Robin M. Gilman

Placental passage and uterine effects of fentanyl.

Using the chronic maternal–fetal sheep preparation, 27 pregnant ewes were studied to determine the effects of intravenous fentanyl on maternal and fetal physiology, with particular reference to its placental passage, and its effects on uterine blood flow and uterine tone. Three doses of fentanyl were studied-50, 75, and 100 μg. Maternal and fetal arterial blood was collected for determination of fentanyl levels. All blood levels, both maternal and fetal, were normalized to the 50-μg dose. The maternal normalized blood levels were found to fit a biexponential equation describing a two-compartment open model. The half-life of the maternal elimination phase was 42 ± 7.0 min with an overall elimination constant (K) of 0.21 min−1. Maternal plasma fentanyl levels decreased very rapidly in the first 10 min after injection, at which time only 9% of the peak value remained. Fentanyl was detectable in fetal blood as early as 1 min and levels peaked at 5 min. Once equilibrium was established between maternal and fetal blood, the maternal levels remained 2.5 times those of the fetal level from 5 min to 60 min after drug injection. Both maternal and fetal drug levels declined in an approximately parallel fashion. No significant deleterious changes were seen in any maternal or fetal cardiovascular or acid-base parameters, and uterine blood flow and uterine tone were also unaffected (P > 0.05).

Ketamine, catecholamines, and uterine tone in pregnant ewes

Blood levels of ketamine, measured in both mother (1,230 ng/ml at 1 minute) and fetus (470 ng/ml at 1 minute) illustrate not only rapidly decreasing levels of the drug after its intravenous administration but also its transplacental passage. Concentrations of norepinephrine, epinephrine, and dopamine did not change in the mother or fetus after ketamine, with the exception of maternal levels of epinephrine, which were significantly higher at 45 minutes than control values (p less than 0.05). Maternal effects of ketamine consisted of increases in mean arterial pressure (7% p less than 0.05), cardiac output (16% p less than 0.01), and respiratory acidosis, all of which were slight and transitory. Although resting uterine tone increased (39% p less than 0.01), the uterine blood flow remained constant. None of the physiologic alterations could be correlated with changes in catecholamine levels. Therefore, the cardiovascular and uterine stimulating properties of ketamine at a dose of 0.7 mg/kg are small and are not the result of increased catecholamine levels in plasma. Further studies are necessary to elucidate the mechanism.

The maternal and fetal cardiovascular effects of epidural fentanyl in the sheep model

Since the demonstration of opiate receptors in the spinal cord in the mid-1970s, investigators have been looking for the most effective epidural narcotic. With the use of the chronically catheterized maternal sheep model, we injected two different doses of preservative-free fentanyl (50 and 100 micrograms) into the epidural space. No statistically significant changes were observed, either in maternal or fetal arterial pressure and acid-base status or in maternal central venous pressure, systemic and pulmonary vascular resistance, cardiac output, and intrauterine pressure (p greater than 0.05). With a dose of 50 micrograms of fentanyl, maternal levels of fentanyl peaked at 60 minutes (50 pg/ml) and the fetal levels of fentanyl peaked at 45 minutes (20 pg/ml). With the 100 micrograms dose of fentanyl, maternal levels of fentanyl peaked at 45 minutes (230 pg/ml) and the fetal levels peaked at 15 minutes (110 pg/ml). We conclude that the injection of 50 and 100 micrograms of fentanyl into the maternal epidural space has no adverse effects on mother or fetus in the sheep model.

Evidence for GABA involvement in the peripheral control of blood pressure and vascular resistance

Abstract Intravenous administration of gamma aminobutyric acid (GABA) caused a dose-related (10–1000 βg/kg) hypotension and bradycardia in enflurane (Ethrane) anesthetized dogs. GABA also caused significant decreases in cardiac output, carotid artery blood flow, and in left and right ventricular stroke work indices. Pulmonary arterial and pulmonary wedge pressures were not affected. However, pulmonary vascular resistance was significantly increased after high doses of GABA. Muscimol (20 βg/kg, IV) produced effects similar to those caused by GABA. Blockade of GABA receptors with picrotoxin (1.5 mg/kg, IV) antagonized all effects of GABA and muscimol. Picrotoxin itself, as opposed to GABA, caused significant increases in mean arterial pressure, pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance. Thus, it is suggested that blood-borne GABA or peripheral GABA-containing neurons may play a role in the control of blood pressure and other cardiopulmonary variables.

