The time is now: addressing the need for training in maternal critical care medicine.

Amongst many high-income countries, indirect medical conditions (e.g. cardiovascular disease, sepsis) now account for the majority of maternal deaths. In response to this concerning rise in indirect causes of maternal deaths, professional societies have developed guidelines that regionalize high-risk obstetric care and prioritize critical care expertise as a requirement for designated 'top' maternity hospitals. Critical care proficiency is mandated by the Accreditation Council for Graduate Medical Education for graduating obstetric anesthesiology fellows. Despite these requirements, no formal obstetric critical care educational curricula or fellowship pathways, combining critical care medicine and obstetric anesthesiology, currently exist. Dual subspecialty training in both obstetric anesthesiology and critical care medicine represents one strategy to improve the care of critically-ill obstetric patients and reduce maternal mortality and morbidity, which is one of the pressing healthcare issues of our time.

Comparison of two oxytocin regimens to prevent uterine atony at cesarean delivery: a randomized controlled trial.

OBJECTIVE: To determine if high-dose oxytocin reduces the need for additional uterotonic agents at cesarean. METHODS: A randomized, double-masked trial of two oxytocin regimens was performed to prevent postpartum uterine atony in laboring women. The pharmacy prepared sequentially numbered oxytocin solutions containing either 10 U/500 mL or 80 U/500 mL of lactated Ringer's solution infused over 30 minutes after cord clamping. The need for additional uterotonic agents was determined by the surgical team. Hypotension was diagnosed and treated with crystalloid or a pressor agent. To detect a 50% decrease in the need for additional uterotonic agents and considering a beta error of 0.2, 220 patients would be required in each group (alpha = 0.05, two-tailed chi(2) test). RESULTS: The low-dose group (n = 163) received 333 mU/min, and the high-dose group (n = 158) received 2667 mU/min of oxytocin. The groups were similar with respect to risk factors for atony. Women in the low-dose group received additional uterotonic medication significantly more often than those in the high-dose group (39% compared with 19%, P <.001, relative risk 2.1, 95% confidence interval 1.4, 3.0). Moreover, more women in the low-dose group received methylergonovine, 15-methyl prostaglandin F(2alpha) or both (9% compared with 2%, relative risk 4.8, 95% confidence interval 1.4, 16) after additional oxytocin (median 20 U) had been added to the study solution. The incidence of hypotension was similar in both groups. CONCLUSION: Compared with an infusion rate of 333 mU/min, oxytocin infused at 2667 mU/min for the first 30 minutes postpartum reduces the need for additional uterotonic agents at cesarean delivery.

Evaluation of low-dose endotoxin administration during pregnancy as a model of preeclampsia.

BACKGROUND: Recent evidence implicates nitric oxide (*NO) in the pathogenesis of preeclampsia. The authors tested the hypothesis that administration of low-dose endotoxin to pregnant rats mimics the signs of preeclampsia in humans and that *NO and *NO-derived species play a role in that animal model. METHODS: Endotoxin was infused at doses of 1, 2 and 10 microg/kg over 1 h to rats on day 14 of pregnancy. Mean arterial pressure, urinary protein, urinary and plasma nitrite plus nitrate (NO2- + NO3-) concentrations, and platelet count were measured before and after the endotoxin infusion. In another group of pregnant rats, the nitric oxide synthase inhibitor L-nitroarginine methyl ester (L-NAME) was administered in drinking water at a dose of 3 mg x kg(-1) x d(-1) starting on day 7 of pregnancy. Endotoxin was then infused at 10 microg/kg on day 14 of pregnancy. Kidneys and uteroplacental units were examined histologically and analyzed immunohistochemically for 3-nitrotyrosine. RESULTS: Endotoxin administration at doses of 2 and 10 microg/kg caused proteinuria and thrombocytopenia in pregnant rats, but did not result in hypertension. Urinary NO2- + NO3- concentration, reflective of tissue *NO production rates, was significantly elevated in pregnant rats that received endotoxin at 10 microg/kg. Ingestion of L-NAME caused hypertension. Tissues from pregnant rats treated with L-NAME, endotoxin at 10 microg/kg, and a combination of L-NAME and endotoxin had increased 3-nitrotyrosine immunoreactivity. CONCLUSION: Nitric oxide either directly or through secondary species plays a significant role in the biochemical and physiologic changes that occur in a rodent model of endotoxin-induced injury.

