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The Effect of Adding Subarachnoid Epinephrine to Hyperbaric Bupivacaine and Morphine for Repeat Cesarean Delivery: A Double-Blind Prospective Randomized Control Trial

Katz, Daniel MD*; Hamburger, Joshua MD*; Gutman, David MD; Wang, Ryan MD*; Lin, Hung-Mo ScD*; Marotta, Michael MD; Zahn, Jeffrey MD*; Beilin, Yaakov MD*

doi: 10.1213/ANE.0000000000002542
Obstetric Anesthesiology: Original Clinical Research Report
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BACKGROUND: Spinal anesthesia has become the most common type of anesthetic for cesarean delivery. The major limitation to spinal anesthesia is that the duration of the anesthetic may not be adequate in the event of a prolonged surgery. Some practitioners add epinephrine to hyperbaric bupivacaine to increase the duration, although its effect has not been fully studied. We therefore aimed to evaluate whether adding epinephrine to the spinal medication prolongs the duration of action of the resultant block in women presenting for repeat cesarean delivery.

METHODS: Sixty-eight patients were randomized to receive no epinephrine (NE group), epinephrine 100 µg (low-dose [LD] group), or epinephrine 200 µg (high-dose [HD] group) with a standardized spinal mixture (1.5 mL 0.75% hyperbaric bupivacaine with 0.25 mg morphine). Sixty-five patients were included for primary analysis. Our primary outcome was time to intraoperative activation of the epidural catheter or postoperative regression of sensory blockade to T-10 dermatome level as measured by pinprick sensation; motor recovery was a secondary outcome, and graded via a Modified Bromage scale.

RESULTS: Block onset time, vital sign changes, and the incidence of hypotension; nausea, and vomiting were similar among groups. Median difference in time to T-10 regression was greatest in the HD group compared to the NE group (median difference [min] [95% confidence interval]: 40 [15–60]; P = .007), followed by the HD group to the LD group (30 [15–45]; P = .007). Comparisons of LD to NE were not significant, but trended to an increase in T-10 regression time (10 [−15 to 30]; P = .76). Median difference in time to knee extension (Bromage 3) was also greatest in the HD group when compared to both the LD and NE group (median difference [min] [95% confidence interval]: 30 [0–60]; P = .034, 60 [0–93]; P = .007). Median difference time to knee extension (min) between the LD and NE group was also significant (37.5 [15–60]; P = .001]. Pain scores during the procedure were higher in the NE group (median [interquartile range] HD: 0 [0–0], LD: 0 [0–0], NE: 0 [0–3]; P = .02) during uterine closure and were otherwise not significantly different from the other groups.

CONCLUSIONS: In this single center, prospective, double-blind, randomized control trial, the addition of epinephrine 200 µg to hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery prolonged the duration of the sensory blockade. Motor blockade was similarly prolonged and block quality may have been enhanced.

From the *Department of Anesthesiology, Pain, and Perioperative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York

Department of Anesthesiology, Medical University of South Carolina, Charleston, South Carolina.

Published ahead of print October 26, 2017.

Accepted for publication August 30, 2017.

Funding: Funding for this study was procured though the Icahn School of Medicine at Mount Sinai.

Clinical Trial # (ClinicalTrials.gov): NCT02369510.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Daniel Katz, MD, Department of Anesthesiology, Pain, and Perioperative Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Pl, KCC 8th Floor Box 1010, New York, NY 10029. Address e-mail to Daniel.Katz@MountSinai.org.

Spinal anesthesia has become the most common type of anesthetic for cesarean delivery.1,2 Both the primary and repeat cesarean delivery rate in the United States is increasing and the overall rate is approximately 30%.3 The major limitation to spinal anesthesia is that the duration of the anesthetic may not be adequate in the event of a prolonged surgery. Repeat cesarean delivery in particular is associated with increased operative time.4 To account for this increased surgical time, a combined spinal epidural (CSE) may be used; however, the epidural component may not always provide adequate anesthesia.5–7

Bupivacaine is the most commonly used local anesthetic for cesarean delivery under spinal anesthesia.8 Bupivacaine, without adjuvant, provides approximately 120 minutes of surgical anesthesia.9 Epinephrine can be used to prolong spinal anesthesia, and when combined with lidocaine or tetracaine has been demonstrated to significantly increase the duration of action perhaps by as much as 2-fold.10 The prolongation of spinal block by epinephrine when added to bupivacaine, however, has been less conclusive.

