Transfer of clonidine and dexmedetomidine across the isolated perfused human placenta.

BACKGROUND: The placental transfer of the alpha 2 receptor agonist clonidine, earlier used as an adjuvant in obstetric epidural analgesia, was compared with the transfer of the newer and more alpha 2-selective agonist dexmedetomidine. METHODS: Term placentas were obtained immediately after delivery with maternal consent and a 2-hour recycling perfusion of a single placental cotyledon was performed. Disappearance from the maternal circulation, accumulation in placental tissue and appearance in the fetal circulation of clonidine or dexmedetomidine with the reference compound antipyrine were followed in 4 experiments for both drugs. RESULTS: At 2 hours the percent dexmedetomidine found in the fetal circulation was 12.5 (SD 5.1)%, while 48.1 (SD 20.3)% was found in the perfused placental cotyledon. A higher mean clonidine than dexmedetomidine concentration was achieved in the fetal circulation (1.90 vs. 0.56 nmol/l, P < 0.05). At 2 hours the percent clonidine found in the fetal circulation was 22.1 (SD 2.4)% (P < 0.05), while 11.3 (SD 3.3)% (P < 0.05) was retained in the perfused placental cotyledon. The transfer indexes, describing maternal-to-fetal transfer of dexmedetomidine and clonidine normalized with the transfer of antipyrine, were 0.88 (SD 0.07) and 1.04 (SD 0.08) respectively (P < 0.05). CONCLUSIONS: Dexmedetomidine disappeared faster than clonidine from the maternal circulation, while even less dexmedetomidine was transported into the fetal circulation. This was due to its greater placental tissue retention, the basis for which probably is the higher lipophilicity of dexmedetomidine.

A clinical and pharmacokinetic comparison of ropivacaine and bupivacaine in axillary plexus block.

The clinical and pharmacokinetic properties of ropivacaine and bupivacaine, both 5 mg/mL, used in axillary plexus block were compared in 60 patients in this randomized, double-blind, parallel-group study. The axillary plexus was identified with a nerve stimulator and 30, 35, or 40 mL of drug, depending on body weight, was injected into the perivascular sheath. In 20 patients, venous blood samples for the pharmacokinetic measurement were obtained over 24 h. The median onset times for anesthesia and complete motor block were in the range of 12-48 min and 5-20 min, respectively. Thirty-eight percent of patients in the ropivacaine group and 29% in the bupivacaine group needed additional nerve block(s) or supplementary analgesia and 7% in the bupivacaine group needed general anesthesia for surgery. Anesthesia was achieved in 52%-86% of the evaluated six nerves in the ropivacaine group and in 36%-87% in the bupivacaine group; the lowest figures were seen in the musculocutaneous nerve. In the pharmacokinetic study the mean peak plasma concentrations (Cmax) were 1.28 +/- 0.21 mg/L in the ropivacaine group and 1.28 +/- 0.47 mg/L in the bupivacaine group and the median times to peak plasma concentration (tmax) were 0.86 h and 0.96 h, respectively. The median terminal half-lives (t1/2) were 7.1 h and 11.5 h in the ropivacaine group and the bupivacaine group, respectively (P = 0.07). No statistically significant differences were found between ropivacaine and bupivacaine in either the clinical or the pharmacokinetic comparisons.

Transfer of lidocaine and bupivacaine across the isolated perfused human placenta.

Drug permeability and pharmacokinetics through the placenta are important factors determining foetal drug exposure. The purpose of the present study was to establish a perfused human placental cotyledon system to assess the placental transfer of lidocaine and bupivacaine, widely used local anaesthetics in obstetric anaesthesia. Term placentas were obtained immediately after delivery with maternal consent and a two-hour recycling perfusion of a single placental cotyledon was performed. Bupivacaine or lidocaine with antipyrine as a reference compound were added to the maternal reservoir and their disappearance from the maternal circulation and appearance to the foetal circulation were followed in five experiments for each drug. Drug concentrations were measured by gas chromatography. Bupivacaine disappeared more rapidly from the maternal circulation than lidocaine. At 2 hr, bupivacaine foetal:maternal concentration ratio was 0.56 +/- 0.12 and 14.6% +/- 2.99 of the total circulating amount was found in the foetal circulation. Lidocaine concentration increased more in the foetal circulation and the foetal:maternal concentration ratio at 2 hr was 0.90 +/- 0.09 (P < 0.01), and 22.1% +/- 2.21 (P < 0.01) was found in the foetal circulation. The maternal to foetal transfer of bupivacaine and lidocaine were 67.2% +/- 0.153 and 98.9% +/- 0.07 (P < 0.05) of that of freely diffusable antipyrine, respectively. Both amide local anaesthetics crossed the dually perfused human placenta rapidly. Bupivacaine disappeared faster than lidocaine from the maternal circulation but less was transferred to foetal circulation. This difference is probably explained by the greater lipophilicity of bupivacaine and hence higher placental binding. These results suggest less foetal drug exposure with bupivacaine than lidocaine.

