Objective: Labor analgesia with the combined spinal epidural approach has been associated with maternal hypotension and fetal heart rate (FHR) changes. The purpose of this study was to estimate whether prophylactic intramuscular ephedrine before combined spinal epidural prevents these complications.
Methods: In a prospective double blind trial, 100 healthy patients with term singletons received intramuscular ephedrine 25 mg or placebo by random allocation before combined spinal epidural. During the first hour after analgesia, maternal heart rate, blood pressure, and need for treatment of significant hypotension were recorded. Fetal heart rate tracings for 1 hour before and for 1 hour after administration of anesthetic were evaluated. Categorical variables were compared with Fisher exact test. Continuous variables were compared with one way analysis of variance for repeated measures. P < .05 was considered significant.
Results: Prophylactic ephedrine reduced the incidence of maternal hypotension after combined spinal epidural (P < .007). In controls, there was a significant increase in the incidence and frequency of late decelerations in the hour following combined spinal epidural compared with the previous hour (P < .005 and P < .01). Compared with controls, there was an increased incidence of fetal tachycardia in patients who received prophylactic ephedrine (P < .006), which was associated with increased FHR reactivity (P < .03).
Conclusion: Although prophylactic ephedrine prevents maternal hypotension and fetal late decelerations, it is associated with fetal tachycardia. The value of prophylactic ephedrine at combined spinal epidural should be weighed against potential changes in fetal heart rate patterns.
Level of Evidence: I
The combined spinal epidural is associated with maternal hypotension and fetal heart rate changes; prophylactic intramuscular ephedrine prevents hypotension and late decelerations but induces fetal tachycardia.
From the Departments of 1Obstetrics and Gynecology and 2Anesthesiology, Columbia University Medical Center, New York, New York; 3Department of Obstetrical Nursing, New York Presbyterian Hospital, New York, New York; and 4Department of Anesthesiology, Pain, and Perioperative Medicine, Brigham and Women’s Hospital, Boston, Massachusetts.
Corresponding author: Jane Cleary-Goldman, MD, Columbia University Medical Center, 622 West 168th Street, PH-16-66, New York, NY 10032; e-mail: firstname.lastname@example.org.
The combined spinal epidural has become an accepted approach for labor analgesia. This technique offers rapid onset of profound pain relief, ability to retain maternal motor function, and minimal drug requirement. However, studies suggest that maternal hypotension occurs in 12–29% of patients who are treated with this technique.1–9 Because of the sudden reduction in pain sensation and perhaps sympathetic deinnervation of the adrenal glands, combined spinal epidural causes a sudden reduction in circulating epinephrine.10–13 As a result, blood pressure decreases secondary to reduced cardiac output and vasodilation. Inhibition of sympathetic innervation of the vasculature causes vasodilation to the level of the blockade. Symptoms of dizziness, nausea, and vomiting may accompany this alteration in blood pressure, while changes in fetal heart rate (FHR) patterns may be indicative of inadequate utero-placental perfusion.14
Hypotension following combined spinal epidural can be successfully treated with intravenous ephedrine.15 Ephedrine increases blood pressure by directly acting on the α and β adrenergic receptors to increase cardiac output and cause vasoconstriction. Ephedrine indirectly increases blood pressure by increasing the release of norepinephrine.
The purpose of this study was to estimate whether prophylactic intramuscular treatment with ephedrine (25 mg) before combined spinal epidural prevents maternal hypotension and fetal heart rate changes. A proactive and preventive approach to maternal hypotension after combined spinal epidural may be beneficial in decreasing the resultant maternal and fetal symptoms that may require clinical treatment, all of which may be alarming to both patients and practitioners.
MATERIALS AND METHODS
After receiving approval from the Columbia University Medical Center Institutional Review Board, 100 healthy normotensive pregnant women were enrolled in this prospective, randomized, double-blinded study after informed consent was obtained. Patients with term (gestational age greater than 37 completed weeks) singletons who requested labor analgesia were offered enrollment in this study. Patients with a history of cardiovascular disease, chronic hypertension, gestational hypertension, and signs of placental insufficiency, such as suspected abruption and intrauterine growth restriction, were excluded. In addition, patients whom the attending anesthesiologist did not consider candidates for combined spinal epidural for anatomic reasons such as scoliosis or morbid obesity were not enrolled in the study.