Bolus maternal cocaine administration does not produce a large increase in fetal sheep cerebral cortical glutamate concentration.

Human cocaine use during pregnancy may result in postnatal neurologic dysfunction and abnormal behavior. L-Glutamate, the major excitatory neurotransmitter in the brain, plays an important role in cerebral cortical development. An optimal level of glutamate is required for normal neuronal development. We tested whether acute cocaine exposure produces large increases in glutamate release in the intact cerebral cortex of the near-term fetal sheep. Cocaine 3.0 mg kg(-1) IV bolus produced the expected increase in maternal and fetal mean arterial pressure, increase in fetal heart rate, decrease in uterine blood flow, and decrease in fetal arterial blood pO2 (N = 5). The percentage increases in extracellular glutamate concentration in the fetal cerebral cortex measured by in utero microdialysis were 7%, 15%, 17%, 17%, and 43% in each fetus (upper 95% confidence bound for the median = 43%). We conclude that if cocaine increases glutamate concentration in the developing cerebral cortex, the increase in magnitude is small relative to the changes produced by other interventions such as ethanol or umbilical cord occlusion. Mechanisms other than increases in cerebral cortical glutamate concentration probably contribute to the neurologic injury associated with prenatal cocaine exposure.

Epidural analgesia during labor.

Epidural analgesia is a commonly employed technique of providing pain relief during labor. The number of parturients given intrapartum epidural analgesia is reported to be over 50 percent at many institutions in the United States. The procedure has few contraindications, the primary ones being patient refusal, maternal hemorrhage and coagulopathy. Induction of epidural analgesia in early labor remains controversial. However, many physicians induce analgesia as soon as the diagnosis of active labor has been established and the patient has requested pain relief. The most common complications occurring with epidural analgesia are maternal hypotension and postdural puncture headache. Retrospective studies have demonstrated an association between epidural analgesia and increases in duration of labor, instrumental vaginal delivery and cesarean section for labor. However, several recent prospective studies have concluded that epidural analgesia does not adversely affect the progress of labor or increase the rate of cesarean section. These remain controversial issues among practicing physicians.

Prophylactic angiotensin II infusion during spinal anesthesia for elective cesarean delivery.

BACKGROUND: Angiotensin II may prove useful in treating regional anesthesia-induced hypotension in obstetric patients, because it causes less uterine vasoconstriction than do other vasoconstrictor drugs (such as phenylephrine). This study compared (1) maternal blood pressure and heart rate and (2) fetal status at delivery in parturients given either prophylactic angiotensin II or ephedrine infusion during spinal anesthesia for elective cesarean delivery. METHODS: Fifty-four women were randomized to receive either angiotensin II or ephedrine infusion intravenously during spinal anesthesia for elective cesarean section delivery. Simultaneous with subarachnoid injection, infusion of angiotensin II (2.5 microg/ml) or ephedrine (5 mg/ml) was initiated at 10 ng x kg(-1) x min(-1) and 50 microg x kg(-1) x min(-1), respectively. The rate of each infusion was adjusted to maintain maternal systolic blood pressure at 90-100% of baseline. RESULTS: Cumulative vasopressor doses (mean+/-SD) through 10, 20, and 30 min were 150+/-100, 310+/-180, and 500+/-320 ng/kg in the angiotensin group and 480+/-210, 660+/-390, and 790+/-640 microg/kg in the ephedrine group. Maternal heart rate was significantly higher (P < 0.001) during vasopressor infusion in the ephedrine group than in the angiotensin group. Umbilical arterial and venous blood pH and base excess were all significantly higher (P < 0.05) in the angiotensin group than in the ephedrine group. CONCLUSIONS: Angiotensin II infusion maintained maternal systolic blood pressure during spinal anesthesia without increasing maternal heart rate or causing fetal acidosis.

Does epidural analgesia during labor affect the incidence of cesarean delivery?

