Anesth Analg 2004;98:497-502
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000096243.74182.5E
OBSTETRIC ANESTHESIA
The Effects of S(+)-Ketamine and Racemic Ketamine on Uterine Blood Flow in Chronically Instrumented Pregnant Sheep
Danja Strümper, MD*,
,
Wiebke Gogarten, MD*,
Marcel E. Durieux, MD PhD*,,
,
Kristian Hartleb, MS*,
Hugo Van Aken, MD PhD*, and
Marco A. E. Marcus, MD PhD*,
*Department of Anesthesiology and Intensive Care Medicine, University Hospital Münster, Münster, Germany, the
Department of Anesthesiology, Pain Therapy and Home Ventilation, University Hospital Maastricht, Maastricht, The Netherlands, and the
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, Virginia
Address correspondence and reprint requests to Danja Strümper, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital Münster, Albert-Schweitzer-Str. 33, 48153 Münster, Germany. Address email to struemper{at}anit.uni-muenster.de
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Abstract
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Ketamine could be a useful maternal analgesic in obstetric surgery, as it might avoid the need for opioid administration and associated side effects in the newborn. Racemic ketamine passes the placental barrier and has oxytocin-like properties but does not seem to affect uterine blood flow (UBF). S(+)-ketamine was recently approved for clinical use, but its effects on UBF have not been evaluated. Therefore, we studied the effects of S(+)-ketamine on maternal and fetal hemodynamic variables. Equianalgesic doses of S(+)-ketamine (10 mg · kg-1 · h-1) or racemic ketamine (20 mg · kg-1 · h-1) were infused in 12 chronically instrumented pregnant sheep. Maternal and fetal vital signs, blood gases, and UBF were recorded over 120 min. Neither compound affected uterine perfusion or maternal and fetal hemodynamics. Whereas racemic ketamine increased maternal (+19%) and fetal (+11%) PCO2 significantly, S(+)-ketamine was without effect. However, both compounds significantly decreased maternal (racemic, -0.05; S(+), -0.03) and fetal (racemic, -0.06; S(+), -0.02) pH. The effects of racemic ketamine and S(+)-ketamine on uterine perfusion are similar, and because of its limited effect on hemodynamics and respiration, S(+)-ketamine might therefore be of interest as an analgesic in the obstetric setting.
IMPLICATIONS: The effects of S(+)-ketamine on uterine perfusion and maternal/fetal hemodynamics are similar to those of the racemic mixture in chronically instrumented pregnant sheep. A decreased effect of S(+)-ketamine, as compared with the racemic mixture, on maternal and fetal PCO2 levels was noted.
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Introduction
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Ketamine is a potentially useful analgesic and/or sedative supplement to either general or regional anesthesia for obstetric surgery; it has limited cardiovascular and respiratory actions in the mother and, in addition, avoids the side effects observed after maternal administration of opioids in the newborn (1–3). Recently, S(+)-ketamine has been introduced in clinical practice. Compared with the racemic mixture, the S(+)-isomer has an approximately twofold greater analgesic potency (4), and its faster disposition half-time, greater clearance rate, and faster demethylation (5–7) might allow better control of the anesthetic procedure. Both isomers pass the placental barrier (8). Although the literature does not reflect complete agreement on the effects of racemic ketamine on uterine motility (8,9) and blood flow (10), any effects noted have generally been considered innocuous. However, this does not imply that S(+)-ketamine would similarly be without detrimental effects. For example, it is conceivable that in the racemic mixture a detrimental effect of S(+)-ketamine on uterine blood flow (UBF) would be masked by a flow-enhancing effect of the R(-)-isomer. If the S(+)-isomer were to be used alone, a decrease in UBF would then be observed. A comparable situation has been described for the psychotomimetic properties of ketamine, where the racemic mixture exhibits properties not shown by either of the isomers (11). As the S(+)-isomer is now increasingly used and has already replaced the racemate in some centers, it is important to determine the effects of S(+)-ketamine on UBF during pregnancy.
We hypothesized that the effects of S(+)-ketamine on UBF would be similar to those of the racemic mixture. To test this hypothesis, we studied in chronically instrumented pregnant sheep the effects of different analgesic/sedative doses of racemic or S(+)-ketamine on UBF, as well as on maternal and fetal hemodynamics, blood gases, and acid-base status.
