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Hemodynamics of Phenylephrine Infusion Versus Lower Extremity Compression During Spinal Anesthesia for Cesarean Delivery: A Randomized, Double-Blind, Placebo-Controlled Study

Kuhn, Jana Christine MD, Dr. Med; Hauge, Tor Hugo MSc, PhD; Rosseland, Leiv Arne MD, PhD; Dahl, Vegard MD, Dr. Med; Langesæter, Eldrid MD, PhD

doi: 10.1213/ANE.0000000000001174
Obstetric Anesthesiology: Research Report

BACKGROUND: Phenylephrine infusion is the current first-line choice for prevention of spinal hypotension during cesarean delivery. The optimal dosage regimen is still undetermined. A mechanical alternative, lower limb wrapping, has been examined in a few small studies showing moderate success. In this trial, we compared the effect of leg wrapping with low-dose phenylephrine infusion and with placebo treatment on systolic arterial blood pressure during spinal anesthesia for cesarean delivery.

METHODS: In this randomized, double-blinded, placebo-controlled study, healthy women received either phenylephrine (n = 38; initial bolus of 0.25 μg kg−1 and infusion of 0.25 μg kg−1 min−1), leg wrapping (n = 38), or no treatment (control; n = 36) during spinal anesthesia for elective cesarean delivery. LiDCOplus was used for continuous minimally invasive hemodynamic monitoring. The extent of decrease in systolic arterial blood pressure (for 13 minutes after spinal induction) was the primary outcome. Cardiac output, systemic vascular resistance, stroke volume, heart rate, neonatal acid–base status, and Apgar score were secondary outcome variables. Mixed model analysis of continuous hemodynamic trends during the first 13 minutes after induction of spinal anesthesia was performed.

RESULTS: In the phenylephrine group, the decrease in systolic arterial blood pressure was significantly less (difference in rate of change, 0.09 mm Hg 5 s−1; 95% confidence interval, 0.02–0.16; P = 0.013); systemic vascular resistance (P < 0.001) was significantly higher; stroke volume (P = 0.41) was similar; and heart rate (P = 0.002) and cardiac output (P < 0.001) were significantly lower compared with the leg wrapping group. Compared with control, the leg wrapping group had a significantly smaller decrease in systolic arterial blood pressure (0.39 mm Hg 5 s−1; 95% confidence interval, 0.32–0.46; P < 0.001), higher stroke volume (P < 0.001), and higher cardiac output (P = 0.001).

CONCLUSIONS: An initial bolus of phenylephrine followed by a low-dose phenylephrine infusion was superior to leg wrapping and no intervention for the prevention of hypotension during spinal anesthesia for cesarean delivery. Phenylephrine prevented hypotension primarily by restoring systemic vascular resistance and did not cause hypertension or a clinically relevant reduction in cardiac output. Leg wrapping prevented hypotension compared with no intervention by limiting modest early spinal anesthesia-mediated venodilation.

From the *Department of Anesthesiology, Critical Care and Emergencies, Bærum Hospital, Vestre Viken Health Trust, Gjettum, Norway; Norwegian Ministry of Trade and Industry, Oslo, Norway; Division of Emergencies and Critical Care, Department of Anesthesiology, Oslo University Hospital, Oslo, Norway; §Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Anesthesiology and Critical Care, Akershus University Hospital, Lørenskog, Norway; and Norwegian National Advisory Unit on Womens’ Health, Oslo University Hospital, Oslo, Norway.

Accepted for publication December 15, 2015.

Funding: This work was supported by the South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF, 2303 Hamar, Norway) by a governmental research grant (grant number 2012095). The Department of Anesthesiology, Bærum Hospital, Norway, supported the conduction of the study through the provision of facilities, equipment, and assistant medical staff.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Jana Christine Kuhn, MD, Dr. Med, Department of Anesthesiology, Critical Care and Emergencies, Bærum Hospital, Vestre Viken Health Trust, Gjettum, Norway. Address e-mail to janiugis@live.de.

