Pulse Pressure and Post-epidural Fetal Heart Rate Changes
Condition: Fetus or Neonate Affected by Maternal Epidural Anesthesia During Labor and Delivery
Study type: Interventional

Summary: 
      Epidural anesthesia, the most common method of pain control in labor, can contribute to
      alterations in maternal blood pressure and/or fetal heart rate changes. As a result, the
      administration of an IV fluid bolus ("preload") is standard prior to epidural placement.
      However, the optimal volume of preload is unknown and no clinical trials have evaluated a
      risk-factor based approach to dosing. Studies in the critical care, trauma, and obstetric
      literature have suggested that a narrow pulse pressure (difference between systolic and
      diastolic blood pressures) is a marker of reduced intravascular volume status and may
      identify women at a higher risk for new onset fetal heart rate changes after epidural
      placement. Therefore, the purpose of this study is to assess if an increased IV fluid preload
      bolus among women with a narrow pulse pressure reduces the risk of new onset fetal heart rate
      changes after epidural placement.
    

Detailed description: 
      Objective:

      To assess the efficacy of increased IV fluid preload for the prevention of post-epidural FHR
      changes in women with narrow pulse pressure

      Hypothesis:

      In individual with narrow pulse pressure, an increased IV fluid bolus will reduce the rate of
      post-epidural FHR changes.

      Background:

      In contemporary obstetric practice, regional anesthesia is the most commonly utilized method
      for pain management in labor. Compared with no anesthesia, neuraxial techniques have been
      associated with an increased risk of maternal hypotension, operative vaginal delivery,
      maternal fever, and cesarean delivery for fetal distress. Following the initial dosing of
      regional anesthesia, maternal hypotension and FHR abnormalities occur with reported
      frequencies of 5-18% and 6-30% respectively.

      Neuraxial anesthesia can induce a sympathetic blockade, which results in decreased maternal
      systemic vascular resistance and venous return. These alterations in the maternal hemodynamic
      profile impact maternal blood pressure, uteroplacental blood flow and fetal perfusion, and
      may contribute to maternal hypotension and changes in the FHR after initiation of regional
      anesthesia. Importantly, these hemodynamic changes generally occur in the setting of a
      constant maternal intravascular volume. Given that the uteroplacental circulation has limited
      capacity for autoregulation, uterine perfusion is sensitive to changes in both maternal blood
      pressure and venous return. This physiology represents the basis for the administration of an
      intravenous (IV) bolus prior to or during the placement of regional anesthesia .

      While maternal hypotension and FHR changes after neuraxial anesthesia are common occurrences,
      limited information on maternal and fetal characteristics or risk factors has been published.
      A recent retrospective cohort study by Miller et al. reported that a narrow maternal pulse
      pressure was a risk factor for post-epidural FHR changes. In this cohort study, women with an
      admission pulse pressure < 45, compared with pulse pressure > 45, had a marked increase in
      the risk of post-epidural FHR changes (27% vs 6%, p < 0.001, OR 5.6 [2.1-14.3], aOR 28.9
      [3.8-221.4]). Interestingly, the incidence of maternal hypotension was not different between
      the two pulse pressure groups (21% vs 25%, p=0.49), suggesting that fetal perfusion is
      sensitive to the reduced venous return associated with increased venous capacitance related
      to reduced sympathetic tone. Further supporting this premise, a study by Vricella et al.
      demonstrated an increased rate of post-epidural maternal hypotension, vasopressor support and
      FHR changes in women with severe preeclampsia, a clinical state of volume contraction,
      compared with normotensive controls. The authors concluded that the vasoconstriction and
      intravascular depletion central to the syndrome of severe preeclampsia make this subset of
      women vulnerable to post-epidural hemodynamic changes and that administration of a standard
      IV fluid bolus may not adequately compensate for increased venous capacitance.

      Data from the critical care and trauma literature further support the use of pulse pressure
      as a marker of hypovolemia. Conventional static indicators of cardiac preload, such as
      central venous pressure (CVP) or pulmonary capillary wedge pressure (PCWP), are poor
      predictors of "volume responsiveness", which is the cardiovascular response (i.e. changes in
      preload) to intravascular volume expansion with IV fluid. However, dynamic parameters such as
      variation in pulse pressure or stroke volume, are highly predictive of volume responsiveness.
      While data on pulse pressure variation are primarily derived from non-pregnant, mechanically
      ventilated individuals, a small case series demonstrated that pulse pressure variation
      accurately reflects volume responsiveness in pregnant women undergoing cesarean delivery
      under regional anesthesia. Additionally, data from the trauma literature have also
      demonstrated pulse pressure to represent an accurate surrogate of stroke volume and marker of
      central hypovolemia. Covertino et al. reported a direct relationship between pulse pressure
      and central volume reductions without any difference in mean arterial pressure. As such,
      pulse pressure may serve as a better maker of central hypovolemia than blood pressure alone.
      Therefore, pulse pressure may better predict low maternal intravascular volume and serve as a
      marker for post-epidural FHR changes.

