Ephedrine and Phenylephrine for Spinal Hypotension
Condition: Spinal Hypotension
MeSH terms: Hypotension
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Spinal anesthesia is widely used as the procedure of choice for cesarean delivery. In
      comparison to epidural anesthesia it is faster, easier to perform, patients are more
      comfortable, complication rates are lower, and it is more cost effective. Spinal anesthesia
      is an accepted technique in elective cesarean sections. However, hypotension, resulted from
      sympathectomy is a common problem, especially in pregnant women.

      Spinal block causes peripheral vasodilation and venous pooling, which may result in maternal
      hypotension. Maternal hypotension after spinal anesthesia for cesarean delivery, without
      prophylactic measures, has a very high incidence (80%-100%). Even though highly investigated,
      spinal induced hypotension remains a major concern, and it has been referred to as the "Holy
      Grail" of obstetric anesthesia. The detrimental effects of the spinal induced hypotension are
      maternal and fetal. Maternal effects are nausea, vomiting and dizziness. Hypotension results
      in reduced uterine and intervillous blood flow with potential fetal hypoxia and acidosis.

      Treatment and prevention of hypotension has been the subject of much investigation and
      controversy. Prophylactic measures include: 1) left lateral tilt, 2) fluid preload, 3)
      vasopressors,4) low dose spinal anesthesia. A 15° left lateral tilt is used routinely during
      cesarean section, to prevent aorto-caval compression, however it is not sufficient as a sole
      method. Left uterine displacement is achieved by tilting the operating table or by placing a
      wedge under the woman's hip. Aorto-caval compression also may increase the spread of spinal
      anesthesia. Among the non-pharmacological interventions studied to minimize the incidence of
      hypotension sitting the patient up for up to 7 min after CSE anesthesia for cesarean section
      reduced intraoperative ephedrine requirement without affecting the success of the spinal
      anesthetic. In contrast, sitting up for 9 min resulted in the need for rescue epidural
      anesthesia without additional benefit.

      Phenylephrine Treatment of vascular failure in shock, shock-like states, drug-induced
      hypotension or hypersensitivity; correction of paroxysmal supraventricular tachycardia;
      prolongation of spinal anesthesia; vasoconstriction in regional analgesia; maintenance of
      adequate level of BP during spinal and inhalation anesthesia. It has a number of important
      attributes for treating spinal hypotension: (i) as an alpha-adrenergic agonist, its mechanism
      of action directly addresses the decrease in systemic vascular resistance following spinal
      anesthesia;(ii) phenylephrine has a faster onset of action compared with ephedrine; (iii)
      ephedrine is associated with a ﬁve-fold increased risk of fetal acidosis; and (iv) ephedrine
      is more likely to cross the placenta and increase concentrations of lactate, glucose, and
      catecholamines in the fetal circulation compared with phenylephrine. However, phenylephrine
      used alone may be accompanied by maternal bradycardia and does not beneﬁt from widespread
      clinical experience, as does ephedrine do. Thus, phenylephrine has not yet become popular,
      particularly for prophylactic use. Clinical experience suggests that phenylephrine may be
      useful in addition to ephedrine when the latter fails to correct hypotension.

      Ephedrine sulphate is a potent sympathomimetic that stimulates both α and β receptors and has
      clinical uses related to both actions. Its peripheral actions, which it owes in part to the
      release of norepinephrine, simulate responses that are obtained when adrenergic nerves are
      stimulated. These include an increase in blood pressure, stimulation of heart muscle,
      constriction of arterioles.
    

Detailed description: 
      Study design:

      A prospective randomized clinical double-blind study using a computer generated randomization
      will be conducted in a Women's Health Hospital, Assuit University. Neither the doctor
      "investigator" nor the participant "parturient" will be aware of the group allocation or the
      drug used. The study drugs will be prepared by one of the supervisor anesthetist (not
      included in the procedure, observation or in data collection). The study will be carried on
      60 parturient scheduled for elective cesarean section under spinal anesthesia. They will be
      randomly allocated into two equal groups of 30 parturient each:

      P group: Phenylephrine 30 µg/minute by syringe pump infusion for30 min. E group: Ephedrine 3
      mg/ minute by syringe pump infusion for30 min. The study solutions (vasopressors) will be
      prepared by another supervisor anesthetist and will be diluted with normal saline (Na Cl
      0.9%) to the same total 50 ml volume in a syringe pump.

      Pre-intervention Assessment:

      All parturient will undergo full pre-anesthetic checkup (according to ASA guidelines)
      including detailed history, physical and systemic examinations. They will be kept NOP (nil
      per mouth) 6-8 hours for solids and 2 hours for water and clear fluids.

      Parturient in the holding area:

      Baseline monitoring readings of the maternal vital signs including HR, NIBP, SpO2 and RR.