Preventing spinal hypotension in elective cesarean delivery has been one of the main research targets within obstetric anesthesia. A stable hemodynamic condition improves maternal safety and reduces morbidity in the form of nausea, distorted consciousness, and fetal acidosis.1

A Cochrane review from 2006 concluded that no single intervention has been proven to eliminate spinal hypotension.2 Studies from the past decade have established prophylactic administration of the α1-adrenergic vasopressor phenylephrine combined with crystalloid cohydration as the current “gold standard” prevention technique, yet there is no definite consensus on the optimal dosage of phenylephrine.3,4 General clinical routine is often in contrast to scientific evidence; many clinicians are still using fluid preload and therapeutic ephedrine.5 Several studies have focused on optimizing the dose of phenylephrine and IV fluids,6–13 and increasing attention has been directed to the dose-dependent negative effect of phenylephrine on cardiac output (CO).7,10,14–16 Several studies using continuous invasive monitoring of hemodynamic variables have contributed to our understanding of the rapid hemodynamic changes during spinal anesthesia.7,14,15

Studies of mechanical prophylaxis alternatives, aiming at increasing venous return by compressing the lower extremities, have shown moderate success.2,17–21 Small sample size and methodologic weaknesses have contributed to the absence of definitive recommendations for clinical practice, and a number of institutions in different countries still base their prophylaxis protocols on leg wrapping.17,22,23

The primary aim of this randomized controlled trial was to compare the prophylactic effect of low-dose phenylephrine infusion and lower limb wrapping on systolic arterial blood pressure (SAP) during spinal anesthesia for cesarean delivery. Second, we examined the hemodynamic effects of an initial phenylephrine bolus before low-dose phenylephrine infusion. Third, this is the first study using continuous invasive monitoring to investigate the hemodynamic effects of lower limb wrapping and to compare a prophylactic intervention directed at the venous system with one acting primarily at the arteriolar level.3,24

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METHODS

The Regional Committee for Medical and Health Research Ethics of Southern Norway (Oslo, Norway), the Data Inspectorate at Oslo University Hospital, and the Norwegian Medicines Agency (Oslo, Norway) approved the study protocol. The randomized controlled trial was registered before patient enrolment with EudraCT (2009-013025-42, Dr. Med. Jana C. Kuhn, May 25, 2009) and ClinicalTrials.gov (NCT 01278238) and was conducted according to Good clinical trial practice and the principles of the Declaration of Helsinki. The data are reported according to the CONSORT guidelines.25 All subjects gave written consent after oral and written information.

This was a prospective, randomized, double-blinded, parallel-group, placebo-controlled study comparing the hemodynamic effects of a prophylactic initial bolus followed by low-dose infusion of phenylephrine, with standardized lower extremity compression, and with no intervention (control) using continuous minimally invasive monitoring.

Healthy pregnant women at term with a singleton pregnancy scheduled for elective cesarean delivery between January 2010 and October 2012 at Bærum Hospital, Norway, were asked to participate. Inclusion criteria were age between 18 and 40 years, height between 160 and 180 cm, prepregnancy body mass index of maximum 32 kg m−2, and absence of preexisting or gestational hypertension/preeclampsia/cardiovascular or cerebrovascular disease/psychiatric or somatic disease (other than well-treated mild asthma/thyroid hypofunction) or contraindications to spinal anesthesia.

The primary outcome measure was the extent of decrease in SAP after induction of spinal anesthesia. Secondary outcomes were change in CO, systemic vascular resistance (SVR), stroke volume (SV) and heart rate (HR), nausea, umbilical artery and vein pH and base excess, and Apgar score at 1, 5, and 10 minutes. In addition, we recorded body mass index, sensory and motor block, time from induction of anesthesia to delivery, operation duration, and adverse effects (pruritus, nausea, and any other eventual adverse event) during the procedure.

One hundred twenty women were randomly assigned to 1 of 3 treatment groups: group 1 (phe) was treated with an initial phenylephrine bolus IV (0.25 μg kg−1) followed by continuous low-dose phenylephrine infusion (0.25 μg kg−1 min−1) and sham leg wrapping (bandages wrapped loosely). Group 2 (leg) received tight bandaging for lower extremity compression and IV placebo infusion of study medicine. Group 3 (control) received placebo study medicine and sham leg wrapping. All persons involved in the handling of the drugs or the care of the participants were blinded to patients’ group assignments.

The hospital pharmacy performed block randomization into 3 groups of equal size, using a pool of sealed and shuffled cards. Study medicine was prepared in 50-mL syringes containing either phenylephrine (Abcur AB, Helsingborg, Sweden) or placebo, marked with a randomization number and neutral study information. Instructions on whether therapeutic or sham wrapping should be performed were put into a sealed envelope for each patient. Randomization codes were not revealed to the investigators until all measurements and calculations had been entered into the database, and statistical methods had been specified.