The effects of epidural ropivacaine and bupivacaine for cesarean section on uteroplacental and fetal circulation.

BACKGROUND: Ropivacaine is a new long-acting amide local anesthetic that has been shown in animal studies to have less dysrhythmogenic and cardiotoxic potential than bupivacaine. The intravenous administration of ropivacaine has not been associated with any detrimental effects on uterine blood flow in pregnant ewes. The purpose of this randomized, double-blind study was to examine the effects of epidural ropivacaine for cesarean section on blood flow velocity waveforms in uteroplacental and fetal arteries with color Doppler ultrasound and to assess whether the block modified fetal myocardial function. METHODS: Healthy parturient women with singleton, uncomplicated pregnancies at term received 115-140 mg 0.5% ropivacaine (n = 11) or 0.5% bupivacaine (n = 10) in incremental epidural doses. The first ultrasound measurement was performed before injection of the study drug. Pulsatility indexes (PI) were derived for the blood flow velocity waveforms of the maternal placental and nonplacental uterine arteries; the placental arcuate artery; and the fetal umbilical, middle cerebral, and renal arteries. The fetal heart then was examined by echocardiography. The PI of the maternal uterine arteries and the fetal umbilical artery were measured 5 min after the injection of the local anesthetic. When sensory analgesia had reached the T6-T4 level, the ultrasound measurement was repeated with the same methods and targets as in the baseline measurement. RESULTS: Both drugs provided adequate surgical anesthesia for cesarean section. In the bupivacaine group, the PI values for the maternal placental and nonplacental uterine arteries increased significantly 5 min after the main dose (P = 0.01, P = 0.002) and when sensory analgesia had reached the T6-T4 level (P = 0.004, P = 0.01) as compared with the baseline measurement. Simultaneously, the PI in the fetal middle cerebral artery decreased significantly (P = 0.02). The PI for the maternal uterine artery increased significantly (P = 0.01) after ropivacaine administration but only on the nonplacental side and not until sensory analgesia had reached the T6-T4 level. No effect on the Doppler indexes obtained from the umbilical artery was observed in either group. There were no significant differences relative to baseline values in any fetal myocardial measurement or in any ultrasound measurement between the groups. Neither drug had any detrimental effect on Apgar scores or umbilical cord acid-base status. None of the neonates' conditions was markedly depressed according to neurobehavioral testing. CONCLUSIONS: Within this small study, epidural 0.5% ropivacaine for cesarean section did not compromise the utero-placental circulation in healthy parturient women with uncomplicated pregnancies. It provided surgical anesthesia that was equally effective as that provided by 0.5% bupivacaine.

Uteroplacental haemodynamics during spinal anaesthesia for caesarean section with two types of uterine displacement.

The effects of two types of uterine displacement, on uterine and umbilical artery blood flow waveforms were investigated in 22 healthy parturients undergoing elective caesarean section. Displacement was accomplished with either a wedge under the right hip or a mechanical displacer plus 5 degrees left lateral tilt of the operating table. The first 14 patients were assigned randomly into one of the two displacement methods and the left (underlying) uterine and umbilical artery blood flow waveforms were recorded. In a further 8 patients the displacer was used and flow velocity waveforms for both the right and left uterine arteries and the umbilical artery were recorded. Arterial resistance was expressed in terms of the pulsatility index (PI). There were no significant changes in Doppler velocimetry recordings after preloading in either group, but blood flow velocity waveform indices for the underlying left uterine artery increased significantly (P < 0.001) following spinal anaesthesia when the mechanical device was used. This finding indicates increased vascular resistance in the left uterine artery and is probably due to mechanical compression. A wedge as a method for displacing the gravid uterus seems preferable since its use had no effect on the blood flow indices. The unaltered umbilical artery index values in the groups suggest a great tolerance of minor changes in maternal uterine circulation on the part of the fetus.

Uteroplacental and fetal circulation during extradural bupivacaine-adrenaline and bupivacaine for caesarean section in hypertensive pregnancies with chronic fetal asphyxia.