All subjects had an indwelling 18-gauge intravenous canula with intravenous crystalloid running at 125 mL/h. All patients received a combined spinal epidural while in the sitting position. Immediately before sterile preparation of their backs, patients were given an intramuscular injection in the deltoid muscle of 25 mg of ephedrine (0.5 mL) or sterile saline (0.5 mL) by random allocation. Random allocation was accomplished with a random number table generated by computer spreadsheet software. Group allocation was given to an uninvolved third-party physician or nurse in a sealed envelope, and this practitioner prepared the study drug. The research assistant then gave the study drug in a 1-mL tuberculin syringe with a 26-gauge needle to the anesthesiologist administering the anesthetic. Both the anesthesia and the obstetric teams were blinded to treatment group.
Each patient underwent a standard combined spinal epidural procedure, in which the epidural space was identified with a 17-gauge Touhy needle, through which the subarachnoid space was entered with a 27-gauge Whitacre needle. An intrathecal injection of 20 μg of fentanyl with 2.5 mg bupivacaine was administered. After placement of the epidural catheter, patients were positioned reclining in the left lateral position. The epidural catheter was infused with bupivacaine 0.06% with 2 μg/mL of fentanyl at a rate of 12 mL/h.
Maternal hypotension, defined as a decrease in systolic blood pressure of more than 25% or an absolute systolic blood pressure less than 90 mm Hg, was treated by the attending anesthesiologist according to the standard practice at our institution. Rescue intravenous boluses of ephedrine were given to patients with hypotension and/or nausea, vomiting, and dizziness. Maternal blood pressure was measured with an automatic oscillometric blood cuff every 5 minutes, and maternal heart rate was monitored continuously with a pulse oximeter (Agilent Technologies, Andover, MA). Maternal hemodynamic variables were recorded every 5 minutes, from the time the study drug was given until 60 minutes after anesthesia was initiated.
Continuous electronic FHR monitoring was obtained per standard practice at our institution. The choice of external versus internal FHR monitoring depended upon the clinical situation and the judgment of the obstetric team managing the patient. Fetal heart rate patterns were serially assessed by the obstetric team, and intrauterine fetal resuscitation was initiated at the obstetric team’s discretion according to the standard practice at our institution. Patients with suspicious FHR patterns (fetal tachycardia, decreased variability, repetitive late decelerations, and moderate-to-severe variable decelerations) were repositioned and administered supplemental oxygen. If the patient was receiving oxytocin, it was discontinued, and terbutaline was administered for uterine relaxation if the obstetric team felt it was indicated for hyperstimulation or for tetanic contractions. Hyperstimulation was defined as contraction frequency of 5 or more in a 10-minute time period, and tetanic contractions were defined as uterine contractions lasting 2 minutes or longer.16 The decision to proceed with cesarean delivery for nonreassuring fetal status was at the discretion of the primary obstetrician.
Fetal heart rate tracings for 1 hour before administration of anesthetic and for 1 hour after the administration of anesthetic were evaluated by a single perinatologist (J.C.G.) who was blinded to treatment group and to time period. National Institute of Child Health and Human Development (NICHD) Research Guidelines were used for the interpretation of the FHR tracings.17 Evaluation of the tracings included documentation of average baseline rate and documentation of presence of tachycardia (FHR > 160 beats per minute [bpm] for > 10 minutes). Variability, defined as fluctuations in the baseline FHR of 2 cycles per minute or greater, was described. Tracings received a grade of 0 for no variability, a grade of 1 for minimal variability (amplitude ≪ 5 bpm), a grade of 2 for moderate variability (amplitude between 6 and 25 bpm), and a grade of 3 for marked variability (amplitude > 25 bpm).
Decelerations were counted and characterized as early, late, variable, or prolonged decelerations as per the NICHD guidelines. Prolonged decelerations, which were defined as a decrease in FHR baseline of more than 15 bpm for greater than 2 minutes but less than 10 minutes, were also documented. Variable decelerations were graded 0 if they were mild (any nadir for < 30 seconds), 1 if they were moderate (nadir at 70–80 bpm for 60 seconds or greater or nadir below 70–80 bpm for 30–60 seconds), and 2 if they were severe (nadir < 70 bpm for > 60 seconds).18 In addition, contraction frequency was documented, and presence or absence of tetanic contractions was recorded.
A sample size of 100 patients was determined to be needed to have 80% power to estimate at least a 20% difference in maternal blood pressure with a standard deviation of 20%. Alpha was set ≪ 0.05. The group-specific means and variance were derived from a previous study.2 Statistical analysis was performed with Analyze-it for Microsoft Excel (Analyze-it Software, Leeds, England). Continuous variables were compared with a one-way analysis of variance (ANOVA). Changes in hemodynamic variables over time were tested with ANOVA for repeated measures, where time was considered a continuous variable. Categorical variables were compared with Fisher exact test.