The use of subarachnoid epinephrine with bupivacaine for cesarean delivery was evaluated twice by Abouleish11,12 with the goal of determining if the epinephrine improved the quality of the blockade. While the authors concluded that the quality of the block was improved as was time until 2 level sensory regression and complete sensory regression, they did not assess duration of surgical anesthesia. The goal of this study was to determine if adding subarachnoid epinephrine to spinal bupivacaine and morphine will prolong the duration of surgical anesthesia for repeat cesarean delivery as measured by time to T-10 regression or activation of the epidural for patient comfort.

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METHODS

Our research protocol was approved by the Institutional Review Board at the Icahn School of Medicine at Mount Sinai Hospital and written informed consent was obtained from each subject. Before enrollment of any patients, the research protocol was registered on clinical trials.gov (NCT02369510) by the lead author (Daniel Katz) on February 17, 2015. All subjects were women scheduled to undergo elective repeat cesarean delivery and all eligible women were approached for study participation. Those with preexisting neurologic disease, allergy to any of the medications, or prior abdominal surgery (such as abdominoplasty) that could impact dermatomal analysis were excluded. All women had agreed to receive a CSE technique for the repeat cesarean delivery.

Before placement of the CSE, each subject was randomly assigned to 1 of 3 groups based on the dose of epinephrine used for the subarachnoid block. All women received 1.5 mL bupivacaine 0.75% (11.25 mg) and 0.5 mL of preservative-free morphine 0.05% (250 μg). Women in the high-dose group (HD) received 0.2 mL of epinephrine 1:1000 (200 µg) for a total volume of 2.2 mL. Women in the low-dose group (LD) received 0.1 mL of epinephrine 1:1000 (100 µg) and 0.1 mL of preservative-free normal saline for a total volume of 2.2 mL. Women in the control group (no epinephrine [NE]) received 0.2 mL of normal saline for a total volume of 2.2 mL. Doses of epinephrine for groups were chosen based on prior studies.11,13

A computer-generated random number program was utilized to assign each subject to her study group. The number generator was balanced in assignment and not organized into blocks. The results of the randomization were sealed in opaque envelopes and opened sequentially immediately before the CSE procedure. The study medication was prepared by 1 of 3 anesthesiologists who was neither involved in the study nor in the clinical care of the patient. A tuberculin syringe with 0.1 mL gradations was used to draw up the epinephrine, while a 3-mL syringe was used to draw up the bupivacaine and morphine. The research assistants and anesthesiologists who performed all of the subsequent assessments as well as the enrolled women were not aware of study group assignment.

Vital sign measurements were recorded in the preoperative holding bay and used as the baseline blood pressure for the study. Before placing the CSE, all patients received a crystalloid fluid bolus of 500 mL. The patient was then seated perpendicular to the long axis of the operating room table (sitting) and a CSE anesthetic was placed at the L2–L3, L3–L4, or L4–L5 interspace, using the loss-of-resistance-to-air technique. Once the epidural space was identified with a 17-gauge Tuohy needle, a 125-mm long, 26-gauge Gertie Marx needle was inserted through the epidural needle into the subarachnoid space. Both the epidural needle and the spinal needle were directed with the bevel in a cephalad direction. After aspiration of cerebrospinal fluid, the anesthetic solution was administered and the spinal needle was removed. A 19-gauge epidural catheter was then inserted into the epidural space and secured with sterile dressing and tape. Immediately after the epidural catheter was secured, the patient was laid down and positioned with left uterine displacement and the epidural catheter was tested for intrathecal or intravascular placement with aspiration, but no test dose was given.