We have studied the effects of an extradural block during Caesarean section using either bupivacaine plain or with adrenaline 85-100 micrograms on blood velocity waveforms of maternal uterine and placental arcuate arteries and fetal umbilical, renal and middle cerebral arteries, in 20 hypertensive parturients with chronic fetal asphyxia. Fetal myocardial function was investigated at the same time by M-mode echocardiography. Extradural anaesthesia resulted in a significant decrease in maternal mean systolic and diastolic arterial pressures in both groups, but this was more marked after plain bupivacaine. There were no significant differences in any of the Doppler recordings relative to baseline values after plain bupivacaine, but after bupivacaine with adrenaline there were significantly increased blood flow velocity indices for the maternal uterine and placental arcuate arteries and significantly decreased indices in the fetal renal and middle cerebral arteries. Neonatal outcome as evaluated by Apgar scores and acid-base values in the umbilical cord were similar in the two groups. The results suggest that adrenaline added to the solution of bupivacaine increased vascular resistance in the uteroplacental circulation, indicating impaired blood flow.

Epidural sufentanil and bupivacaine for labor analgesia and Doppler velocimetry of the umbilical and uterine arteries.

BACKGROUND: The pain of parturition is associated with major physiologic alterations mediated by neurohumoral factors and increased activation of the sympathetic nervous system. Epidural local anesthetics abolish or alleviate many of the pain-mediated responses by reducing maternal catecholamine levels, inducing sympathectomy and consequent vasodilatation. The hormone response to surgical stress is not attenuated after epidural opioids as efficiently as after local anesthetics. Opioid receptors may modulate sympathetic outflow at a spinal level. This study was performed to compare the effects of epidural sufentanil and bupivacaine on the uterine and placental circulation. METHODS: Utilizing a prospective randomized, double-blind study design, 30 healthy women at term were examined employing a color Doppler technique to assess and compare the effects of analgesia using sufentanil or bupivacaine epidurally during the first stage of labor on blood flow velocity waveforms in the uterine and umbilical arteries. RESULTS: Effective analgesia was provided by both drugs, bupivacaine and sufentanil. Uterine and umbilical blood velocity waveform indices did not change significantly. There was, however, a significantly greater incidence of fetuses with changes in heart rate tracings in the sufentanil group, decreased variability being the most frequent. Maternal side effects attributable to sufentanil were common but mild. No patient became hypotensive in either group. CONCLUSIONS: Epidural sufentanil and bupivacaine provide effective analgesia with acceptable side effects during the first stage of labor in healthy parturients. Neither drug had any detrimental effects on blood flow indexes reflecting peripheral vascular resistance in the umbilical and uterine arteries in healthy parturients.

Ephedrine and phenylephrine for avoiding maternal hypotension due to spinal anaesthesia for caesarean section. Effects on uteroplacental and fetal haemodynamics.

The effects of i.v. vasopressors on Doppler velocimetry of the maternal uterine and placental arcuate arteries and the fetal umbilical, renal and middle cerebral arteries were studied during spinal anaesthesia in 19 healthy parturients undergoing elective caesarean section. Fetal myocardial function was investigated at the same time by M-mode echocardiography. The patients were randomized into two groups, to be given either ephedrine or phenylephrine as a prophylactic infusion supplemented with minor boluses if systolic arterial pressure decreased by more than 10 mmHg from the control value. Both the vasopressors restored maternal arterial pressure effectively. The ephedrine group showed no significant differences in any of the Doppler velocimetry recordings relative to the baseline values, but during the phenylephrine infusion the blood flow velocity waveform indices for the uterine and placental arcuate arteries increased significantly and vascular resistance decreased significantly in the fetal renal arteries. Healthy fetuses seem to tolerate these changes in uteroplacental circulation well, however, since the Apgar scores for the newborns and the acid-base values in the umbilical cord were within the normal range in both groups. The results suggest that some caution is required when selecting the specific vasopressor agent, the dosage and the mode of administration for the treatment of maternal hypotension secondary to spinal anaesthesia for caesarean section.

Effects of extradural bupivacaine with adrenaline for caesarean section on uteroplacental and fetal circulation.