Maternal age, weight, heart rate, and baseline blood pressure were similar between the 2 groups (Table 1). However, the control group had significantly more nulliparous patients compared with the ephedrine group (76% versus 44%, P < .002). Characteristics of the neonates (5-minute Apgar scores < 7, birth weight, and neonatal intensive care unit admissions immediately after delivery) were not different between the 2 groups (Table 2). Time elapsed from initiation of analgesia to delivery was similar for both groups, 6 hours and 14 minutes ± 41 minutes for the ephedrine group and 5 hours and 20 minutes ± 48 minutes for the control group.
Under control conditions, both systolic and diastolic blood pressure was reduced after the spinal analgesic dose (Fig. 1). Systolic blood pressure reached its nadir 10 minutes after the spinal dose. As a group, patients who received 25 mg intramuscular ephedrine before combined spinal epidural did not have a significant reduction in systolic blood pressure during the first hour after the administration of anesthetic. Systolic blood pressures were lower in patients who received placebo than in those who received ephedrine after combined spinal epidural (Fig. 1A; repeated measures ANOVA, P < .05). Diastolic blood pressure decreased in both groups after combined spinal epidural, but there was no difference between groups (Fig. 1B). Maternal heart rate was not changed in either group after combined spinal epidural (Fig. 1C).
Thirty-two percent of patients in the control group had a reduction in systolic blood pressure of 25% or more within the first hour after combined spinal epidural. Treatment with prophylactic intramuscular ephedrine prevented this change (Fisher exact test, P < .02). Patients in the control group (32%, 16/50) were also more likely to require rescue treatment for hypotension on clinical grounds than patients in the ephedrine group (8%, 4/50) (Fisher exact test, P < .02). Uterine contractions had decreased frequency after combined spinal epidural in the control group (2.7 minutes between contractions before combined spinal epidural and 3.1 minutes between contractions after, P < .02). There was no change in the ephedrine group after combined spinal epidural.
When the FHR tracings from the first hour were compared with the tracings the hour after combined spinal epidural, there was an increased incidence and number of late FHR decelerations in the control group (P < .005 and .01). There were also an increased number of variable FHR decelerations in both the control group and the ephedrine group (P < .03 and .02). There was no change in the incidence or number of early decelerations in either group. There was no increase in the incidence of prolonged decelerations in either group, and there were no emergency cesarean deliveries for nonreassuring fetal status performed during the study period.
When the FHR tracings from the hour after the combined spinal epidural were compared between the 2 groups, there was no statistically significant difference with regards to FHR variability, early decelerations, variable decelerations, late decelerations, and prolonged decelerations. Ephedrine prophylaxis was strongly associated with fetal tachycardia (Table 2, P < .006). Episodes of tachycardia ranged between 10 and 60 minutes (average 25.69 minutes ± 14.76 minutes). However, there were also increased rates of FHR reactivity in the ephedrine group compared with the control group (Table 2, P < .03).
When the FHR tracings from the hour after the combined spinal epidural were compared between the hypotensive (n = 22) and the normotensive (n = 78) patients, there were no statistically significant differences with regards to FHR reactivity, FHR variability, fetal tachycardia, early decelerations, variable decelerations, late decelerations, and prolonged decelerations (Table 3). There was no statistical significance between the neonatal outcomes of the 2 groups.
In this prospective, randomized, double-blinded trial, prophylactic treatment with intramuscular ephedrine prevented the reduction in systolic blood pressure and the need for ephedrine rescue treatment that occurs in many patients after combined spinal epidural for labor analgesia (Fig. 1, Table 2). However, prophylactic ephedrine resulted in an increased incidence of fetal tachycardia. Overall, there was little evidence for decreased fetal well-being in the group that received prophylactic ephedrine, and increased FHR reactivity was also noted in this group. In the control group, an increase in late decelerations was noted when the FHR tracings from the hour before combined spinal epidural were compared with the hour after combined spinal epidural. No differences in early, variable, late, and prolonged decelerations were noted when the FHR tracings from the hour after combined spinal epidural were directly compared between the 2 groups. Late decelerations may be indicative of uteroplacental insufficiency. Ephedrine supports the maternal circulation and may protect against these FHR changes. An alternative hypothesis suggests that FHR changes happen after combined spinal epidural in response to decreased activation of uterine β receptors when epinephrine decreases and removes a tonic negative influence on uterine contractility. We did not identify any increase in contraction rate. Our study was not designed to detect changes in uterine pressure because few patients had internal pressure monitoring, and as a result, this issue remains unanswered.
