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The Effects of Vasopressin and Oxytocin on the Fetoplacental Distal Stem Arteriolar Vascular Resistance of the Dual-Perfused, Single, Isolated, Human Placental Cotyledon

Downing, John W. MD; Baysinger, Curtis L. MD; Johnson, Raymond F. BS; Paschall, Ray L. MD; Shotwell, Matthew S. PhD

doi: 10.1213/ANE.0000000000001449
Obstetric Anesthesiology: Original Laboratory Research Report

BACKGROUND: Vasoactive agents administered to counter maternal hypotension at cesarean delivery may theoretically intensify the hypoxemic fetoplacental vasoconstrictor response and, hence, negatively impact transplacental oxygen delivery to the fetus. Yet, this aspect of their pharmacodynamic profiles is seldom mentioned, let alone investigated. We hypothesized that vasopressin, a potent systemic vasoconstrictor, and oxytocin, a uterotonic agent administered routinely at cesarean delivery, which, in contrast to vasopressin, possesses significant systemic vasodilator properties, would not influence distal stem villous arteriolar resistance.

METHODS: The dual-perfused, single, isolated cotyledon, human placental perfusion model was used to examine the resistance response of the fetoplacental circulation to oxytocin and vasopressin in placentae harvested from healthy women. Twelve of a total of 17 individual experiments were conducted successfully during which either oxytocin (n = 6) or vasopressin (n = 6) was introduced into the fetal reservoir in concentration increments of 10−1 M. Fetoplacental distal stem villous arteriolar perfusion pressure (FAP) was measured continuously. The fetal circuit concentration of either oxytocin or vasopressin was raised in a stepwise fashion from 109 to 10−5 M or 10−11 to 10−6 M, respectively. Both reservoirs were then purged of drug, after which 1-mL 1.0 mM 5-hydroxytryptamine (2.5 µM), an agent well known to manifestly increase fetoplacental distal stem villous arteriolar resistance, was introduced into the fetal circuit. A significant increase in FAP from baseline in response to exposure to 5-hydroxytryptamine confirmed that the fetoplacental vasoconstrictor response remained reactive. The primary outcome of this study was changes in FAP after incremental dosing of vasopressin and oxytocin.

RESULTS: No changes in FAP were observed with either oxytocin or vasopressin regardless of the drug concentration tested. For each drug and concentration, a mean pressure change greater than ±10 mm Hg was excluded with 95% confidence. In contrast, 5-hydroxytryptamine significantly increased perfusion pressure in all 12 successful experiments.

CONCLUSIONS: Oxytocin and vasopressin do not influence human fetoplacental distal stem villous arteriolar resistance. The neutral impact of vasopressin noted here is thus analogous to the reported negligible influence of the drug on human pulmonary arteriolar resistance. Neither drug seems likely to adversely influence the compensatory hypoxemic fetoplacental vasoconstrictor response.

From the Departments of *Anesthesiology and Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.

Accepted for publication May 9, 2016.

Funding: Departmental.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to John W. Downing, MD, Division of Obstetric Anesthesia, Department of Anesthesiology, 4202 Vanderbilt University Hospital, 1211 22nd Ave South, Nashville, TN 37232. Address e-mail to john.downing@vanderbilt.edu.

Spinal and combined spinal-epidural anesthesia for cesarean delivery frequently triggers significant maternal hypotension that usually responds to ephedrine or phenylephrine administration, alone or in concert, the latter currently considered the first choice.1,2 However, if maternal hypotension proves refractory to ephedrine and/or phenylephrine, a backup vasopressor acting independently of the sympathetic nervous system, namely vasopressin, may prove invaluable.3 The use of arginine vasopressin, a nonapeptide, as a rescue vasopressor to treat epidural anesthesia-induced intractable hypotension, may be advantageous.4

Oxytocin, an octapeptide, is a “high-alert” drug used widely for decades by obstetricians as a uterotonic agent.5 Oxytocin is administered routinely by anesthesiologists immediately before or soon after placental delivery at cesarean delivery.6 Structurally, vasopressin and oxytocin, both neurohypophyseal hormone derivatives, are strikingly similar. Paradoxically, vasopressin strongly constricts, whereas oxytocin dilates, systemic arteries. Consequently, oxytocin may acutely exacerbate maternal hypotension.7

Neither vasopressin nor oxytocin constricted human villous artery segments.8 In the absence of meconium, oxytocin did not influence fetoplacental distal stem villous arteriolar perfusion pressure (FAP).9 We hypothesized that vasopressin and oxytocin would not increase the resistance response of the fetoplacental circulation. The familiar dual-perfused, single, isolated cotyledon, human placental model was used to test our hypothesis.10,11

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METHODS

The study protocol was approved by Vanderbilt University Human Research Protection Program and was conducted with informed, written patient consent. Fresh placentae delivered vaginally or abdominally were harvested from healthy women at term. Exclusion criteria included preeclampsia, diabetes, cardiopulmonary disease, morbid obesity, substance abuse, overt placental pathology, fetal intrauterine growth restriction, macrosomia, major fetal anomalies, nonreassuring fetal heart rate pattern, preterm (<37 weeks) gestation, and postmature (>40 weeks) pregnancy.