The time of injection of subarachnoid medication was recorded and noted as t0. Sensory level was assessed every 2 minutes thereafter using pinprick with an 18-gauge blunt needle bilaterally in the midclavicular line after baseline assessment to pinprick on the shoulder. Patients were asked to report when the 2 stimuli were “exactly the same.” All testing was done in the caudad to cephalad direction until a thoracic-4 (T-4) sensory level was obtained or 10 minutes had passed. All patients were catheterized with a urinary catheter before the onset of the procedure. Blood pressure, heart rate, and oxygen saturation were recorded every 2 minutes for the first 10 minutes and then every 5 minutes until 25 minutes. Hypotension defined as >30% decrease in systolic blood pressure from baseline or the presence of symptoms consistent with hypotension, eg, lightheadedness or nausea, were recorded and treated with either phenylephrine 100 µg or ephedrine 5 mg depending on the heart rate. Nausea and vomiting as elicited by direct question were also recorded at similar time intervals. If the patient experienced hypotension, nausea, or vomiting beyond 25 minutes, it too was recorded and treated. Verbal pain scores on a scale of 0–10 (0 = no pain and 10 = worst imaginable pain) were recorded at the time of skin incision, delivery, uterine closure, and end of procedure. Uterine exteriorization, if performed, was also recorded. If the patient expressed discomfort during the procedure, supplemental analgesic/sedative medications were given at the discretion of the anesthesiologist. If it was felt that the discomfort was due to circumstances other than inadequate surgical anesthesia, anxiety, or diaphragmatic referred pain, intravenous medications were given; otherwise the epidural catheter was activated. If the epidural catheter was activated, the study was terminated and that time was considered the time that both the primary sensory end point and secondary motor end point were reached for the purpose of statistical analysis.

Table 1.

Table 1.

Apgar scores at 1 and 5 minutes as well as the need for neonatal tracheal intubation or intensive care unit admission were also noted. Beginning 60 minutes after block placement, the patients were monitored for block regression with the same pinprick test described above as well as motor assessment utilizing the Modified Bromage Scale14 (Table 1). If the surgery had not completed at 60 minutes, sensory sensation was checked by pinprick under the drapes in the same fashion as for spinal onset. Motor assessment was not assessed until surgery was completed. These tests were repeated every 15 minutes until a T-10 dermatomal level regression was achieved and the patient was able to extend their knees (Modified Bromage 3). Patient satisfaction score was elicited on arrival to the recovery room on a 1–5 Likert scale.

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Statistical and Power Analysis

Descriptive data were presented as mean (standard deviation [SD]), median (interquartile range [IQR]), median (95% confidence interval [CI]), or n (%). For group comparisons of categorical variables, either χ2 tests, Fisher exact test, or Jonckheer Terpstra trend tests were used depending on whether the outcomes were in nominal or ordinal scale. For continuous variables, analysis of variance, log-rank test, or Kruskal-Wallis tests were used, as appropriate. For time to event analyses (time to T-4, time to Bromage score 3, and time to T-10), log-rank tests were used for comparing the group differences. Median survival time (ie, time for half of the sample to reach event) was reported for each group with 95% CIs. In cases where multiple comparisons were made for time, an appropriate correction for multiple comparisons was made in statistical analysis. Analysis was performed using SAS 9.4 (SAS Institute Inc, Cary, NC) and SPSS 23 (IBM Corp, Armonk, NY) and P value <.05 was considered statistically significant.

Our primary outcome variable for which the sample size was calculated, time to T-10 regression or activation of the epidural for patient comfort, was specifically defined as the difference in time between spinal injection (t0) and the time of intraoperative epidural activation for patient comfort; among those who did not require epidural activation, the regression time was recorded as the time until sensation to pinprick test returned to a level no higher than T-10 dermatome.

Our sample size calculation was performed using nQuery Advisor 7.0 and PASS (PASS 12.NCSS, LLC, Kaysville, UT). Based on clinical experience, we assumed a difference of 20–30 minutes between groups would be significant. Prior studies demonstrated SDs of 5–15 minutes between groups depending on measurement and spinal mixture.11,12 To account for a slightly larger size of SD, a SD of 20 minutes was chosen. The number of pairwise comparisons were set to 3 based on our study design. The sample size was calculated under the 2 independent samples t test assumptions with a difference of means of 25 minutes and a common SD of 20 minutes. It was determined that a sample size of 14 patients per group would be needed for a α error rate of .017 and a power (1 − β) of .8. To account for patients who may drop out or experience study violations, more than 14 patients were recruited per group. For all other end points, the statistical significance was set to .05 as these end points were exploratory in nature.

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RESULTS

Over the course of 1 year, 68 patients were recruited to participate in the study. Of the 68 patients randomized, 3 patients were withdrawn due to spillage of part of the spinal medication during spinal injection. Of the 65 remaining patients, 8 required activation of the epidural catheter due to discomfort during the procedure. The distribution of these patients can be found in the consort diagram (Figure 1). Demographic data are presented in Table 2. No clinically important differences were found between the groups.