Our findings are in accord with those from a recent study by Kreiser et al,19 which demonstrated that intravenous infusion of ephedrine after epidural analgesia reduces the incidence of major FHR changes. However, in contrast to our study, 2 obstetricians, rather than one, evaluated the tracings, which could have resulted in interobserver bias in the study by Kreiser et al. In addition, a recent bulletin of The American College of Obstetricians and Gynecologists (ACOG)20 on intrapartum FHR monitoring recommends that additional studies are needed to determine the safety and efficacy of combined spinal epidural in labor. The ACOG document suggests the timeliness of this study.
Despite randomization, the control group had significantly more nulliparous patients than the ephedrine group. This finding is likely secondary to chance because there was no systemic problem with our randomization technique. These results are unlikely to have affected our results because there is no physiologic reason that nulliparous and multiparous patients should have different FHR patterns in the hour immediately following regional anesthesia.
Intramuscular ephedrine treatment has enjoyed mixed success in preventing hypotension from a surgical spinal block.21–29 The positive effect of intramuscular ephedrine on maternal blood pressure in this study, as opposed to studies of women undergoing cesarean delivery, is potentially related to the smaller dose of the local anesthetic used for labor analgesia and thus the lower level of sympathetic blockade compared with that required for surgical anesthesia. Whereas a dermatomal level of only T10 is required for labor analgesia, a dermatomal level of T4 or higher is required for abdominal surgery.
In this study, in the control group, blood pressure reached its lowest point 10–30 minutes after spinal injection. During the time period when a patient may need rescue treatment, the anesthesiologist has often finished the procedure and left the patient’s room. Results of this study suggest that prolonged observation may be necessary to promptly identify and treat patients in need of rescue treatment after combined spinal epidural.
Several studies have suggested an increased incidence in FHR changes following combined spinal epidural.5,30,31 Mardirosoff et al14 published a systematic review of 24 randomized trials between 1991 and 2001 of labor analgesia with intrathecal opioid versus nonintrathecal opioid analgesia. This review indicated that there is an increased risk for fetal bradycardia that was not associated with an increased risk for cesarean delivery after treatment with intrathecal opioids. Bradycardia was defined by each study, occurred within one hour of injection of the study drug, and was not associated with hypotension. More recently, Wong et al32 evaluated FHR tracings from 720 nulliparous patients randomly assigned to intrathecal fentanyl or systemic hydromorphone at their first request for labor analgesia. A single perinatologist reviewed the FHR tracings for 30 minutes before and 30 minutes after administration of anesthetic. A higher rate of prolonged and late decelerations was noted in the intrathecal group in the half hour following administration of anesthetic. Similar to our study, these FHR changes did not result in any adverse neonatal outcomes or in the need for any emergent cesarean deliveries.
Prophylactic treatment with 25 mg intramuscular ephedrine did not cause any adverse maternal side effects except for a very small but statistically significant increase in systolic blood pressure (SBP) at 5 minutes after injection (SBP 129 ± 2 and 126 ± 2 mm Hg; Fig. 1A). The increased blood pressure was not clinically significant as demonstrated by the fact that it was not symptomatic in any parturients. There has been concern about reactive hypertension in previous studies that used intramuscular ephedrine before cesarean delivery, but only a 50-mg dose was associated with hypertension in those studies.21,22 Because of the nature of ephedrine’s effects on the autonomic nervous system, prophylactic ephedrine should be used with caution in patients with cardiovascular disorders.
The findings of our study have important implications for obstetric practice. Combined spinal epidural without prophylactic ephedrine is associated with an increase in late decelerations when the FHR tracings the hour before combined spinal epidural are compared with the FHR tracings the hour after combined spinal epidural. Prophylactic ephedrine prevents the reduction of systolic blood pressure and the need for ephedrine rescue treatment that occurs in many patients after combined spinal epidural for labor analgesia. Although prophylactic ephedrine was associated with signs of fetal well-being, such as reactivity, it was also associated with fetal tachycardia. Nonetheless, FHR changes in the control group resolved spontaneously or were easily treated with rescue ephedrine. There was no need for urgent delivery in either group after combined spinal epidural. It is important to note that our study was not powered to determine small differences in cesarean delivery rates. In clinical practice, the benefits of combined spinal epidural should be weighed against the potential changes in the FHR. In patients where combined spinal epidural is thought to be the optimal technique for labor analgesia and where there is no maternal contraindication to ephedrine, the use of prophylactic ephedrine may be beneficial to prevent maternal hypotension and to potentially avoid fetal late decelerations.
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