Placentae were transported within 10 to 15 minutes of their delivery to the perfusion laboratory where a fetal chorionic artery and vein serving a discrete cotyledon were cannulated with 5F gauge polyethylene infant feeding tubes, external diameter 1.7 mm and length 38 cm (Sherwood Medical Corp, St. Louis, Mo) (Figure 1). The chorionic cannulae were connected in circuit via Tygon R-3603 formula tubing (internal diameter 2.4 mm, external diameter 4.8 mm, wall thickness 1.7 mm; Fisher Scientific, Atlanta, GA) to a reservoir containing heparinized Krebs-Ringer bicarbonate buffer, human albumin 2.0 g/100 mL, and glucose 150 mg/100 mL.

Figure 1

Figure 1

Each cotyledon was mounted in a Plexiglas chamber, maternal surface upward. Three blunt-tipped 19F needles were inserted 2 to 3 mm below the maternal chorionic plate and then connected to a second reservoir primed with the same Krebs Ringer/albumin/glucose solution. Both reservoirs were equilibrated with 21% oxygen (O2), 5% carbon dioxide (CO2), and 74% nitrogen (N2). Perfusate pH (7.4), PO2, PCO2, and temperature (37°C) were kept constant. Peristaltic roller pumps provided a maternal flow rate of 12 mL/min. Depending on the size of each cotyledon, fetal circuit flow rates (2–4 mL/min) were adjusted to produce basal FAP between 60 and 80 mm Hg. Fetal perfusate volume was monitored to ensure equality between the umbilical arterial and venous flow rates (mL/min) and to check for leaks from either circuit.

Maternal intervillous pressure and FAP in millimeter of mercury (mm Hg) were measured continuously using in-line pressure transducers calibrated previously against a mercury manometer and linked to a Hewlett Packard (78342A) monitor (Hewlett Packard, Palo Alto, CA). Flow rate (Q) was assumed proportional to FAP and inversely related to placental distal stem villous arteriolar vascular resistance (UaVR). Because Q = FAP ÷ UaVR, then FAP = Q × UaVR. FAP changes with constant flow rate (mL/min) mirrors alterations in UaVR. The designated end-point FAP for each phase of the experiment used for analysis was the reading recorded 15 minutes after each incremental change (10−1 M) in drug concentration. Each cotyledon was perfused for an hour to allow pressures on the maternal and fetal sides of the placenta to stabilize.

In separate experiments conducted on a cohort basis, first, diluted oxytocin (initial concentration 10 units/mL, USP; APP Pharmaceuticals, LLC, Schaumburg, Ill) was added to the fetal circuit through a concentration range of 10−9 to 10−5 M. Then, diluted vasopressin (initial concentration 20 units/mL, USP; APP Pharmaceuticals, LLC) was added to the fetal circuit in increments of 10−1 M, which raised the vasopressin concentration from 10−11 to 10−6 M. Maternal intervillous pressure and FAP were recorded at time 0 and then immediately before each step increase in drug concentration at 15, 30, 60, 90, 120, 150, and 180 minutes.

After a 30-minute purge of both reservoirs, 1-mL 2.5 µM 5-hydroxytryptamine was added to the fetal reservoir. The resultant increase in FAP was recorded over 30 minutes as an endurance test of the fetoplacental vasoconstrictor response. Human umbilical blood vessels constrict vigorously when exposed to 5-hydroxytryptamine (5-HT).12 Umbilical and chorionic plate arterial specimens from women with normal pregnancies also contract forcefully in response to 5-HT.13,14 Furthermore, the ultrastructure of healthy placental tissue after 6 hours of in vitro normoxic, dual placental perfusion remains largely unharmed.15 Because our experiments lasted <6 hours, we relied on a single evaluation, namely a 5-HT challenge test, to confirm continuing placental viability. If the cotyledon failed to respond to the 5-HT challenge, the results of that experiment were discarded.