Table 2.

Table 2.

Figure 1.

Figure 1.

Most patients achieved a T-4 level of anesthesia (lack of sensation to pinprick no higher than T-4 dermatomal level) with no difference among groups in time to reach the T-4 level or number of patients failing to reach T-4 (Table 3). There was no significant difference in pain scores at skin incision, uterine incision, or at end of the procedure. Pain scores at uterine closure, however, were greater in the NE group (median [IQR] HD: 0 [0–0], LD: 0 [0–0], NE: 0 [0–3]; P = .02). Additional intravenous analgesics were required in 12 patients (4 per group) and did not differ statistically between groups (P = .50). Uterine exteriorization occurred in all groups (n [%]: 3 [14] HD, 10 [45] LD, 7 [33] NE) and was not associated with either activation of the epidural nor with anesthetic adjuncts (P = .15).

Table 3.

Table 3.

Our primary end point, time to T-10 regression or intraoperative activation of the epidural, was significantly greater in the HD group as compared to the other 2 groups (median [95% CI] HD: 165 minutes [150–180], LD: 135 minutes [120–150], NE: 120 minutes [45–150]; P = .001; log-rank test) (Table 4). Median difference in time to T-10 regression or intraoperative activation of the epidural was greatest in the HD group compared to the NE group (median difference [min] [95% CI]: 40 [15–60]; P = .007, Kruskal-Wallis test), followed by the HD group to the LD group (30 [15–45]; P = .007, Kruskal-Wallis test). Comparisons of LD to NE were not significant, but trended to an increase in T-10 regression time (10 [−15 to 30]; P = .76, Kruskal-Wallis test).

Table 4.

Table 4.

Our secondary end point of time to knee extension (Modified Bromage 3 score) or intraoperative activation of the epidural was greatest in the HD group as well (median [95% CI] HD: 172 minutes [150–210], LD: 150 minutes [135–150], NE: 120 minutes [105–120]; P < .001, log-rank test). Median difference in time to knee extension (Bromage 3) or activation of the epidural for patient comfort was also greatest in the HD group when compared to both the LD and NE group (median difference [min] [95% CI]: 30 [0–60], P = .034, 60 [0–93], P = .007, Kruskal-Wallis test). Median difference time (min) between the LD and NE group was also significant (37.5 [15–60] P = .001, Kruskal-Wallis test; Table 4).

There was no significant differences in the incidence of hypotension between groups (Figure 2) nor was there a difference in the overall requirement for vasopressor agents (P = .28) or for treatment for nausea and vomiting (P = .78).

Figure 2.

Figure 2.

There was no significant difference in patient satisfaction among groups with most patients selecting the highest score of 5 or “completely satisfied” (HD: 85%, LD: 90%, NE: 87%; P = .31). No differences were seen between neonatal Apgar Scores with all scoring >7 at both 1 and 5 minutes (P = .34), and no neonates were admitted to the intensive care unit or intubated during the study.

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DISCUSSION

In our randomized, double-blind, placebo-controlled trial, we were able to demonstrate significant prolongation of sensory blockade with the addition of epinephrine 200 µg to subarachnoid hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery without any increase in side effects.

It has been standard practice in our unit to add epinephrine to subarachnoid local anesthetic to enhance or to prolong the resultant anesthetic.11,15–17 The mechanism of action of epinephrine is related to both vasoconstriction that alters diffusion of the local anesthetics and its α-2 agonist properties.18 Post et al19 demonstrated an increase in bupivacaine concentrations in spinal cord tissue of mice when as little as 1 µg/µL was added to a spinal injection. In this study, animals injected with the epinephrine solution had measurable levels of bupivacaine in tissue samples at 60 minutes, compared to none in the plain solution. The effect of α2 receptor agonism in the spinal cord has also been investigated. One of the earlier mouse studies by Ossipov et al20 demonstrated that α2 agonism in the spinal cord had analgesic properties independent of opiate receptors. Since that time, a plethora of studies have investigated these effects and have identified 3 distinct α2 receptors. Activation at the α2 receptor site inhibits adenylyl cyclase through Gi proteins. Potassium channels are activated, and combined with inhibition of N-type calcium channels are likely responsible for the analgesic effects of α2 agonists.21–23

Prolongation of the duration of the subarachnoid local anesthetic has been clearly demonstrated when epinephrine is added to lidocaine or tetracaine,10 both local anesthetics that cause vasodilation and have low protein binding.17 However, the results have been less consistent with bupivacaine.24 Chambers et al24 added epinephrine 200 µg to hyperbaric bupivacaine for transurethral resection of the prostate and did not find a significant difference in 2- or 4-level block regression or regression to T-12 dermatome. They did, however, find a difference in total block duration of about 35 minutes.