Study medicine and sealed wrapping instructions were delivered to the operating room on the morning of surgery. The patients had no premedication or IV prehydration but were allowed to drink clear liquids up to 2 hours before surgery. Fluid intake for the 24 hours before surgery and fasting time based on patient self-report were recorded. When the patient arrived at the operating room, an 18-gauge IV cannula was inserted in each forearm. Standard monitoring with electrocardiography and pulse oximetry was attached. A 20-gauge arterial line was inserted in the left radial artery after local anesthesia by an anesthetic skin patch (EMLA, AstraZeneca, London, United Kingdom). The arterial blood pressure set was connected, and the transducer was placed at the level of the heart and zeroed. The LiDCOplus monitor (LiDCO Ltd., Cambridge, United Kingdom)26 was connected for continuous hemodynamic monitoring. Calibration of CO was performed when the women had been lying supine with a wedge pillow beneath the right hip for 5 minutes, and hemodynamic variables were identified as stable by the LiDCO device. Mean SAP for a 1-minute period was calculated; the threshold SAP for the administration of rescue pressor was defined as SAP <80% of this mean value or <90 mm Hg.

To maintain blinding of all staff participating in patient care, leg wrapping was performed after visual shielding between the head of the bed and lower extremities was erected. To insure consistent leg compression in all patients, wrapping was performed by 1 of 3 operational technical assistants trained and exclusively dedicated to conduct this procedure. In leg patients, elastic bandages (12 cm × 7 m, Wero Medium Kompressionsbinda, Wero Swiss, Rothrist, Switzerland) were applied tightly from the metatarsus to groin with overlap by one third between layers. In the phe and the control groups, bandages were slackly laid around the legs.

The legs were covered, and the patient was turned into the left lateral position. Spinal anesthesia was induced in the L2 to L3 vertebral interspace with a 27-gauge pencil-point spinal needle. All groups received spinal anesthesia with 10 mg hyperbaric bupivacaine, 20 μg fentanyl (total volume, 2.4 mL). At the time of spinal injection, study medicine infusion (by syringe pump; Alaris PK, Basingstoke, United Kingdom) and rapid cohydration with 1000 mL 0.9% saline were started. The patient was then turned back into the supine position with a wedge pillow under the right hip. The operating table was briefly tilted to the right to support even distribution of spinal anesthesia before returning it to the zero position (with left uterine displacement). After 5 minutes, the upper sensory level of anesthesia was measured bilaterally as loss-of-cold sensation using ethyl chloride spray (WariActiv, Kältespray, Walter Ritter, GmbH + Co. KG, Hamburg, Germany) moving from caudad to cephalad. Motor block was graded according to the modified Bromage scale (0–3).27 Patients were asked to report any nausea, pruritus, or other possible adverse effects during the perioperative period.

Oxygen was administered through nasal catheter at a flow rate of 2 L min−1 during the operation. A bolus of 30 μg IV phenylephrine was given as a rescue medication in case of hypotension. If hypotension was combined with bradycardia (HR < 55 beats min−1), and/or mean arterial blood pressure (MAP) was below 60 mmHg, a bolus of 5 mg IV ephedrine was given. Administration of rescue pressor was repeated at 2-minute intervals if hypotension persisted. According to our protocol, the study medicine infusion would be stopped if SAP were >150 mm Hg for >3 minutes.

After delivery, 5 international units oxytocin were slowly injected as an IV bolus. Arterial and venous blood was sampled from the umbilical cord and analyzed (Radiometer ABL800 FLEX analyzer, Radiometer A/S, Copenhagen, Denmark). The midwife recorded Apgar scores at 1, 5, and 10 minutes. IV infusion of the study medicine was stopped, leg bandages were removed, and sensory and motor block level were reexamined at the end of surgery. The study ended when the patient was transferred to the postoperative unit.

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Statistical Analysis

The primary outcome of this trial was continuous decrease in SAP during the shortest period from spinal induction to delivery. Because of the absence of reliable blood pressure data under leg-wrapping treatment, and to secure a statistically significant difference between the control and the active comparator, we based our calculation on observed differences between control and phe groups.7 We expected a maximum decrease in SAP of 20 mm Hg in the phe group, a maximum decrease in SAP of 30 mm Hg in control patients, and a general SD in SAP of 12 mm Hg.7 We considered 10 mm Hg as a clinically relevant mean difference in SAP between the groups. According to our calculations (SamplePower 3.0; SPSS, Chicago, IL), a power level of 81% and a significance level of 0.05 could be achieved with 24 patients in each group if 2 groups were being compared. We expanded the group size to 40 to compensate for the third intervention and for possible dropouts.