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Statistical Analysis

Figure 2

Figure 2

The target sample size of 6 placentae per drug was selected a priori according to the precedent of similar studies.11,16,17 The effects of vasopressin and oxytocin on FAP were assessed using a linear mixed-effects regression technique. This method was applied separately for the vasopressin and oxytocin experiments. A random intercept was used to account for correlation among repeated measurements on each placental preparation and variability in baseline pressure. Drug concentration was treated as a categorical factor with 6 levels for vasopressin and 5 for oxytocin. Baseline (drug-naive) and 5-HT were treated as separate categories. FAP measurements in the 5-HT experiments were significantly more variable (among placental preparations) than those associated with vasopressin or oxytocin. To account for this observation, the variance in FAP measurements associated with the 5-HT experiments was estimated separately from that of the vasopressin or oxytocin measurements. Residual and random effects diagnostics were implemented using graphical techniques. For each drug and concentration category, the model-adjusted mean FAP was reported with Wald-type pointwise 95% confidence interval (CI) (Figure 2). The differences in mean FAP, relative to the basal mean, were also reported with Wald-type pointwise 95% CI. No adjustment was made to constrain the familywise type-I error probability. All statistical analyses and graphics were implemented using open source R software version 3.0.2 [R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL: http://www.R-project.org/].

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RESULTS

A total of 17 placentae were harvested. The results from 5 experiments were discarded: 2 because the baseline FAP fell significantly outside the designated protocol range, and 3 after failure of the preparation to respond to the final 5-HT challenge test. Twelve successful perfusion experiments were completed, 6 with each agent.

Figure 3

Figure 3

Incremental addition to the fetal reservoir of vasopressin concentrations (10−11 M through 10−6 M) did not alter the average FAP (Figure 2). Similarly, incremental supplements of oxytocin (10−9 M through 10−5 M) produced no FAP changes. For each drug and concentration, a mean pressure change greater than ±10 mm Hg was excluded with 95% CI (Figure 3). Except for 5-HT, the CI half-widths were 6.4 mm Hg and 6.8 mm Hg for oxytocin and vasopressin, respectively. The addition of 5-HT after system purging increased FAP substantially from baseline on average by 83% (61 mm Hg; 95% CI, 38–85) and 123% (94 mm Hg; 95% CI, 53–134) after exposure to vasopressin and oxytocin, respectively, indicating that the fetoplacental vasoconstrictor response remained robust.

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DISCUSSION

This study confirms our hypothesis that vasopressin does not influence FAP in the dual-perfused, single, isolated, human placental cotyledon. Our findings with oxytocin agree with a previous study that reported no increase in FAP with oxytocin in healthy dual-perfused cotyledons.9 (Curiously, oxytocin did manifest vasoconstrictive activity in meconium-contaminated placentae.9) Previously, others reported that neither vasopressin nor oxytocin, regardless of concentration, constricted human stem villous arterial segments.8 Previous investigations pertaining to the efficacy of agents that produce vasoconstriction in other arterial beds showed that exposure of the dual-perfused, single, isolated human placental cotyledon to norepinephrine, epinephrine, methoxamine, and low-dose phenylephrine does not increase FAP, whereas 5-HT, ephedrine, high-dose phenylephrine, and hypoxemic challenges do raise FAP.10,11

Similar to epinephrine, norepinephrine, renin, and angiotensin, vasopressin is a stress hormone that supports physiological homeostasis and hemodynamic stability.4,18 Remarkable structural similarities between oxytocin and vasopressin favor cross-reactions, in that oxytocin possesses antidiuretic properties and vasopressin exhibits uterotonic properties.19,20 Results reported here suggest that the administration of either vasopressin or oxytocin to the mother would have little effect on the fetoplacental circulation.

The placenta and the lungs both oversee gas exchange and redistribute blood flow under hypoxic conditions. Analogous to the pulmonary hypoxic vasoconstrictor response, the hypoxemic fetoplacental vasoconstrictor response is physiologically geared to counter maternal/fetal circulatory mismatch (Qm/Qf inequalities), although the mechanisms involved are not as well defined as they are for the lungs.10,21 Maternal uteroplacental ischemia and reduced intervillous oxygen tension instigate pervasive hypoxemic fetoplacental vasoconstriction that increases downstream resistance to umbilical artery blood flow and raises FAP, leading to absent or reversed end-diastolic flow, cor placentale, and ultimately, fetal death.10

In contrast to the lack of the effect of vasopressin on the fetoplacental circulation under circumstances that induce fetal hypoxia, vasopressin generates several critical changes in the circulatory dynamics of the fetus.22 Fetal hypoxemia induces massive vasopressin release, resulting in vasoconstriction, hypertension, and bradycardia. These changes are indicative of circulatory adjustments in response to the hypoxia and stress of birth and are the basis for the protective redistribution of blood flow to the fetal brain and adrenal glands. Thus, vasopressin appears fundamental to compensatory circulatory centralization in the asphyxiated fetus.23 Evidence supporting the latter premise can be found in a report by DeVane and Porter,24 who discovered that umbilical arterial and, to a lesser degree, umbilical venous, vasopressin concentrations were greatest in stressed versus nonstressed neonates, especially after vaginal delivery.