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Methods
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The study protocol was approved by the local Animal Care and Use Committee and follows institutional guidelines as well as international guidelines for the provision of care to laboratory animals. Twelve pregnant ewes (mean weight, 63.6 ± 9.0 kg) with a mean gestational age of 120 days (range, 118–122 days; term, 145 days) were studied.
Mother and fetus were instrumented as described previously (12). Briefly, polyvinyl catheters were placed under general anesthesia into the maternal external jugular vein and carotid artery as well as into the fetal caval vein and aortic artery via tibial vein and artery. A closely-fitting 20 MHz Doppler flow probe (Baylor College of Medicine, Houston, TX), internal diameter 4–6 mm, was secured around a branch of the uterine artery supplying the pregnant horn of the uterus and used for measurement of UBF. UBF is reported as Doppler shift in the 20 MHz signal. An additional catheter was placed in the amniotic fluid cavity and secured to a fetal hind limb for amniotic fluid pressure measurements. Approximated amniotic fluid loss was replaced with warmed sterile NaCl 0.9%, the uterus was closed, and all catheters were tunneled subcutaneously. Catheters were irrigated daily with sterile heparinized saline; animals were allowed free access to water and standard sheep food and received prophylactic antibiotics (cefamandol, gentamicin) daily. A time period of 72 h was allowed for animals to fully recover from surgery.
Maternal mean arterial blood pressure, maternal heart rate, amniotic fluid pressure, fetal mean arterial blood pressure, and fetal heart rate were measured using a disposable strain gauge (Eco Trans DPT-7003; pvb Medizintechnik, Kirchseeon, Germany). Fetal mean arterial blood pressure was corrected by subtracting amniotic fluid pressure. Arterial blood samples for determination of maternal and fetal blood gases as well as acid-base status were processed immediately after sampling (ABL 505, Radiometer Copenhagen, Denmark) and corrected for maternal temperature. The blood gas analyzer was calibrated daily with reference liquid samples (Multicheck, Radiometer, Copenhagen). After the experiment, animals were killed with IV potassium chloride under propofol anesthesia.
Equipotent doses of S(+)-ketamine and the racemic mixture were calculated based on the observation that the S(+)-isomer is approximately twice as potent as the racemic mixture (12). We studied 6 animals receiving S(+)-ketamine and 6 animals receiving the racemic mixture. Each experiment was preceded by a period of 30 min during which baseline hemodynamic measurements were obtained. After an initial bolus of 1 mg/kg S(+)-ketamine or 2 mg/kg racemic ketamine, the target infusion rate (10 mg · kg-1 · h-1 S(+) ketamine or 20 mg · kg-1 · h-1 racemic ketamine) was approached gradually (S(+) ketamine: 2 mL · kg-1 · h-1 for 10 min, 4 mg · kg-1 · h-1 for 15 min, 8 mg · kg-1 · h-1 for 30 min; racemic ketamine 4 mL · kg-1 · h-1 for 10 min, 8 mg · kg-1 · h-1 for 15 min, 16 mg · kg-1 · h-1 for 30 min). The appropriate target infusion rate was then maintained for 30 min, followed by a 30-min recovery period.
UBF and amniotic fluid pressure, as well as maternal and fetal mean arterial blood pressure, heart rate, arterial blood gases, and acid-base status, were recorded at baseline, 3 min after the bolus administration, at the end of the infusion, and at the end of the recovery period. Blood loss associated with sampling was replaced with 2 mL NaCl 0.9%.
Sample size analysis revealed a required group size of 6 animals to detect a 30% decrease in UBF with a power of 0.8. A 30% change was considered the minimal clinically significant amount. Changes over time and between groups were analyzed using two-way analysis of variance for repeated measurements, followed by Tukey test if needed. If data did not pass normality test, Friedman repeated-measurement analysis of variance on ranks was performed. A P value <0.05 was considered to be significant. Data are presented as mean ± SD.
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Results
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A total of 13 animals were operated on. One fetus died within 24 h after the procedure because of a dislodged catheter and subsequent bleeding. Twelve treatments were performed in the remaining 12 sheep.
Effects of Racemic and S(+)-Ketamine on Maternal Hemodynamics
No significant changes were observed in maternal mean arterial blood pressure after either bolus administration (8% ± 10%) or during racemic ketamine infusion (-16% ± 19%). However, racemic ketamine induced acute hypotension (systolic blood pressure <65 mm Hg) in two animals; these were excluded from analysis. In the remaining animals, maternal mean arterial blood pressure changed neither after bolus administration of S(+)-ketamine (13% ± 18%) nor during infusion (6% ± 12%) (Fig. 1A).