Hemodynamic data were stored in the LiDCOplus monitor and downloaded as .csv text files for each patient when the patient was discharged from the postoperative unit. Construction of the dataset was performed using MATLAB version R2013a (The MathWorks, Natick, MA). The uneven sampled beat-to-beat dataset was transformed into evenly sampled sliding averages with a window size of 10 seconds and a slide of 5 seconds. The median value of the sliding averages of the 30-second period before spinal induction was used as the baseline value for the figures and statistical analyses. Time 0 for hemodynamic analyses was defined as the end of spinal injection. Data were cleansed for extreme values and outliers, as described in a previous study.28 A second round of data cleansing involved an artifact removal algorithm.29 All data were constructed, and all case exclusions were performed before breaking the randomization codes, to ensure against biased handling of the data.

Statistical analyses were performed in SPSS (version 21.0). We used the linear mixed model to analyze the continuous changes in hemodynamic variables as a function of time. Treatment groups were treated as fixed factors. We made an adjustment for baseline differences by excluding the main effect of group from the model and introduced a quadratic effect of time (uncentered) to account for the dynamism in hemodynamic trends. We further introduced a random intercept and a random effect of time to handle dependencies in the data and inhomogeneous variances among groups. The residuals of the mixed model analyses were normally distributed, and the same analysis was applied for all hemodynamic variables. Hemodynamic analyses were run for the first 13 minutes, which equaled the shortest interval from induction of spinal anesthesia to delivery.

Single-point comparisons of maximal changes in hemodynamic variables and of the other secondary end points are based directly on the actual observed data. Determination of normality was performed by visual assessment of normality plots (histogram and q-q) or, when in doubt, by Kolmogorov–Smirnov test. If 1-way analysis of variance of normally distributed residuals indicated statistically significant group differences, subsequent pairwise t tests were performed. In case of significant group differences in Kruskal-Wallis tests for nonparametric data, the Mann-Whitney U test was used for subsequent pairwise comparisons. Categorical data were analyzed with Pearson χ2 test. Normally distributed data are presented as mean and SD. Median and range, or interquartile range, are shown for nonnormally distributed data.

All reported P values are uncorrected. The significance level for overall tests of group differences was 0.05. Adjustment for pairwise group comparisons was performed ad modum Bonferroni by dividing the 0.05 significance level by the number of comparisons (3), which gave a corrected significance level of 0.017. No adjustments were made for the number of outcome variables.

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RESULTS

The study flow chart shows patient numbers and group allocation (Fig. 1). Patient characteristics (Table 1) including baseline hemodynamic variables (Table 2) in the 3 groups (phe, leg, and control) were similar.

Table 1

Table 1

Table 2

Table 2

Figure 1

Figure 1

The phe group had significantly less continuous decrease in SAP compared with the leg group (difference in rate of change, 0.09 mm Hg 5 s−1; 95% confidence interval [CI], 0.02–0.16; P = 0.013) and with the control group (0.48 mm Hg 5 s−1; 95% CI, 0.41–0.55; P < 0.001; Fig. 2A and Table 3) during the 13-minute analysis period. The phe group had less maximal decrease in SAP (P < 0.001) and shorter time to maximal decrease in SAP compared with the control group (Table 2). Comparing the leg with the control group, there was no significant difference in maximal decrease in SAP (Table 2), but continuous decrease in SAP was less (0.39 mm Hg 5 s−1; 95% CI, 0.32–0.46; P < 0.001; Table 3 and Fig. 2A). The incidence of hypotension was lower in the phe group than in the control group (P = 0.004; Table 4). There was no reactive hypertension in any of the groups.

Table 3

Table 3

Table 4

Table 4

Figure 2

Figure 2

SVR decreased in all groups, but continuous SVR was significantly higher in the phe than in the leg (P < 0.001) and control groups (P < 0.001; Fig. 2B and Table 3). SV increased in all groups, but continuous SV was significantly higher in the phe (P = 0.001) and leg groups (P < 0.001) than in the control group (Fig. 2C and Table 3). HR increased in all groups, but continuous HR was significantly lower in the phe group compared with the leg (P = 0.002) and control groups (P = 0.002; Fig. 2D and Table 3). There was no significant group difference in maximal increase in CO (Table 2), but continuous CO was significantly lower in the phe (P < 0.001) and control groups (P = 0.001) compared with the leg group (Fig. 2E and Table 3). The chronology of hemodynamic changes within the treatment groups is illustrated in the Supplemental Digital Content 1 (Supplemental Figure, http://links.lww.com/AA/B362). Umbilical blood gas values were within normal range and without significant between-group differences (data not shown). Further secondary outcomes are presented in Table 4.