Although we have demonstrated no influence of vasopressin and oxytocin on the fetoplacental circulation here, their potential ability to change maternal uteroplacental blood flow for the worse bears discussion. Both vasopressin (a full agonist) and oxytocin (a partial agonist) constrict isolated rat uterine resistance arteries by activating the vasopressin V1A receptor subtype; vasopressin is 57 times more potent than oxytocin.25 During pregnancy, the uterine artery contractile response to oxytocin is less pronounced because of oxytocin receptor desensitization or conversion to less responsive V1A receptors, which is not the case for vasopressin.26

On the basis of the results of animal experiments, Treschan and Peters18 cautioned that vasopressin was probably unsuitable for use as a vasopressor in the labor suite. Vasopressin strongly contracted isolated human uterine artery segments with or without endothelium, obtained from nonpregnant patients.27 However, oxytocin acted similarly.28 In preeclamptic patients, Allen et al29 observed that, when compared with all the other vasoconstrictors they tested, vasopressin was the strongest contractile agonist of intramyometrial arterial rings. Constriction by oxytocin only occurred with high concentrations. In contrast to their effects on maternal vessels, vasopressin and oxytocin induced relatively feeble vasoconstrictor responses in fetal stem villous arteries.

In this context, it should be mentioned that the clinical infusion of phenylephrine has been shown to significantly increase uterine and placental arcuate artery blood flow Doppler velocity waveform indices.30 As a result, caution was recommended when selecting vasopressors and their dosage for cesarean delivery. However, similar to vasopressin, no change in umbilical arterial resistance was observed with phenylephrine. The latter finding, together with the results reported here for vasopressin and oxytocin, suggests a dearth of appropriate receptors for these 3 vasoactive ligands within the placenta.9,11

Despite downregulation of V1A receptors during pregnancy, clinical measures of uterine artery dynamics show that oxytocin increases uterine artery vascular resistance under some circumstances. Doppler uterine artery flow velocity waveform changes during oxytocin challenge testing (OCT) showed that oxytocin increased uterine artery resistance, more so when the OCT was positive.31 Uterine artery reactivity during contractions was higher with oxytocin-induced versus spontaneous labor.32 In the setting of a positive OCT, presumably indicating fetal hypoxemia, umbilical artery resistance increased acutely.33 In these studies, an increase in the fetal middle cerebral artery pulsatility index, indicating that cerebral blood flow was sustained at the expense of a decrease in fetoplacental blood flow, was noted. This portent was more pronounced in OCT-positive fetuses exhibiting evidence of imminent compromise.

Our study has some limitations. We used an in vitro preparation, the experiments were few in number, and we did not perform an a priori sample size analysis. However, the placental model used here is well established, and the possibility of large FAP changes was excluded with high confidence. We therefore submit that the number of experiments performed was appropriate. In addition, the choice of the 5-hydroxytryptamine challenge test as the only determinant of cotyledon viability might be criticized.

However, as noted earlier, 5-HT powerfully constricts human fetoplacental vasculature.12–14 Furthermore, the ultrastructure of healthy human placental tissue tolerates prolonged in vitro normoxic placental perfusion.15 Therefore, because our experimental times were relatively brief, a single test for continuing placental viability was deemed appropriate.

In conclusion, the ideal vasopressor for treating hypotension in obstetric patients should sustain uteroplacental perfusion while, at the same time, conserving the compensatory hypoxemic fetoplacental vasoconstrictor response. On the basis of our in vitro findings and the discussion presented earlier, we propose that clinical studies of vasopressin for the treatment of neuraxial anesthesia-induced hypotension in the setting of cesarean delivery are warranted.

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DISCLOSURES

Name: John W. Downing, MD

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Name: Curtis L. Baysinger, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Name: Raymond F. Johnson, BS

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Name: Ray L. Paschall, MD

Contribution: This author helped design the study and prepare the manuscript.

Name: Matthew S. Shotwell, PhD

Contribution: This author helped analyze the data, and prepare the manuscript.

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

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