There is substantial evidence that there is an increased incidence of cesarean delivery among patients who receive epidural analgesia during labor. The controversy as to whether there is a causal relationship between epidural analgesia and cesarean delivery. Two prospective, randomized studies suggest that epidural analgesia may increase the incidence of operative delivery in laboring women. However, retrospective population-based studies suggest that the introduction of an epidural analgesia service, or the increased use of epidural analgesia, does not increase the cesarean delivery rate. It is possible that epidural analgesia during labor may increase the risk of cesarean delivery in selected patients. Such an effect--if it exists at all--appears to be small in contemporary practice. Furthermore, the availability and use of epidural analgesia may encourage other patients to undergo an adequate trial of labor or attempt vaginal birth after cesarean delivery. It is important to consider the impact of epidural analgesia on the total population of obstetric patients. Maternal-fetal factors and obstetric management, not epidural analgesia, are the most important determinants of the cesarean delivery rate. Finally, physicians should remember that pain relief is itself a worthy goal.

Magnesium sulfate adversely affects fetal lamb survival and blocks fetal cerebral blood flow response during maternal hemorrhage.

Magnesium sulfate is commonly used in high-risk pregnancies, even though its actions in the fetus during maternal/fetal stress are not completely understood. The present study tested the hypothesis that magnesium sulfate alters the fetal cerebral blood flow response to hypoxemia produced during maternal hemorrhage. It was conducted in instrumented near-term fetal lambs at 123 days of gestation. Experimental treatment involved four periods of maternal hemorrhage over a 60-min period during fetal infusion of 0.25 g (n = 5) or 0.30 g (n = 6) magnesium sulfate, or normal saline (n = 11). The level of fetal cerx500l blood flow was determined using radiolabeled microspheres. For all three treatment groups, maternal hemorrhage produced fetal hypoxemia and some fetal demise. During fetal infusion of saline, 1 of 11 (9%) of the fetuses died; with the 0.25-g magnesium sulfate regimen, 1 of 5 (20%) died; and with the 0.30-g magnesium sulfate regimen, 3 of 6 (50%) of the fetuses died. Magnesium sulfate caused an increase in the proportion of fetal death produced by maternal hemorrhage (P < 0.05). Among surviving fetuses, hemorrhage-induced hypoxemia increased fetal cerebral blood flow during saline infusion. In contrast, infusion of magnesium sulfate had an inhibitory effect on this compensatory increase in fetal cerebral blood flow (P = 0.003). These data indicate that, in the sheep, magnesium sulfate increases fetal mortality and inhibits the compensatory increase in fetal cerebral blood flow during maternal hemorrhage-induced fetal hypoxemia.

Dose-dependent effects of acute in vivo ethanol exposure on extracellular glutamate concentration in the cerebral cortex of the near-term fetal sheep.

The cerebral cortex is a target site of ethanol teratogenesis. L-Glutamate is a major excitatory neurotransmitter that plays an important neurotrophic role in brain development. It has been proposed that optimal function of the glutamate neuronal system is required for normal brain development; overactivation could lead to excitotoxic-induced neuronal injury, whereas underactivation could delay/restrict brain development. The objective of this study was to test the hypothesis that acute in vivo ethanol exposure alters basal glutamate release in the fetal cerebral cortex. The experimental approach involved measuring fetal cortical extracellular glutamate concentration using the technique of in vivo microdialysis. Near-term fetal sheep were chronically instrumented with a microdialysis probe placed in the parasagittal cortex. At 124 +/- 3 days of gestation, the effects of maternal intravenous infusion of 2 g or 4 g ethanol/kg maternal body weight or an equivalent volume of saline, given as four equally divided doses over 5 hr, on fetal cerebral cortical extracellular glutamate concentration were determined. None of the three treatment regimens produced fetal or maternal demise during the time course of the study. There was an ethanol dose-dependent increase, p = 0.005, in extracellular glutamate concentration in the fetal cerebral cortex. This increase was paroxysmal in nature and was not directly related to the fetal blood ethanol concentration. In view of the proposed role for glutamate in neuronal development, this apparent ethanol-induced increase in glutamate release may be important in the pathogenesis of ethanol teratogenesis involving the cerebral cortex.