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Figure 1. A, mean maternal arterial blood pressure (MMAP, mm Hg) during infusion of different dosages of racemic or S(+)-ketamine. Mean ± SD; n = 6 in each group. B, maternal heart rate (MHR, bpm) during infusion of different dosages of racemic or S(+)-ketamine. Mean ± SD; n = 6 in each group. 1 = baseline; 2 = bolus administration of 2 mg/kg racemic ketamine or 1 mg/kg S(+)-ketamine); 3 = infusion of 20 mg · kg-1 · h-1 racemic ketamine or 10 mg · kg-1 · h-1 S(+)-ketamine for 30 min; 4 = after 30 min recovery period.
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Maternal heart rate did not change during racemic ketamine or S(+)-ketamine infusion (Fig. 1B). In one of the two animals who became hypotensive, 2 mg · kg-1 · h-1 racemic ketamine induced profound bradycardia (from 110 to 64 min-1); as mentioned above, this animal was excluded from the remainder of the study.
Effects of Racemic and S(+)-Ketamine on UBF
Neither racemic ketamine nor the S(+)-isomer affected UBF significantly. However, a nonsignificant trend was observed for UBF to increase after bolus administration of racemic ketamine (22% ± 45%) and to decrease during infusion of larger doses (-25% ± 12% at 20 mg · kg-1 · h-1, Fig. 2). This was not noted with S(+)-ketamine. Amniotic fluid pressure was not affected in either group (data not shown).
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Figure 2. Uterine blood flow (UBF, kHz) during infusion of different dosages of racemic or S(+)-ketamine. Mean ± SD; n = 6 in each group. 1 = baseline; 2 = bolus administration of 2 mg/kg racemic ketamine or 1 mg/kg S(+)-ketamine); 3 = infusion of 20 mg · kg-1 · h-1 racemic ketamine or 10 mg · kg-1 · h-1 S(+)-ketamine for 30 min; 4 = after 30 min recovery period.
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Effects of Racemic and S(+)-Ketamine on Fetal Hemodynamics
Fetal mean arterial blood pressure did not change during infusion of either racemic or S(+) ketamine (Fig. 3A). Fetal heart rate similarly was unaffected by the compounds (Fig. 3B).
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Figure 3. A, mean fetal arterial blood pressure (FMAP, mm Hg) during infusion of different dosages of racemic or S(+)-ketamine. Mean ± SD; n = 6 in each group. B, fetal heart rate (FHR, bpm) during infusion of different dosages of racemic or S(+)-ketamine. Mean ± SD; n = 6 in each group. 1 = baseline; 2 = bolus administration of 2 mg/kg racemic ketamine or 1 mg/kg S(+)-ketamine); 3 = infusion of 20 mg · kg-1 · h-1 racemic ketamine or 10 mg · kg-1 · h-1 S(+)-ketamine for 30 min; 4 = after 30 min recovery period.
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Effects of Racemic and S(+)-Ketamine on Maternal and Fetal Blood Gases and Acid-Base Status
Racemic ketamine had significant effects on maternal and fetal blood gases and acid-base status. Maternal pH decreased after bolus administration, and maternal PCO2 levels increased during infusion at 20 mg · kg-1 · h-1. Fetal PCO2 increased during infusion of racemic ketamine at 20 mg · kg-1 · h-1. Fetal pH was lower after bolus administration and during infusion as compared with baseline (Table 1).
Maternal pH decreased after bolus administration of S(+)-ketamine. No effects were observed on either maternal or fetal PCO2 levels, although fetal PCO2 tended to decrease. Fetal pH decreased after bolus administration (Table 2).
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Discussion
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Our study demonstrates that S(+)-ketamine does not adversely affect UBF or maternal or fetal hemodynamics. Although maternal and fetal pH decreased after bolus administration and during infusion of larger doses, the changes were minor (<0.9%) and probably clinically insignificant. However, the animals studied were healthy and presumably had adequate placental circulation. Although the use of ketamine as an analgesic in parturients with impaired placental circulation (such as the preeclamptic patient) might be of interest (as newborns in these cases might already be depressed and therefore particularly sensitive to the effects of opioids), extrapolating our data to this population is not warranted.