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DISCUSSION

This randomized controlled trial demonstrated that an initial bolus followed by low-dose phenylephrine infusion is superior to leg wrapping and to sham treatment for the prevention of spinal hypotension during cesarean delivery. Leg wrapping is associated with less hypotension than no intervention.

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Main Findings on Prevention of Hypotension

The incidence and severity of hypotension were lowest in the phe group, as expressed by higher continuous SAP compared with the leg and control groups, and less maximal decrease in SAP and a lower incidence of hypotension compared with the control group. Leg wrapping had a moderate prophylactic effect compared with control, leading to higher continuous SAP in the leg group than in the control group. A Cochrane review from 2006,2 based on 7 studies, concluded that leg wrapping or alternative techniques for lower limb compression had a moderate effect preventing hypotension compared with control. Our study confirms this finding with the use of continuous invasive monitoring and demonstrates that leg wrapping has a limited prophylactic effect on hypotension compared with phenylephrine infusion. Therefore, prophylactic use of phenylephrine in combination with IV fluids3 should remain the method of choice for prevention of spinal hypotension during cesarean delivery. Lower limb wrapping may be recommended only as an alternative means of hypotension prophylaxis, in settings where logistic or economic availability of the “gold standard” prophylaxis phenylephrine is not provided. Manual application of elastic bandages is simple and was emphasized as the most effective technique in a review on different methods of lower limb compression.17

The sudden vasodilation induced by spinal anesthesia was not completely prevented by the initial bolus of phenylephrine (0.25 μg kg−1), but the decrease in SVR, the incidence of hypotension, and the maximum decrease in SAP in our study were less than in a trial7 using the same continuous rate of low-dose infusion without an initial bolus. In another study, hypotension was counteracted faster by therapeutic phenylephrine boluses than by therapeutic continuous infusion.16 These findings may support the addition of an initial bolus to a low-dose infusion regimen. Dyer et al.15 showed the hemodynamic effects of therapeutic phenylephrine boluses of 80 μg, which were a 75% peak increase in SVR about 30 seconds after administration and a 36% peak MAP increase after 62 seconds. These findings may suggest that better prevention of the rapid decrease in SVR might have been achieved by increasing the initial bolus to somewhere <80 μg in our study.

Different approaches for optimizing phenylephrine administration have been recently studied, trying to balance hypotension and maternal discomfort against adverse effects. Phenylephrine regimens based on intermittent boluses reduce hypotension13,15,16 but require more physician interventions and fail to keep MAP as close to baseline as continuous infusion.13 Studies using high-dose phenylephrine infusions (100–120 μg min−1) in conjunction with cohydration reported incidences of hypotension as low as 1.9% and even 0%,6,9 but correspondingly high incidences of hypertension (up to 80%) and of bradycardia (>30%).9 Studies of variable-rate infusions11,13 achieved lower incidences of hypotension (<15%) than our and other low- or medium-dose regimens.9,10 However, the true incidence of hypotension in studies using intermittent monitoring6,9–13,16 may be more frequent than reported, because they may miss a certain percentage of hypotensive episodes compared with studies using continuous hemodynamic monitoring.30 With an incidence of bradycardia of 2.6% and no reactive hypertension, our regimen had fewer adverse effects than previously studied variable-rate and low- or medium-dose infusions (incidences of hypertension 10%–40% and bradycardia 8%–15%).9–11,13

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Further Hemodynamic Findings

A rapid and profound reduction in SVR preceded a decrease in SAP in all treatment groups (Supplemental Digital Content 1, Supplemental Figure, http://links.lww.com/AA/B362). This observation confirms that a sudden and marked arterial vasodilation is the main hemodynamic effect of spinal anesthesia.3 The decrease in SVR was only attenuated by phenylephrine, which shows that leg wrapping does not counteract arterial dilation and that prophylaxis by the α1-agonist phenylephrine is the more physiologic approach to prevention of spinal hypotension.

In contrast, the leg-wrapping approach is based on the historic, but recently questioned, concept of impaired venous return being the most relevant factor in spinal hypotension.17,24,31 The increase in CO in all 3 groups in our study shows that spinal anesthesia does not cause any major venodilation with reduction of venous return. However, an interesting finding is that the increase in SV after the decrease in afterload was greater in the leg group than in the control group patients. This may indicate that there is some minor venodilation after induction of spinal anesthesia, which contributes to hypotension. Higher SV in the leg group compared with the control group, when afterload was low in both groups, suggests that preload was kept closer to baseline in the leg group by mechanical limitation of blood redistribution to the lower extremity veins.