Analysis of statistical tests to compare visual analog scale measurements among groups.

BACKGROUND: A common type of study performed by anesthesiologists determines the effect of an intervention on pain reported by groups of patients. The goal of this study was to evaluate the effectiveness of t, analysis of variance (ANOVA), Mann-Whitney, and Kruskal-Wallis tests to compare visual analog scale (VAS) measurements between two or among three groups of patients. These results may be particularly helpful during the design of studies that measure pain with a VAS. METHODS: One VAS measurement was obtained from each of 480 nulliparous women in labor who were receiving oxytocin (149), nalbuphine (159), or epidural bupivacaine (172). Multiple simulated samples were then drawn from these data. These simulated samples were used in computer simulations of clinical trials comparing VAS measurements among groups. t and ANOVA tests were performed before and after an arcsin transformation was used, to make the data closer to a normal distribution. VAS measurements were also compared after they were divided into five ranked categories. RESULTS: The statistical distributions of VAS measurements were not normal (P < 10(-7)). Arcsin transformation made the distributions closer to normal distributions. Nevertheless, no statistical test incorrectly suggested that a difference existed among groups, when there was no difference, more often than the expected rate. t or ANOVA tests had a slightly greater statistical power than the other tests to detect differences among groups. Because arcsin transformation both decreased differences among means and reduced the variance to a lesser extent, it decreased power to detect differences among groups. Statistical power to detect differences among groups was not less for a five-category VAS than for a continuous VAS. CONCLUSIONS: We conclude that t and ANOVA, without an accompanying arcsin transformation, are good tests to find differences in VAS measurements among groups.

Tubal versus uterine transfer of cryopreserved embryos: a prospective randomized trial.

OBJECTIVE: To compare pregnancy rates after fallopian tubal and uterine transfer of cryopreserved embryos. DESIGN: Prospective randomized trial with assignment to treatment groups by a random number table. SETTING: University of Iowa Hospitals and Clinics, a tertiary care academic institution. PATIENTS: Forty patients with patent fallopian tubes and at least three cryopreserved embryos. INTERVENTIONS: Cryopreserved embryos were thawed and transferred to the fallopian tube by laparoscopy or to the uterus by a transcervical catheter. MAIN OUTCOME MEASURES: Clinical and ongoing pregnancy rates. RESULTS: Tubal transfer of cryopreserved embryos resulted in statistically higher clinical (68% versus 24%) and ongoing pregnancy rates (58% versus 19%) when compared with uterine transfer. CONCLUSIONS: Tubal transfer of cryopreserved embryos is highly effective and offers an improved pregnancy rate when compared with uterine transfer of embryos. This method of transfer should be considered in patients with patent fallopian tubes and at least three cryopreserved embryos.

An evaluation of the effect of anesthetic technique on reproductive success after laparoscopic pronuclear stage transfer. Propofol/nitrous oxide versus isoflurane/nitrous oxide.

BACKGROUND: Laparoscopic pronuclear stage transfer (PROST) is the preferred method of embryo transfer after in vitro fertilization in many infertility programs. There are scant data to recommend the use or avoidance of any particular anesthetic agent for use in women undergoing this procedure. The authors hypothesized that propofol would be an ideal anesthetic for laparoscopic PROST because of its characteristic favorable recovery profile that includes minimal sedation and a low incidence of postoperative nausea and vomiting. The purpose of the study was to compare propofol and isoflurance with respect to postanesthetic recovery and pregnancy outcomes after laparoscopic PROST. METHODS: One hundred twelve women scheduled for laparoscopic PROST were randomized to receive either propofol/nitrous oxide or isoflurane/nitrous oxide for maintenance of anesthesia. RESULTS: Visual analog scale scores for sedation were lower in the propofol group than in the isoflurance group at all measurements between 30 min and 3 h after surgery. More women experienced emesis and were given an antiemetic during recovery in the isoflurance group than in the propofol group. However, the percentage of pregnancies with evidence of fetal cardiac activity was 54% in the isoflurane group compared with only 30% in the propofol group (P = 0.023). Also, the ongoing pregnancy rate was greater in the isoflurane group than in the propofol group (54% vs. 29%, P = 0.014). CONCLUSIONS: Propofol/nitrous oxide anesthesia was associated with lower clinical and ongoing pregnancy rates compared with isoflurane/nitrous oxide anesthesia.