The use of intrathecal epinephrine with bupivacaine for cesarean delivery has only been reported in 3 studies, 1 study by Moore et al13 examining block onset time, and 2 conducted by Abouleish et al11,12 who primarily investigated block quality.

In the study by Moore et al,13 66 patients presenting for elective cesarean delivery were randomized to hyperbaric bupivacaine and fentanyl with escalating doses of epinephrine in each arm (0, 100, and 200 µg). Sensation to pinprick was measured at 1-minute intervals for the first 10 minutes. Mean onset time to spinal level T-4 was prolonged by about 2 minutes with both 100 and 200 µg epinephrine added to hyperbaric bupivacaine and fentanyl. Moore et al13 hypothesized that this difference in onset time was due to the decrease of pH of the injectate when adding epinephrine which caused a higher portion of bupivacaine to be in its ionized form. This would result in less nonionized bupivacaine, the form that is required for bupivacaine to exert its sodium channel blocking effects thus delaying onset. In contrast to Moore et al,13 Abouleish et al12 found that the addition of epinephrine had no effect on spinal onset time, with all patients approaching T-4 level within 5 minutes, obtaining an optimal spinal level within 10 minutes. Abouleish et al14 mentions Moore et al’s13 hypothesis in his study and notes that when one takes into account the effect of the volume of injectate compared to cerebral spinal fluid volume that the pH effect of adding the epinephrine should be negligible. Our results are more in line with those found by Abouleish et al11,12 as we found no significant difference in onset time between groups (median min [IQR] HD: 8 minutes [6–8], LD: 6 minutes [6–8], NE: 8 minutes [6–10]). Both Abouleish et al11,12 and Moore et al13 found slightly faster onset times in all their groups compared to our study population which may be related to subtle differences in dosing. Moore et al13 added fentanyl to their admixture and Abouleish et al11,12 varied the bupivacaine dose based on patient height. It should be noted that in our study, patients sat for both the spinal placement and catheter placement which may have slightly altered our onset times when comparing our results to the studies listed above. It is possible that with this technique more time in the sitting position was required, which may have altered the qualities of the block when compared to a traditional spinal injection.

Block quality and duration of blockade as measured by time to 2 segment regression were investigated by Abouleish et al12 in 2 separate studies. In their first study, Abouleish11 randomized 63 parturients to either hyperbaric bupivacaine or hyperbaric bupivacaine plus 200 µg epinephrine. Their primary outcome, quality of analgesia, was better in the epinephrine group with 97% of patients reporting “excellent” or “very good” analgesia versus 61% in the control group. Secondary end points such as time to onset of anesthesia and the incidence of side effects such as hypotension, nausea, vomiting, and dose of ephedrine were similar between groups. Sensory blockade was prolonged by 15 minutes as measured by time to 2-segment regression (mean min [SD]: 90.1 minute [4.4] Epi group, 75.7 minutes [3.2] control group).

In their second study, Abouleish et al12 randomized patients to receive hyperbaric bupivacaine plus either 200 µg epinephrine, 0.2 mg morphine, or their combination (200 µg epinephrine and 0.2 mg morphine). Similar to the prior work, no difference in onset time was noted between groups, and sensory blockade as measured by 2 dermatome regression was only mildly prolonged (~10 minutes) with addition of epinephrine. Nausea, vomiting, and pruritus were significantly greater in both groups containing morphine injections. Block quality was best in the patients who received both epinephrine and morphine as compared to the other 2 groups.