      Non-invasive Cardiac Output Monitoring:

      The patients will positioned in the supine position, with uterine displacement to the left
      lateral for several minutes and the electrodes of the noninvasive cardiac output monitor are
      placed to measure cardiac output. Baseline reading of cardiac output will be recorded before
      any intervention using NCCOM3 cardiodynamic monitor. . From this apparatus we will get HR,
      EF, CO /CI, SVR

      Uterine blood flow evaluation:

      Baseline uterine blood flow will be recorded in the holding area and before any intervention
      using SONO Ace R5 by the obstetric supervisor. Colour Doppler ultrasound will be used to
      demonstrate the main ascending branches of left and right uterine arteries as they cross over
      the hypogastric vessels just before they enter the uterus at the uterine-cervical junction.
      The high pass filter was set at 125 Hz and the uterine artery will be obtained immediately
      after the crossing of the hypogastric artery. The sample vol¬ume will be placed on the artery
      with an angle of about 0°. After detection of blood flow and visu¬alization of the waveform
      of the uterine artery, five blood flow indices will be automatically cal¬culated:

      The pulsatility index (PI) (PI=PSV-EDV/TAMXV); The resistance index (RI) (RI=PSV-EDV/PSV);
      The peak systolic velocity (PSV, units of cm/s); The end-diastolic velocity (EDV, units of
      cm/s). TAMXV: Time averaged maximum velocity PSV: Peak systolic velocity. EDV: End-diastolic
      velocity At least three consecutive correctly imaged blood flow velocity waveforms will be
      analyzed; both right and left uterine arteries diameters will be measured on a perpendicular
      B-mode view of the longitudinal vessel section at maxi¬mum magnification. Mean values of
      bilateral uterine RI and PI will be used for statistical analysis.

      Then intravenous cannula 18 G will be inserted into forearm vein under local anesthesia and
      no premeditated drugs will be given to all women. Ringer's Lactate solution 10ml/kg will be
      infused for all women participating in the study over 20-30-minutes, and then will be
      transferred to the operating room.

      Parturient in the operating room:

      The previous monitoring data will be recorded again for the second time (including vital
      data, maternal non-invasive cardiac output and uterine blood flow). Then the study solutions
      will be started to infuse according to the previous description ( to prevent hypotension
      mostly occur with spinal anesthesia during cesarean section).Then subarachnoid block will be
      carried out under complete aseptic condition while the in the sitting position and the table
      in the horizontal level using 25 G pencil point spinal needle, intrathecal block will be
      performed at level of L 3-4 or L 4-5 vertebral interspaces, 12.5 mg (2.5 ml) of hyperbaric
      bupivacaine 0.5% and 300 ug morphine sulphate will be injected intrathecally at the rate of
      1ml/15 second (12) in all parturients for anesthesia. Immediately after end of injection of
      drugs intrathecally, the parturient will be placed in the supine position with left uterine
      displacement. Sensory block will be assessed using loss of sensation in response to cold
      sensation using piece of ice along midclavicular line bilaterally every 2 minutes until reach
      the level of T5 dermatome.

      A third monitoring reading of the vital data, maternal non-invasive cardiac output and
      uterine blood flow will be taken 15 minutes after spinal block and before the surgical
      operation (cesarean section) starts.

      Intra-operative Assessment:

      After subarachnoid block all will be monitored for HR, NIBP, SpO2 and RR every 5 minutes till
      the end of the surgery. All parturients will be continuously monitored intra-operatively for
      any episodes of hypotension, hypertension, bradycardia or tachycardia. Hypotension: defined
      as more than 20% decrease in maternal systolic blood pressure from the baseline. It will be
      treated with intravenous crystalloid fluid bolus or drug boluses (1 ml) of the study drug
      according the groupwhen needed. The total dose of drug boluses will be calculated when used.
      Hypertension defined as more than 29% increase in maternal systolic blood pressure from the
      baseline, if occurred, drug infusion will be stopped until the effect ends, then the infusion
      will be started again. If relapse occur for 2 times, the drug infusion will be stopped and
      the case will be excluded from the study.

      Neonatal Evaluation:

      Arterial blood sample will be collected from the fetal umbilical cord immediately through
      double clamp segment after birth (about 10 cm of umbilical cord during clamping will be
      sufficient to withdraw the sample). Analysis of the fetal umbilical arterial blood gas will
      be performed. An umbilical blood PH of less than 7.2 will be considered fetal acidosis (19).
      To assess the acid-base status and oxygenation of the fetus at delivery. Blood is drawn
      separately with heparinized syringes from both an umbilical artery and umbilical vein from a
      doubly clamped segment of the umbilical cord. If both umbilical vein and artery blood show
      low PO2 (below 30 and 15 mmHg) and high pco2 (above 40 and 50 mmHg) , respectively
      uteroplacental insufficiency was present.

      All newborns will be evaluated by pediatrician regarding the APGAR score at 1st. and 5th
      .minutes of birth.

      Study outcomes Primary outcome

      1- The difference in maternal cardiac output between the study groups Secondary outcomes

        1. The difference in uterine blood flow indices by Doppler

        2. The difference of intraoperative maternal vital singes.

        3. The rate of occurrence of neonatal morbidity.

        4. Complications or side effects of medications.

        5. Parturient satisfaction.

      Statistical analysis:

      Data will be collected and will be analyzed using SPSS version 20 (SPSS, Inc., Chicago,
      Illinios, USA). Normally distributed numerical data will be presented as mean +_SD, rang,
      number and percentage. Numerical variables will be compared among the three groups using the
      Kruskal-Wallis test and Mann-Whitney test. Categorical variables will be compared among the
      three groups using the Chi-Square test and Fisher's exact test. P-value of less than 0.05
      will be considered significant.
    

Intervention name(s): Phenylephrine; Ephedrine
Intervention type(s): Drug; Drug
Intervention description(s): 30 patients will receive Phenylephrine 30 µg/minute by syringe pump infusion for 30 minutes.; 30 patients will receive Ephedrine 3 mg/ minute by syringe pump infusion for 30 minutes.
Intervention MeSH terms: Phenylephrine; Oxymetazoline; Ephedrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: Ephedrine; Phenylephrine; Spinal Hypotension; Cesarean Section; Maternal Cardiodynamics