Doppler ultrasonography (CDU). METHODS: From June 1995 to July 1996, 156 patients suffering from erectile dysfunction were submitted to penile dynamic CDU at our institution. From June to December 1995 (Group 1), patients with rigid erection at the end of the test were invited to wait 90 min for a review. If detumescence had not occurred at the first review, they were invited to wait another 60 min for a second review. If detumescence had not occurred at this stage, they were given an intracavernous injection (ICI) of etilefrin to induce detumescence. To test the validity of the findings obtained in Group 1, from January to July 1996 (Group 2) patients with rigid erection and resistance index (RI) < or = 1.00 at the end of penile dynamic CDU were sent home and invited to return to the hospital if erection lasted more than 2 h, while those with rigid erection and RI > 1.00 were immediately given an ICI of etilefrin to induce detumescence. RESULTS: Of the 62 patients in Group 1, 31 yielded a rigid erection. Seven refused to wait for a review. They were given an ICI of etilefrin and excluded from the study. Of the 24 evaluable patients, 10 presented spontaneous detumescence at the first review. RI was < or = 1.00 in 7, and > 1.00 in the other 3. None of the remaining 14 patients presented spontaneous detumescence at the second review. RI was > 1.00 in all of them. They were successfully managed with an ICI of etilefrin. Of the 94 patients in Group 2, 43 yielded a rigid erection. Twenty had a RI < or = 1.00 and therefore were sent home. None of them returned to the hospital. Contacted by phone, they all said that spontaneous detumescence had occurred within a couple of hours. Of the 23 patients with RI > 1.00, 22 were immediately given an ICI of etilefrin. One who refused returned to the hospital 4 h later with a prolonged erection which was successfully managed with an ICI of etilefrin. CONCLUSIONS: This study showed that RI is a reliable prognostic factor for prolonged erection. In patients with RI > 1.00 at the end of penile dynamic CDU, immediate prevention of prolonged erection is recommendable to avoid unpleasant sequelae.

Sympathovagal effects of spinal anesthesia assessed by the spontaneous cardiac baroreflex.

BACKGROUND: The changes in sympathovagal balance induced by spinal anesthesia remain controversial. The spontaneous baroreflex method allows the continuous assessment of the spontaneous engagement of the cardiac baroreflex, giving an index of sympathovagal balance. The purpose of this study was to follow the effects of spinal anesthesia on spontaneous baroreflex sensitivity. METHODS: Continuous electrocardiogram and noninvasive blood pressure were recorded in 24 patients scheduled for elective inguinal hernia repair and randomly assigned to three groups: (1) no volume loading, (2) volume loading of 15 ml/kg lactated Ringer's solution, and (3) continuous infusion of etilefrine (an ephedrine-like drug). Each patient was studied before, during, and after bupivacaine-induced spinal anesthesia (mean sensory block: T4). Spontaneous baroreflex sensitivity and parameters of time-domain analysis of heart rate variability were calculated from 30 min of recording of each period. RESULTS: No significant change in spontaneous baroreflex slope or parameters of time-domain analysis were observed after regional anesthesia in any group. However, three patients experienced episodes of bradycardia and hypotension in the absence of a high block; these three patients showed an increase in spontaneous baroreflex sensitivity and time-domain parameters. CONCLUSIONS: Using a noninvasive, continuous technique to estimate cardiac sympathovagal balance, no significant variation in autonomic balance induced by spinal anesthesia was observed. However, untoward episodes of bradycardia and hypotension occurred in three patients, who could not be prospectively identified by the parameters studied.

Changes in etilefrine-induced CNS effects when associated with theophylline.

A diverse set of techniques (curiosity, chimney test, changes in barbiturate-induced sleep time, spontaneous motor activity, swimming ability, body temperature) was used to study theophylline (T)-induced changes in CNS etilefrine (E). T antagonized the depressive effects produced by high doses of E. Nevertheless, the LD50 of E was not modified when both drugs were administered simultaneously.

Pharmacological analysis of positive chronotropic and inotropic responses to etilefrine in isolated dog heart preparations.

