Phenylephrine in Spinal Anesthesia in Preeclamptic Patients
Condition: Preeclampsia; Hypotension
MeSH terms: Pre-Eclampsia; Hypotension
Study type: Interventional

Summary: 
      Hypotension remains a common clinical problem after induction of spinal anesthesia for
      cesarean delivery. Maternal hypotension has been associated with considerable morbidity
      (maternal nausea and vomiting and fetal/neonatal acidemia). Traditionally, ephedrine has been
      the vasopressor of choice because of concerns about phenylephrine's potential adverse effect
      on uterine blood flow. This practice was based on animal studies which showed that ephedrine
      maintained cardiac output and uterine blood flow, while direct acting vasoconstrictors, e.g.,
      phenylephrine, decreased uteroplacental perfusion. However, several recent studies have
      demonstrated that phenylephrine has similar efficacy to ephedrine for preventing and treating
      hypotension and may be associated with a lower incidence of fetal acidosis. All of these
      studies have been performed in healthy patients undergoing elective cesarean delivery.

      Preeclampsia complicates 5-6% of all pregnancies and is a significant contributor to maternal
      and fetal morbidity and mortality. Many preeclamptic patients require cesarean delivery of
      the infant. These patients often have uteroplacental insufficiency. Given the potential for
      significant hypotension after spinal anesthesia and its effect on an already compromised
      fetus, prevention of (relative) hypotension in preeclamptic patients is important. Spinal
      anesthesia in preeclamptic patients has been shown to have no adverse neonatal outcomes as
      compared to epidural anesthesia when hypotension is treated adequately. Due to problems
      related to management of the difficult airway and coagulopathy, both of which are more common
      in preeclamptic women, spinal anesthesia may be the preferred regional anesthesia technique.
      Recent studies have demonstrated that preeclamptic patients may experience less hypotension
      after spinal anesthesia than their healthy counterparts. To our knowledge, phenylephrine for
      the treatment of spinal anesthesia-induced hypotension has not been studied in women with
      preeclampsia. The aim of our study is to compare intravenous infusion regimens of
      phenylephrine versus ephedrine for the treatment of spinal anesthesia induced hypotension in
      preeclamptic patients undergoing cesarean delivery. The primary outcome variable is umbilical
      artery pH.
    

Detailed description: 
      The study will be approved by the Northwestern University Institutional Review Board.
      Eligible women admitted to the Labor and Delivery Unit of Prentice Women's Hospital will be
      approached for study participation immediately after the routine preanesthetic evaluation.
      This usually occurs shortly after admission to the Labor and Delivery Unit. Women who agree
      to participate will give written, informed consent at this time.

      Preparation and initiation of spinal anesthesia will proceed according to routine practice at
      our institution. A 16-gauge IV catheter will be inserted under local anesthesia in the
      pre-operative labor and delivery suite. An IV infusion of lactated Ringer's solution will be
      started at a minimal rate to maintain vein patency. Patients will be premedicated with
      metoclopramide 10 mg and ranitidine 50 mg IV at least 30 minutes prior to procedure for
      aspiration prophylaxis. Patients will be allowed to rest undisturbed for several minutes in
      the left lateral tilt position, during which heart rate (HR) and systolic blood pressure
      (SBP) will be taken every 1-2 minutes for at least 3 measurements. Baseline HR and SBP will
      be the mean of these three recordings.

      The subjects will be randomized according to a computer-generated randomization table to one
      of two groups: Group 1 will receive a phenylephrine infusion and Group 2 will receive an
      ephedrine infusion. All study medications will be prepared by an investigator not involved in
      the care of the patient or collection of data. Both the anesthesiologist managing the
      patient's anesthetic, as well as the patient, will be blinded to the study medication.

      Upon arrival to the operating room, 30 mL of 0.3 M sodium citrate will be given orally and
      standard monitoring will performed, including non-invasive BP, electrocardiography and pulse
      oximetry. Oxygen will be given at 3 liter per minute by nasal cannula. Fetal heart rate will
      be monitored by external cardiotocography until the time of surgical preparation. 500 mL of
      lactated Ringer's solution will be given as a bolus concurrently with the start of the spinal
      anesthesia procedure. Spinal anesthesia will be induced with patients in the sitting
      position. After sterile skin preparation and draping, the skin will be infiltrated with
      lidocaine, a 25 gauge Whitacre needle will be inserted at the L3-L4 vertebral interspace (±
      one vertebral interspace) and bupivacaine 0.75%, 1.6 mL (12 mg), fentanyl 15 μg and morphine
      150 μg will be injected intrathecally. Patients will be immediately placed supine with left
      uterine displacement. SBP will be measured every 1 minute beginning 1 minute after spinal
      injection for 10 minutes, then every 2.5 minutes for the remainder of the procedure.
      Patients' hemodynamic data will be recorded throughout the procedure and printed at the end
      of the surgery. Five minutes after spinal injection, the sensory level of anesthesia will be
      assessed by loss of pinprick discrimination using von Frey hairs. If the patient fails to
      obtain at least a T6 sensory level of anesthesia, that patient will be withdrawn from the
      study. Preincision antibiotics, magnesium sulfate and uterotonic agents will be administered
      intraoperatively per routine practice.