We have studied the effects of an extradural block using bupivacaine with adrenaline 90-100 micrograms on blood flow in the maternal uterine and placental arcuate arteries and the fetal umbilical, renal and middle cerebral arteries, using a colour Doppler technique in eight healthy parturients undergoing elective Caesarean section. Fetal myocardial function was investigated simultaneously by M-mode echocardiography. Maternal heart rate increased and diastolic arterial pressure decreased after extradural administration of bupivacaine with adrenaline. The latter effect was relieved by increasing the infusion rate in every case and none of the patients required vasopressors. There were no significant differences in maternal or fetal blood velocity waveforms, and no significant changes were found in any of the fetal myocardial measurements relative to control values. These observations suggest that extradural anaesthesia using bupivacaine with adrenaline does not have an adverse effect on vascular resistance in the uteroplacental or fetal circulations or on fetal myocardial function in normal pregnancy when bupivacaine-adrenaline is administered fractionally and maternal hypotension is prevented by rapid crystalloid volume loading.

Uteroplacental and fetal haemodynamics during extradural anaesthesia for caesarean section.

We have studied the effects of extradural anaesthesia with bupivacaine (plain) in eight healthy parturients undergoing elective Caesarean section, on blood flow in maternal uterine and placental arcuate arteries and in fetal umbilical, renal and middle cerebral arteries, using a colour Doppler technique. Simultaneously, fetal myocardial function was investigated by M-mode echocardiography. Maternal and fetal blood velocity waveform indices did not change significantly. We found no changes in fetal myocardial function with extradural anaesthesia, except for an increase in the right ventricular inner end-diastolic dimensions. These results suggest that extradural anaesthesia has no detrimental effects on uteroplacental and fetal circulations in the uncomplicated pregnancy when maternal hypotension is avoided with rapid prehydration.

Visceral pain during caesarean section under spinal and epidural anaesthesia with bupivacaine.

In a randomized study, the incidence of visceral pain was evaluated in 46 patients undergoing elective caesarean section under spinal or epidural anaesthesia with 0.5% bupivacaine. If the patient experienced pain during the operation, a standard visual analogue scale ranging from 0 to 10 was used to assess the degree of pain. Visceral pain occurred in 12/23 patients in the spinal group and in 13/23 patients in the epidural group. In neither group was a correlation found between the cephalad level of analgesia or the intensity of cutaneous analgesia in the sacral region, and the presence of visceral pain.

Does ephedrine influence newborn neurobehavioural responses and spectral EEG when used to prevent maternal hypotension during caesarean section?

The recovery of 16 infants born by elective caesarean section with spinal anaesthesia, in which either ephedrine or fluid load was used to prevent maternal hypotension, were studied using Scanlon's neurobehavioural tests and a computerized EEG. Neurobehavioural testing showed no differences between the ephedrine and the non-ephedrine groups of infants at ages of 3 h, 1 day, 2 days and 4-5 days, whereas the spectral EEG showed significant differences between the two groups during the first 2 h after delivery, which had disappeared 24 h later. It is suggested that small doses of ephedrine given to the mother i.v. to prevent hypotension during spinal anaesthesia have short-lived effects on the neonate's central nervous system, which will be detected in the spectral EEG, but not in neurobehavioural tests.

Effects of anaesthesia for caesarean section on the computerized EEG of the neonate.

The effects of anaesthetic techniques and drugs on 18 neonates born after elective Caesarean section were studied, employing computerized EEG. Three different groups, epidural, spinal and general anaesthesia, were compared with each other and with a control group after normal vaginal delivery. A new computerized EEG method, Zero Band Power Rate (ZBPR) analysis, was devised for this study and implemented together with conventional spectral EEG estimates of five frequency bands. ZBPR analysis was found to be much more sensitive than conventional spectral analyses for detecting differences between the study groups. Significant differences occurred between the general anaesthesia group and the epidural and control groups and also between the spinal group and the epidural and control groups. No significant difference was seen between the epidural group and the control group. Significant differences were attributed to the clinical use of two drugs: thiopentone in the general anaesthesia group and ephedrine in the spinal group. The effects of these drugs on the neonatal EEG were reflected in decreased ZBPR values, particularly during sleep.

Intervillous blood flow during caesarean section with prophylactic ephedrine and epidural anaesthesia.