Positive chronotropic and inotropic responses to etilefrine (alpha-[(ethylamino)methyl]-m-hydroxybenzyl alcohol), an orally active cardiovascular agent, were investigated in isolated dog right atrial and left ventricular preparations. Intravenous administration of etilefrine to a support dog increased heart rate and mean systemic blood pressure, and increased sinus rate and atrial contractile force in the isolated right atrium perfused with blood from the support dog. Etilefrine injected intra-arterially to isolated atria and ventricles induced dose-dependent positive chronotropic and inotropic effects. Etilefrine was about 100 times less potent than isoproterenol. The effects of etilefrine in isolated atria were significantly inhibited by treatment with atenolol, but were not significantly inhibited by ICI 118,551. The effects of etilefrine were partially inhibited by imipramine. These results indicate that etilefrine is a highly selective beta-1 adrenoceptor agonist and suggest a moderate catecholamine-releasing activity by tyramine-like action in the blood-perfused dog heart.

[Use of etilefrin as local vasoconstrictor in lower gynecologic surgery ]. / Utilisation de l'étiléfrine comme vasoconstricteur local dans la chirurgie gynécologique par voie basse.

In this randomized prospective study the authors have compared the effectiveness and side-effects of two local vasoconstrictor agents, etilefrine (Effortil) and ornithine 8 vasopressin (Por 8) in vaginal gynaecological surgery. Thirty-three patients entered the trial and were divided into two groups: G1 (15 patients) received Effortil, and G2 (18 patients) received Por 8. The products, administered at random, were diluted in saline 40 ml and injected into the cervix through 6 points. A 3-minute interval was allowed between injection and incision. The results were assessed on the basis of trans- and postoperative haemorrhage and haemodynamic variations. Palor of the cervix was achieved after 3 minutes in both groups; moderate bleeding was observed in only one of the G1 patients. Postoperative renewal of packing was necessary in 2 patients in G1 and 4 patients in G2. No electrocardiographic anomaly was recorded in any of the two groups. Diastolic BP was significantly higher in G2 than in G1 (P less than 0.002, Fisher test). Systolic BP was also elevated in that group (P less than 0.03, chi 2 test). Moderate reduction in heart rate was observed in both groups (P less than 0.3, Fischer test), but severe (48 beats/min) bradycardia was noted in one G2 patient.

Effects of dihydroergotamine and etilefrine on experimentally-induced postural hypotension in dogs.

The effects of dihydroergotamine and etilefrine on experimentally-induced postural hypotension were examined. Although dihydroergotamine at 3 and 10 micrograms/kg (i.v.) increased blood pressure (BP), it did not affect cardiac output (CO). However, dihydroergotamine at 10 micrograms/kg reduced the decrease in CO induced by the tilt. Therefore, it is suggested that the increase in BP is induced by the contraction of resistance vessels, and that the inhibition of the decrease in CO due to tilt is induced by the contraction of capacitance vessels. Etilefrine at 0.1 mg/kg (i.v.) increased BP and heart rate (HR), however, it did not attenuate the decrease in BP induced by the tilt. Although it tended to increase CO, it did not attenuate the decrease in CO. It is suggested that the increase in BP is due to the contraction of resistance vessels, and to the increase in cardiac contractile force and HR. In this study, dihydroergotamine and etilefrine did not attenuate the decrease in BP due to tilt, though dihydroergotamine inhibited the decrease in CO due to tilt. As an explanation, it is suggested that dihydroergotamine induces contraction of resistance vessels as well as capacitance vessels, however the effects of the drug on resistance vessels is weak, and that etilefrine has little or no effect on capacitance vessels. In our previous study, midodrine, an alpha-1 agonist, attenuated the decreases in BP and CO due to tilt, and it has been suggested that the inhibition was induced by the contraction of capacitance vessels. Therefore, dihydroergotamine, etilefrine and midodrine show different pahrmacological profiles in experimentally-induced postural hypotension.

Etilefrine and amezinium reduce uterine blood flow of pregnant guinea pigs.

Etilefrine and Amezinium are used during pregnancy to prevent hypotension and fetal growth retardation. The effect of these drugs on uterine blood flow (UBF), uterine vascular resistance (UVR) and fetal growth are, however, unknown. 31 guinea pigs were injected daily with Etilefrine (3 X 0.14 mg/kg) and Amezinium (0.14 mg/kg) from day 30 to day 60. Uterine blood flow was measured with radioactive-labeled microspheres. Uterine vascular resistance was calculated from arterial blood pressure and uterine blood flow. 10 guinea pigs treated with 0.9% sodium chloride served as controls. As a response to Etilefrine and Amezinium, UBF fell by 68 and 48%, respectively, accompanied by an increase in UVR. The fetal weight decreased only slightly. It is concluded that long-term application of anti-hypotensive drugs may be hazardous to uterine blood flow and fetal growth.

The action of relaxin, fenoterol and etilefrine on uterine motility of the rat.