In line with both studies conducted by Abouleish et al,11,12 we also found that the quality of the block was enhanced with epinephrine 200 µg as demonstrated by lower pain scores at uterine closure in the high-dose epinephrine group (median [IQR] 0 [0–0] HD, 0 [0–0] LD, 0 [0–3]; P = .02). This stage of the procedure is often stimulating and has been used in the past to examine quality of blockade.25

In terms of sensory block prolongation, we found that the median duration of the block was prolonged by 40 minutes with 200 µg epinephrine as compared to the NE group and 10 minutes with 100 µg of epinephrine, although the latter was not statistically significant. Our findings are consistent with those found by Abouleish et al12; however, our block extension times are much greater. This can be explained by the differences between study designs. We determined duration of action based on T-10 regression for sensory block and knee extension, whereas Abouleish et al14 examined time to 2 segment regression. Time to T-10 regression and time to knee extension were chosen as opposed to 2 segment regression as we felt these end points were more clinically relevant, which could therefore alter clinical practice. T-10 dermatome was selected as it was deemed to be the lowest possible spinal dermatome that would allow for continuation of abdominal surgery. This is based on the dermatomal coverage needed during the surgery including the uterus (T-10), lesser splanchnic nerve (T-10–T-12), and the skin incision (T-12). Although the innervation of the peritoneum may crossover to higher dermatomes, at the time of spinal regression to T-10 (120–165 minutes) peritoneal closure is often complete, and may not even be routinely performed,26 at which point a T-10 level would be adequate for the surgery. Furthermore, some have found that T-10 level sensory level was sufficient for cesarean delivery.27 Knee extension was considered the motor strength outcome, because at this point, the patient can be discharged from the postanesthesia care unit.28

Other end points such as hemodynamic effects and side effects of intrathecal epinephrine in our study both support prior works in the area. Similar to Abouleish et al,11,12 we did not find differences in the overall incidence of hypotension, vasopressor use, or nausea and vomiting during the procedure. Likewise, our study did not find significant differences in vital signs such as blood pressure and heart rate throughout the study, which is not surprising as the study design allowed for the treatment of hypotension based on either patient complaints or vital sign changes. Given that all patients in the study had blood pressure measurements via a noninvasive blood pressure cuff, it is not surprising that a patient would complain of symptoms that would warrant treatment before the completion of blood pressure cuff cycling during the early stages of the neuraxial block further confounding vital sign measurements.

Our study has several limitations. To discern the effect of adding the epinephrine alone to our spinal mixture, no additives other than morphine were allowed. While this gives a clear picture of the effects of epinephrine, several other additives such as fentanyl are commonly used. Our study did not investigate the effects of combinations of epinephrine and fentanyl. Likewise, our dose of morphine, while within the range of standards of practice, may be considered to be at the upper end of the spectrum, but since patients in all groups received the same dose it should not have an impact on the study findings.29 Additionally, our study was performed in a single large quaternary academic center and was performed only on repeat cesarean deliveries. Another limitation of the study was the presence of the epidural catheter. Although our institutional review board believed it was ethically necessary to include the epidural component to protect patients in case those in the LD and NE group required additional analgesic agents, it gave the anesthesiologists involved a convenient way to treat patient discomfort. In this instance, several patients may have received additional epidural boluses that they would not have otherwise received without the catheter. Furthermore, some of the epidural activation may have not been due to block regression, but may have been due to differences in quality of blockade, which is known to be different secondary to epinephrine addition to hyperbaric bupivacaine.

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CONCLUSIONS

In this single center, prospective, double-blind, randomized control trial, the addition of high-dose epinephrine (200 µg) to hyperbaric bupivacaine and preservative-free morphine for repeat cesarean delivery prolonged the duration of the sensory blockade. Motor blockade was similarly prolonged and block quality may also have been enhanced, although these secondary end points were exploratory in nature. Adding epinephrine to the spinal medication is a reasonable and useful approach in patients undergoing repeat cesarean delivery where the operative time may be prolonged.

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DISCLOSURES

Name: Daniel Katz, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: Joshua Hamburger, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: David Gutman, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: Ryan Wang, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: Hung-Mo Lin, ScD.

Contribution: This author helped design the study, as well as interpret data and prepare the manuscript.

Name: Michael Marotta, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: Jeffrey Zahn, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

Name: Yaakov Beilin, MD.

Contribution: This author helped design and execute the study, as well as interpret data and prepare the manuscript.

This manuscript was handled by: Jill M. Mhyre, MD.

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