We administered a 15 mg i.v. bolus of ephedrine at the commencement of epidural blockade to nine healthy parturients scheduled for elective caesarean section. Nine other patients did not receive prophylactic ephedrine before epidural anaesthesia (control group). Lactated Ringer solution, 30 ml/kg, was infused before and during blockade, and left uterine displacement was used to minimize aortocaval compression. A133Xe i.v. technique was used to measure intervillous blood flow (IBF) before and 20-25 min after epidural block. The mean arterial pressure (MAP) decreased after epidural blockade in the ephedrine group by 0.67 +/- 0.8 (mean +/- s.d.) kPa and by 1.20 +/- 1.1 (mean +/- s.d.) kPa in the control group. In spite of the decrease in MAP, IBF increased by 6% in patients receiving ephedrine (N.S.), whereas it decreased by 11% in the control group (N.S.). In the ephedrine group there was in this preliminary study a trend to increasing IBF during falling perfusion pressure (MAP). The results of this preliminary study suggest that ephedrine will not affect IBF, but to prevent maternal hypotension ephedrine should be used as an i.v. infusion instead of a bolus injection.

Regional anaesthesia and uterine blood flow.

Sufficient placental blood flow is mandatory for the well-being of the fetus. The delicate balance between uterine perfusion pressure and uterine vascular resistance can be critically disturbed during epidural anaesthesia. Maternal hypotension is common when extensive block for Caesarean Section is used. If hypotension as well as aortocaval compression is avoided and sufficient preload (Ringer's lactate) is used intervillous blood flow (IBF) will not significantly change. Ephedrine given to prevent or treat maternal hypotension will not adversely effect IBF. Lumbar epidural analgesia used for pain relief during labor (10 ml dose of local anaesthetic (1.a.] will significantly (p less than 0.05) improve IBF in healthy parturients. Epinephrine (less than or equal to 50 micrograms), added to the local anaesthetic, will not decrease IBF. IBF can be severely reduced in pregnancy-induced hypertension (PIH) since the fetus is chronically asphyxiated it is crucial to avoid any further decrease in IBF. Extensive sympathetic blockade (T8) using epidural analgesia (10 ml dose of 1.a.) has been shown to significantly (p less than 0.01) improve IBF in parturients with PIH by decreasing uteroplacental vascular resistance.

Effect of extradural analgesia using bupivacaine and 2-chloroprocaine on intervillous blood flow during normal labour.

The effect of lumbar extradural analgesia on intervillous blood flow (IBF) during labour was studied in 26 healthy parturients using an i.v. bolus injection of xenon-133. There was a 19% decrease (n.s.) in mean IBF in six parturients (non-extradural control group). Mean IBF increased by 37.5% when 0.25% bupivacaine 10 ml was used and by 35.2% when 2% 2-chloroprocaine 10 ml was used (n.s.). When the two extradural groups were combined, the mean difference between IBF1 and IBF2 was 45 +/- 112 ml min-1 dl-1. This increase is statistically significant (P less than 0.05). The improvement in IBF after extradural block was considered to be a result of the decreased uterine vascular resistance, as no significant changes were observed in arterial pressure, uterine activity or uterine tone.

Epinephrine does not alter human intervillous blood flow during epidural anesthesia.

The effect of epinephrine given epidurally with local anesthetics on uterine blood flow is controversial. Previous work in pregnant ewes demonstrated a transient but significant (14 per cent) decrease in uterine blood flow when 2-chloroprocaine with epinephrine (10 micrograms/l) was used. The authors administered 2-chloroprocaine, 10 ml, with epinephrine (5 micrograms/ml) to 12 healthy women during the first stage of labor. By use of intravenously injected 133Xe, intervillous blood flow was measured before and 15-20 min after epidural anesthesia to a somatic level of at least T10. Intervillous blood flow did not change significantly despite a decrease in mean blood pressure of 11 torr. These conflicting results are probably best explained by methodologic and species differences. It is postulated that human placental vasculature, unlike that of the ewe, undergoes vasodilation when perfusion pressure is decreased to maintain placental blood flow.

Neurologic activity of infants following anesthesia for cesarean section.

Elective cesarean section was performed in a consecutive series of 30 patients with full-term pregnancies who were not in labor. Epidural (lidocaine, 1.5 per cent, with epinephrine, 1:200,000) and general anesthesia (thiopental, nitrous oxide-oxygen, succinylcholine infusion) was used alternately. Neonatal acid-base values and Apgar scores showed no significant difference between the two anesthetic groups, and most infants were vigorous at birth. The neurologic recoveries of the infants showed no significant difference between the two groups. In the group receiving epidural anesthesia, there was a significant correlation between maternal hypotension and weak rooting and sucking reflexes of the infants during the first two days. All infants of high-risk obstetric patients in the series, independent of anesthetic technique used, had abnormal neurologic activity, as evidenced by either depression of muscle tone and the reflexes or all the tested variables. Neurologic assessment as followed in this series is a sensitive indicator of the effects of fetal stress factors acting during cesarean section.