Similar SV, in spite of higher SVR, in phe compared with leg group patients may indicate that preload is better in the former. The physiologic mechanism for this may be an α-agonist–mediated splanchnic venous recruitment by low doses of phenylephrine.32,33 Thus, our results suggest that phenylephrine restores arterial blood pressure by acting on both the arterial and the venous side of the vascular system, whereas the effect of leg wrapping is limited to the latter.

Reduced afterload and subsequent baroreceptor-mediated tachycardia induced a rapid and prominent increase in CO in all 3 groups. The following gradual HR reduction restored CO to baseline in the phe group. In contrast, untreated arterial vasodilation led to persistently higher HR and CO in the leg group patients, indicating a suboptimal effect of pure preload stabilization on the overall hemodynamic condition.

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Apgar and Umbilical Blood Gas Values

All umbilical blood gas and Apgar scores were within normal range, showing that the maternal hemodynamic condition was well tolerated by newborns in all 3 groups. Good neonatal outcome has been reported after both high- and low-dose phenylephrine infusions in healthy mothers.6,7,10,12,13 In case of prenatal maternal or fetal impairment, the condition of the newborn may depend on optimal hemodynamic prophylaxis.10,31 However, this has not yet been investigated in any randomized controlled trial.

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Limitations

Our rescue pressor doses were adapted to the protocol of a similar study.7 A larger phenylephrine bolus would have been more in line with current clinical routine and might have reduced the number of rescue doses needed. An inevitable protocol handicap was the risk of patient unblinding with respect to leg wrapping. To prevent such unblinding, the difference between therapeutic and sham leg wrapping was not specified in the patient information.

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CONCLUSIONS

Low-dose phenylephrine infusion is superior to leg wrapping and to no intervention for preventing spinal hypotension during cesarean delivery. Phenylephrine rapidly reverses the main derangement induced by spinal anesthesia, which is a decrease in SVR because of arterial vasodilation. Our findings suggest that phenylephrine also contributes to the maintenance of preload by splanchnic venoconstriction. Administering phenylephrine as a low-dose infusion with a small initial bolus stabilizes arterial blood pressure without clinically significant adverse effects. We assume that prevention of the initial decrease in arterial blood pressure can be further improved by increasing the initial bolus.

Leg wrapping prevents hypotension compared with no intervention by venous recruitment from the lower extremities. Concerning the recent debate on the role of venous and arterial circulation in obstetric spinal hypotension, our study confirms that spinal anesthesia does not decrease venous return. However, our findings suggest that there is modest venodilation after induction of spinal anesthesia that contributes to hypotension.

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DISCLOSURES

Name: Jana Christine Kuhn, MD, Dr. Med.

Contribution: This author is the principal investigator and helped conceive the study, design the study, conduct the study, recruit patients, collect the data, analyze the data, interpret the data, present the data, and write the paper.

Attestation: Jana Christine Kuhn approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, is the archival author.

Name: Tor Hugo Hauge, MSc, PhD.

Contribution: This author helped analyze the data, present the data, and revise the paper.

Attestation: Tor Hugo Hauge approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Leiv Arne Rosseland, MD, PhD.

Contribution: This author helped design the study, analyze the data, interpret the data, and revise the final paper.

Attestation: Leiv Arne Rosseland approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Vegard Dahl, MD, Dr. Med.

Contribution: This author helped design the study, recruit patients, collect the data, and revise the final paper.

Attestation: Vegard Dahl approved the final manuscript and attests to the integrity of the original data reported in this manuscript.

Name: Eldrid Langesæter, MD, PhD.

Contribution: This author is a principal scientific advisor and helped analyze the data, interpret the data, present the data, and revise the final versions of the paper.

Attestation: Eldrid Langesæter approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

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ACKNOWLEDGMENTS

The authors thank Elisabet Andersson, Registered Nurse Anesthetist, Department of Anesthesiology, Bærum Hospital, Vestre Viken Health Trust, Gjettum, Norway, for her dedicated and excellent assistance during the data collection. The authors also thank Magne Thoresen, PhD, Professor, Head of the Department of Biostatistics, University of Oslo, Oslo, Norway, for precious advice during the process of statistical analysis.

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