      An unblinded investigator will prepare solutions of phenylephrine 100 μg per mL and ephedrine
      8000 μg per mL (potency phenylephrine:ephedrine 80:111). The investigator will place 20 mL of
      the study medication into a syringe which will be given to the managing anesthesiologist for
      infusion via a syringe pump. The infusion will be attached to the IV cannula at the most
      distal. The infusion will be initiated immediately after completion of the spinal injection
      at a rate of 1 mL per minute and continued for a minimum of two minutes after which the
      infusion will either be stopped, continued or increased based on the SBP measurement each
      minute. The goal will be to maintain SBP ≥ 80% baseline, but not > 160 mmHg. After each
      measurement of SBP, the infusion will be stopped if the SBP is greater than 80% baseline SBP,
      and the infusion will be continued or restarted if the SBP is approximately equal to 80%
      baseline SBP.12 The infusion will be increased by 1 mL per minute if the SBP measurement is
      less than 80% baseline. For the purpose of this study, we will define hypotension as a
      decrease in SBP to < 80% of baseline.13 Each time there is a SBP measurement demonstrating
      hypotension as defined above, the patient will receive a 1 mL IV bolus of the study solution
      via the infusion pump and the infusion will be increased by 1 mL per minute. The infusion and
      bolus protocol will be continued until delivery, after which further management will be at
      the discretion of the managing anesthesiologist to maintain SBP. If the baseline SBP > 160
      mmHg, the infusion will not be started until the SBP decreases to 160 mmHg. Infusion
      management will then proceed as described above.

      The total volumes of the study solutions given by infusion and bolus up to the time delivery
      will be recorded. Bradycardia (defined as HR < 60 bpm) associated with an SBP equal or
      greater to baseline SBP will be treated by stopping the study solution and bradycardia
      associated with SBP < 80% baseline will be treated with atropine intravenously. Hypotension
      unresponsive to study medication will be treated with epinephrine (10 μg/mL) intravenous
      boluses (1 mL) until correction of hypotension. Nausea or vomiting not associated with
      hypotension will be treated with ondansetron 4 mg IV.

      After delivery, oxytocin 10-20 IU will be given by slow IV infusion per routine. The infant's
      1 and 5 minute Apgar scores will be assessed by the nurse or pediatrician blinded to patient
      group. The results of routine umbilical cord blood gas analysis will be recorded.
    

Intervention name(s): Ephedrine; Phenylephrine
Intervention type(s): Drug; Drug
Intervention description(s): Ephedrine concentration: 8 mg/mL. The infusion will be initiated immediately after completion of the spinal injection at a rate of 1 mL/min and continued for a minimum of 2 min after which the infusion will be stopped, continued or increased based on the SBP each minute. After each SBP measurement the infusion will be stopped if SBP > 80% baseline, and the infusion will be continued or restarted if the SBP is approximately equal to 80% baseline. The infusion will be increased by 1 mL/min if the SBP < 80% baseline. Each time there is hypotension the patient will receive a 1 mL IV bolus of the study solution and the infusion will be increased by 1 mL/min until delivery.; Phenylephrine concentration: 100 mcg/mL. The infusion will be initiated immediately after completion of the spinal injection at a rate of 1 mL/min and continued for a minimum of 2 min after which the infusion will be stopped, continued or increased based on the SBP each minute. After each SBP measurement the infusion will be stopped if SBP > 80% baseline, and the infusion will be continued or restarted if the SBP is approximately equal to 80% baseline. The infusion will be increased by 1 mL/min if the SBP < 80% baseline. Each time there is hypotension the patient will receive a 1 mL IV bolus of the study solution and the infusion will be increased by 1 mL/min until delivery.
Intervention MeSH terms: Phenylephrine; Oxymetazoline; Ephedrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Preeclampsia; Spinal Anesthesia; Hypotension; Cesarean Delivery; Phenylephrine; Ephedrine