      Pregnancy itself is associated with alterations in blood pressure with decreased vascular
      tone and widening of the pulse pressure. Normal pulse pressure and variations in pregnancy
      are poorly described. However, in otherwise healthy non-pregnant adults, stroke volume is
      approximately 1.7 times the pulse pressure. Given that the stroke volume in a term pregnancy
      is approximated to be 100 mL/min, a normal pulse pressure in pregnancy should be
      approximately 60 mmHg. Therefore, a level of 45 mmHg has been proposed to define a low pulse
      pressure in pregnancy.

      Notably, no prospective studies have evaluated a risk-factor based approach, namely the use
      of maternal volume status, to guide the volume of the IV fluid bolus administered prior to
      neuraxial anesthesia. The investigators hypothesize that in individuals with narrow pulse
      pressure, an increased IV fluid bolus will reduce the rate of post-epidural FHR changes.
      While pulse pressure variation has been best characterized as a marker of fluid
      responsiveness in previously healthy critically ill patients, this parameter is only readily
      obtained through use of an automated device (FloTrac/Vigileo system, Edwards Lifesciences,
      Irvine, CA) that requires an arterial line. Furthermore, pulse pressure variation has
      primarily been assessed in mechanically ventilated patients, which is rare in the obstetric
      setting. Therefore, based on the preliminary data by Miller et al., the investigators plan to
      use pulse pressure (and not pulse pressure variation) as a marker of intravascular volume
      this study with a cut point of 45 mmHg to define low pulse pressure. Given that previous
      studies have used IV fluid preload doses ranging from 500-1500 mL, the IV fluid dosing
      regimens that will be used in this study represent variations in the standard of care. A
      practical study design is proposed using current practice patterns for a low risk
      intervention in a low risk population.

      Study Design:

      Prospective Randomized Controlled Trial

      Study Protocol:

      Women meeting eligibility criteria will be recruited and randomized in a 1:1 ratio into two
      study groups: standard IV fluid bolus prior to epidural placement (500 mL Lactated Ringers)
      or "volume replacement" IV fluid bolus of 1500mL Lactated Ringers. IV fluid boluses will be
      infused over 30 minutes and administered within 1 hour of epidural placement. A third group
      will also be recruited as a control, which will include women with a pulse pressure > 45 on
      admission (and otherwise meet the aforementioned inclusion/exclusion criteria). The control
      group will receive the standard preload bolus of 500 mL prior to epidural placement.

      This is a practical study using standard clinical practice methods to assess vital signs.
      Maternal vital signs (blood pressure, heart rate) will be collected in the left lateral
      recumbent position after an initial 5 minute period without activity. Automated devices will
      be used to assess blood pressure and pulse pressure at the following times: on admission,
      immediately prior to infusion of IV fluid bolus in preparation for epidural placement,
      immediately following IV fluid bolus infusion, at epidural test dose (T=0), every 5 minutes
      for 30 minutes (T=0 to T=30), and then every 10 minutes for the next 30 minutes (T=30 to
      T=60).

      The chart will be abstracted to identify changes in the FHR and interventions. Continuous
      external (or internal, if placed for typical obstetric indications), fetal monitoring will be
      performed before and after epidural placement as is standard on our L&D unit. Treatment of
      hypotension with administration of vasopressors or additional IV fluid boluses along with the
      treatment of FHR abnormalities (maternal position changes, supplemental oxygen
      administration, tocolytic use, cessation of oxytocin) will be recorded. Operative delivery
      for non-reassuring fetal status in the 60 minutes after epidural placement will be recorded.
      Additionally, maternal demographic and medical/obstetric data, maternal and neonatal delivery
      and outcome data will be recorded.

      The technique for epidural placement and dosing will be standardized as follows. Epidural
      dosing will consist of 5 mL of 0.125% bupivicane with 10 mcg/mL of fentanyl. This standard
      bolus dose will be administered and levels of sensory block and numeric patient pain scores
      will be recorded. If patients have not achieved a pain score of 4 or less at 15 minutes after
      the epidural bolus, an additional bolus will be administered to achieve appropriate pain
      control. The volume of additional epidural bolus will be recorded.

      Two independent obstetricians blinded to the randomization group and delivery outcome will
      interpret the FHR tracing for one hour before and after epidural placement. The FHR tracings
      will be divided into 15 minute epochs and categorized using the standard ACOG categories: I,
      II and III. Additional information including FHR baseline, FHR variability, and the presence
      or absence of accelerations or decelerations will be recorded for each 15min epoch.
      Discrepancies between the tracing interpretations will be reviewed by a third obstetrician
      for development of a consensus interpretation.
    

Intervention name(s): Lactated Ringer's
Intervention type(s): Drug
Intervention description(s): 1500 cc of IV Fluid (crystalloid) used for preload prior to epidural administration in the treatment arm. Control arm receives 500 cc.
Other intervention name(s): Ringer's Lactate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: pulse pressure; fetal heart rate; epidural analgesia; hypotension; preload; fluid bolus; central hypovolemia