A comparison of T4 and T7 dermatomal levels of analgesia for caesarean section using the lumbar epidural technique

We compared analgesia to the T4 dermatomal level with analgesia to the T7 level with and without prophylactic intramuscular administration of ephedrine 25 mg to determine the adequacy and side effects of such analgesia for caesarean section. Unmedicated patients were prehydrated (727 ± 303 ml of saline solution) and kept in a left lateral tilt position. Sufficient three per cent chloroprocaine was given to obtain analgesia to the T7 (T6-T8) dermatomal level (455 ± 128 mg) or to the T4 (T3-T5) dermatomal level (758 ± 168 mg). Patients who received analgesia to the higher level required less narcotic than those who received analgesia to the lower level (21 per cent versus 48 per cent) (p < 0.05). The incidence of hypotension in patients with analgesia at the T4 level was 21 per cent for those receiving ephedrine and 64 per cent for those who did not receive ephedrine (p < 0.05). Intramuscular administration of ephedrine 25 mg was not associated with increased plasma levels of norepinephrine, epinephrine or dopamine. There was no difference in Apgar score, behavioural test scores, neonatal acid-base status or oxygenation in children of mothers in the different groups. We conclude that a T4 dermatomal level of analgesia, combined with intramuscular administration of ephedrine 25 mg, provides more maternal comfort than a T7 level of analgesia does, with or without ephedrine, and is without significant maternal or foetal side effects.RésuméOn a comparé l’analgésie épidurale remontant à D4 à l’analgésie à D7 (avec ou sans administration intramusculaire prophylactique d’éphédrine 25 mg) pour évaluer l’efficacité et les effets secondaires de la technique lors de césariennes. Des patients qui n’avaient pas été prémédiquées ont été d’abord hydratées (solution physiologique 727 ± 303ml) et maintenues en position latérale gauche inclinée. De la chloroprocaïne 3 pour cent a été administrée en quantité suffisante pour atteindre D7 (455 ± 128mg)ouD4(758 ± 163 mg). Les patientes dont le niveau analgésique était le plus élevé ont eu besoin de moins de narcotiques que celles dont le niveau était plus bas (21 pour cent contre 48 pour cent) (p < 0.05). L’incidence d’hypotension chez les patientes analgésiées jusqu’à D4 a été de 21 pour cent pour celles qui avaient reçu de l’éphédrine et de 64 pour celles qui n’en avaient pas reçu (p < 0.05). L’administration intramusculaire d’éphédrine 25 mg n’a pas produit d’élévation des taux plasmatiques de norépinéphrine, d’épinéphrine ou de dopamine. Le score d’Apgar, les tests comportementaux, l’équilibre acido- basique ou l’oxygénation ont été identiques chez les mères des différents groupes. Les auteurs concluent qu’une analgésie au niveau D4 avec une injection intramusculaire d’éphédrine 25 mg procure plus de comfort à la mère qu’au niveau D7 avec ou sans éphédrine et que cette analgésie ne présente pas d’effets secondaires significatifs pour la mère et pour le nouveau-né.

Nitroglycerin Therapy for Phenylephrine-Induced Hypertension in Pregnant Ewes

Obstetrical situations in which endogenous or exogenous vasoactive amines precipitously increase maternal blood pressure and decrease uterine blood flow may be associated with increased maternal morbidity and mortality and with development of fetal acidosis and distress. We examined the effectiveness of nitroglycerin in lowering maternal blood pressure and increasing uterine blood flow during the infusion of the alpha-adrenergic agent phenylephrine. During the phenylephrine infusion maternal blood pressure increased 20%, cardiac output decreased 25%, total peripheral vascular resistance increased 60%, pulmonary arterial pressure increased 40%, uterine blood flow decreased 50%, and fetal arterial pH decreased from 7.37 to 7.30 (p < 0.05). While maintaining the phenylephrine infusion at a constant rate, the infusion of nitroglycerin rapidly returned maternal systemic pressure and pulmonary arterial pressure to control values, decreased total peripheral resistance to 18% above control, increased cardiac output to 12% below control, increased uterine artery blood flow to 30% below control, and increased the fetal arterial pH from 7.30 to 7.35 (p < 0.05). It is concluded that maternal hypertension resulting from intense alpha-adrenergic stimulation may be treated rapidly and effectively by the intravenous infusion of nitroglycerin with a partial restoration (20%) of uterine artery blood flow toward control.