In uterine motility tests in virgin rats, the inhibitory action of the peptide hormone relaxin has been compared with the actions of fenoterol and etilefrine. At molecular levels, relaxin and fenoterol showed similar uterine inhibitory activity. Etilefrine was markedly less effective in inducing uterine relaxation. By pretreatment with propranolol, the inhibitory action of both fenoterol and etilefrine could be prevented but not the tocolytic effect of relaxin. Etilefrine, in higher doses, developed alpha-receptor activity as demonstrated by resumed uterine contractions. The doses required to induce beta 2- and alpha-activities differed by a factor of approximately 4,000.

Venoconstrictor agents mobilize blood from different sources and increase intrathoracic filling during epidural anesthesia in supine humans.

The authors studied the effects of dihydroergotamine (DHE) and etilefrine hydrochloride (E) on the regional distribution of 99mTc-marked erythrocytes during epidural anesthesia in eight supine men to determine if vasoactive agents with venoconstrictor action would enhance cardiac filling during epidural anesthesia. Radioactivity was recorded with a gamma camera, and its distribution determined in the thorax, abdomen, and limbs. Arterial and central venous pressure, heart rate, and calf volume by plethysmography were measured. During epidural anesthesia with a sensory block up to T4/5, DHE (7.5 micrograms/kg) reduced the radioactivity, i.e., blood volume, in both the innervated (-5.9 +/- 3.5%) and denervated muscle/skin (-16.9 +/- 7%) regions, and increased it in both the intrathoracic (+7.0 +/- 2.3%), and splanchnic vasculature (+4.2 +/- 3.2). In contrast, E (6 micrograms X kg-1 X min-1) decreased the blood volume most markedly in the splanchnic region (-5.4 +/- 0.7%) and increased it in the thorax (+2 +/- 0.6%). All these changes were statistically significant. The combined effects were estimated to be equivalent to a transfusion of nearly 1.01 of blood. Both drugs reversed the hypotensive action of epidural anesthesia. During epidural anesthesia, DHE preferentially constricted the capacitance vessels in skeletal muscle and skin irrespective of the state of innervation, whereas E preferentially constricted the splanchnic vasculature. In the doses used, the two agents replenished in an additive fashion the central circulation during epidural anesthesia.

Interactions of dihydroergotamine with etilefrine in human leg veins in vitro and in situ.

The aim of the present study was to provide evidence for an interaction of dihydroergotamine (DHE) and etilefrine (Et) with regard to their constrictor effect on human leg veins both in vitro and in situ. In isolated strips of the femoral vein, DHE exerted a concentration-dependent sustained contraction which also continued after washing out the preparation. Et induced a reversible contraction of the strip at considerably higher concentrations as compared to DHE and noradrenaline. When DHE (0.01 mumol/l) and Et (6 mumol/l) were simultaneously applied, there was only an additive venoconstrictor effect. The influence of DHE and Et on the compliance of dorsal foot veins was studied in 14 male volunteers by means of a variable differential transformer. In the short-term experiment, an oral dose of 10 mg DHE was ineffective, whereas after the subcutaneous injection of 1 mg DHE a significant venoconstrictor effect was observed. Et, orally given in a dose of 10 mg, was also ineffective, while 20 mg Et caused a short-lasting effect which could not be augmented by the concurrent intake of 10 mg DHE. When 10 mg Et were administered 30 or 60 min after a single oral dose of 10 mg DHE, a distinct venoconstrictor effect occurred. These findings suggest that no pharmacodynamic synergism of the two drugs can be expected when DHE and Et directly act on the veins. The augmentation of the venoconstrictor in situ effect of Et after pretreating the volunteers with DHE could result from an amelioration of the oral bioavailability of Et by DHE, i.e., from a pharmacokinetic interaction of the two drugs.

[Intracavernous injection of etilefrine hydrochloride in iatrogenic priapism].

Intracavernous injection of etilefrine hydrochloride (1 or 2 mg) was performed on four patients with fully erected penis after intracavernous injection of 40 mg of papaverine hydrochloride. One case needed three injections of etilefrine hydrochloride (1 mg), but the erection disappeared in the other three cases within 10 minutes after a single injection of 2 mg of etilefrine hydrochloride. The injection resulted in complete detumescence and relief of the erection in all cases. These observations strongly suggest that the intracavernous injection of etilefrine hydrochloride is effective in treating not only iatrogenic priapism but also priapism due to other etiologies. Also, it might be useful to control erection time after intracavernous injection therapy for impotence.