Glutamate release from the ovine fetal brain during maternal hemorrhage. A study using chronic in utero cerebral microdialysis.

BACKGROUND: Glutamate has been implicated in the pathophysiology of neuronal injury associated with cerebral hypoxia-ischemia. A model using chronic in utero microdialysis was developed to sample the extracellular space of the fetal brain. Using this model, we tested the hypothesis that glutamate efflux from the parasagittal parietal cortex of near-term fetuses would increase during maternal hemorrhage. METHODS: Twelve near-term fetal sheep were instrumented with vascular catheters, and a microdialysis probe(s) was implanted into the parasagittal parietal cortex. After a 3-day recovery period, the animals were subjected to maternal hemorrhage until either the fetal pH was < 7.00 or the fetus died. The extracellular glutamate concentration in the collected dialysate was determined by high pressure liquid chromatography (HPLC). RESULTS: Maternal hemorrhage resulted in an 80-90% decrease in uterine blood flow, a decrease fetal po2, and a mixed metabolic and respiratory fetal acidosis. There were two groups of fetuses, survivors (n = 5) and nonsurvivors (n = 7). The nonsurvivor group showed a large increase (10-30-fold) in peak glutamate release (P = 0.0015). Survivors demonstrated a small (threefold) increase that was not statistically significant (P = 0.065), unless one animal with very low probe recovery was excluded (P = 0.0048). CONCLUSIONS: Extracellular glutamate release from the fetal brain can occur during maternal hemorrhage with fetal acidemia. The pathophysiologic role (if any) of glutamate release in the survivors remains to be elucidated. Our results are consistent with the hypothesis that in utero release of glutamate occurs during periods of fetal asphyxia. This experimental preparation of chronic fetal brain microdialysis can be used to monitor the brain extracellular concentration of any dialyzable substance in response to stress, including maternal hemorrhage.

Does early administration of epidural analgesia affect obstetric outcome in nulliparous women who are receiving intravenous oxytocin?

BACKGROUND: Some studies suggest that epidural analgesia prolongs labor and increases the incidence of cesarean section, especially if it is administered before 5 cm cervical dilation. The purpose of the current study was to determine whether early administration of epidural analgesia affects obstetric outcome in nulliparous women who are receiving intravenous oxytocin. METHODS: Informed consent was obtained from healthy nulliparous women with a singleton fetus in a vertex presentation, who requested epidural analgesia while receiving intravenous oxytocin at at least 36 weeks' gestation. Each patient was randomized to receive either early or late epidural analgesia. Randomization occurred only after the following conditions were met: (1) the patient requested pain relief at that moment, (2) a lumbar epidural catheter had been placed, and (3) the cervix was at least 3 but less than 5 cm dilated. Patients in the early group immediately received epidural bupivacaine analgesia. Patients in the late group received 10 mg nalbuphine intravenously. Late-group patients did not receive epidural analgesia until they achieved a cervical dilation of at least 5 cm or until at least 1 h had elapsed after a second dose of nalbuphine. RESULTS: Early administration of epidural analgesia did not prolong the interval between randomization and the diagnosis of complete cervical dilation, and it did not increase the incidence of malposition of the vertex at delivery. Also, early administration of epidural analgesia did not result in an increased incidence of cesarean section or instrumental vaginal delivery. Thirteen (18%) of 74 women in the early group and 14 (19%) of 75 women in the late group underwent cesarean section (relative risk for the early group 0.94; 95% confidence interval 0.48-1.84). Patients in the early group had lower pain scores between 30 and 120 min after randomization, and were more likely to experience transient hypotension. Infants in the late group had lower umbilical arterial and venous blood pH and higher umbilical arterial and venous blood carbon dioxide tension measurements at delivery. CONCLUSIONS: Early administration of epidural analgesia did not prolong labor or increase the incidence of operative delivery, when compared with intravenous nalbuphine followed by late administration of epidural analgesia, in nulliparous women who were receiving intravenous oxytocin.