The chronically instrumented pregnant sheep preparation is an established model to study hemodynamic effects of anesthetics. It permits continuous recording of UBF and vital signs, as well as serial fetal and maternal blood sampling in an awake animal. Fetal size and development are comparable to those of humans. Although dosing requirements for ketamine range widely among species (13), ketamine requirements in sheep are relatively similar to those in humans. Our dose, therefore, is close to that required for anesthetic induction. We did not assess objectively the sedative effects of the compounds in our study. However, at the most rapid infusion rate, the animals appeared drowsy and sedated to a similar degree in both groups. We chose these rather large doses as we anticipated observing differences between the drugs more likely in this manner.
Fetal heart rate and blood pressure did not change during infusion of racemic ketamine in this study. This is similar to observations in earlier reports, although transplacental transfer of ketamine and a trend of fetal norepinephrine and epinephrine concentrations to increase could be detected in a previous study (8). Importantly, we found that administration of the S(+) enantiomer to the mother did not adversely affect fetal hemodynamics.
Infusion of racemic ketamine 20 mg · kg-1 · h-1 caused a significant increase of maternal PCO2 whereas changes in maternal pH were apparent only after bolus administration. No effects on maternal or fetal PO2 were observed. Fetal pH was decreased at every time point during infusion of racemic ketamine, and fetal PCO2 was increased during larger doses. This is in contrast to the observations of Craft et al. (8), who did not find any changes in fetal pH, PCO2, or PO2 after administration of 0.7 mg/kg racemic ketamine IV to the mother. This discrepancy might be explained by the different dose regimens used in these two studies and is probably attributable to diminished maternal spontaneous breathing. In contrast to the effects of racemic ketamine, no significant changes in fetal PCO2 occurred in our study after administration of S(+) ketamine.
Stable maternal hemodynamics and respiratory function should be maintained during analgesia for surgical interventions during pregnancy to ensure fetal well being. If the fetus is delivered during the procedure, neonatal respiratory depression from opiate administration to the mother is of concern. Ketamine might therefore be an alternative to opioids in this setting, as it can provide profound analgesia (14) without significant hemodynamic or respiratory depression (15). Because ketamine has stimulating effects on the cardio-circulatory system (16) and may provoke psychotic reactions (17), its use in eclamptic patients or patients with hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome as well as patients with a positive history of psychic disorders should be avoided. IV administration of 1.5 mg/kg ketamine in humans as a mono-anesthetic for cesarean delivery was not associated with maternal awareness or neonatal depression, provided that the induction-to-delivery-interval was less than 10 min and the uterine incision-to-delivery was less than 90 s (18). Transient neonatal depression was observed with induction-to-delivery intervals more than 10 min or if uterine incision-to-delivery was more than 90 s. As prolonged uterine manipulation may adversely affect uteroplacental and umbilical cord circulation (19), neonatal depression in this case may not be directly attributed to the administration of ketamine. Neonatal respiratory depression has, however, been described after administration of 2 mg/kg racemic ketamine to the mother in rhesus monkeys 103–126 min before delivery (20). Therefore, it should not be assumed that maternal administration of racemic ketamine will necessarily be without fetal effects. Actions of S(+)-ketamine on newborn respiratory function have not been reported, but the lack of effect on maternal and fetal PCO2 levels observed in the present study suggest that these actions might be less significant than those of the racemic mixture.
In summary, our data indicate that the effects of S(+)-ketamine on uterine perfusion and maternal/fetal hemodynamics are similar to those of the racemic mixture. A decreased effect of S(+)-ketamine, as compared with the racemic mixture, on maternal and fetal PCO2 was noted. Therefore, it might be of interest as an analgesic adjunct in the obstetric setting, and further studies to determine its effects on the newborn appear warranted.
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Acknowledgments
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Supported, in part, by a research grant (MA 1 2 98 14) from the Innovative Medizinische Forschung (IMF), Münster, Germany.
We thank Stefan Brodner for expert technical assistance.
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Footnotes
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Presented, in part, at the German Anesthesiologists Congress 2001, Nürnberg, Germany and the Annual Meeting of the American Society of Anesthesiologists 2001, New Orleans, Louisiana.
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References
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Accepted for publication September 4, 2003.
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Abstract
Introduction
