Dexmedetomidine vs. Remifentanil for Pre-eclampsia During Caesarean Delivery
Condition: Pregnancy; Severe Pre-eclampsia
MeSH terms: Eclampsia; Pre-Eclampsia
Study type: Interventional
Phase: Phase 2

Summary: 
      Preeclampsia is a pregnancy-specific, multisystem disorder that complicates approximately 5 %
      of pregnancies.

      Tracheal intubation in the women with severe pre-eclampsia is usually associated with
      exaggerated transient increases in blood pressure, heart rate and maternal plasma
      catecholamine concentrations. These changes may lead to maternal cerebral oedema,
      haemorrhage, left ventricular failure, pulmonary oedema or mortality, and reduce uterine
      blood flow which may adversely affect the neonatal wellbeing. Therefore, the attenuation of
      the haemodynamic responses to tracheal intubation in this unique group of patients is
      demanding for the best of both mother and foetus.

      The use of single remifentanil boluses of 0.5 to 1 µg/kg reduces effectively the haemodynamic
      and catecholamine responses to laryngoscopy and tracheal intubation in severe pre-eclamptics
      during Cesarean delivery under general anesthesia. Unfortunately, the use of 1 µg/kg doses
      are associated with more maternal hypotension and neonatal respiratory depression requiring
      resuscitation. Moreover, the use of preinduction remifentanil bolus of 0.5 µg/kg followed by
      a continuous infusion at 0.15-0.2 µg/kg/min is associated with significant attenuation of the
      maternal stress response to tracheal intubation with variable degree of neonatal depression
      in non-pre-eclamptic women. Whereas, the use of infusion rates of 0.1 µg/kg/min or less is
      less likely to produce neonatal depression.

      In our previous study, we demonstrated that the preoperative administration of
      dexmedetomidine 0.4 and 0.6 µg/kg/h, a specific alpha 2-adrenoceptor agonist, blunts the
      maternal haemodynamic and hormonal responses to Caesarean delivery under sevoflurane
      anaesthesia without adverse neonatal effects. However the use of 0.6 µg/kg/h doses is
      associated with higher postoperative sedation scores.
    

Detailed description: 
      We hypothesize that the preoperative intravenous dexmedetomidine (0.4 µg/kg/h) and
      remifentanil (0.1 µg/kg/min) infusions will have comparable maternal haemodynamic responses
      to tracheal intubation, surgical stimulation and extubation after uncomplicated Caesarean
      delivery under general anesthesia in parturients with severe pre-eclampsia, without adverse
      neonatal effects.

      Anaesthetic management will be standardized in all studied patients. Oral ranitidine 150 mg
      and metoclopramide 10 mg will be given the night before and on the morning of surgery, with
      0.3 mol/L sodium citrate 30 mL given 15 min before induction. Magnesium sulphate will be
      given as a loading dose of 4 g intravenously, followed by i.v. infusion of 1g/hour for
      seizures prophylaxis.

      Intravenous boluses of hydralazine 5 mg at 20-min intervals will be used if SAP increases
      above 160 mm Hg or DAP above 110 mm Hg, to keep the diastolic blood pressure at approximately
      90 mmHg and the doses used will be recorded.

      The studied population will be allocated randomly to one of two groups, (n = 18, in each), by
      drawing sequentially numbered sealed opaque envelopes containing a software-generated
      randomization code (Random Allocation Software, version 1.0.0, Isfahan University of Medical
      Sciences, Isfahan, Iran), to receive either dexmedetomidine (0.4 µg/kg/h) or remifentanil
      (0.1 µg/kg/min) starting 20 and 5 min before induction of anaesthesia, respectively, and will
      be discontinued after peritoneal closure. The dexmedetomidine and remifentanil solutions
      looked identical.

      One anaesthesiologist who is not otherwise involved in the study, will prepare the study
      solutions, install them in the infusion pumps, set up the dose according to the assigned
      randomized dose, and will mask the infusion pumps with an opaque sheet throughout the
      procedure to ensure the blindness of the assessors. Another anaesthesiologist who will be
      blinded to treatment regimen provided perioperative care. A third anaesthesiologist will
      collect perioperative data. All staff in the operating room will be unaware of patient
      allocation.

      Maternal monitoring will include three lead-electrocardiography, non-invasive blood pressure,
      and pulse oximetry. Left uterine displacement will be maintained.

      After preoxygenation for 3 min, rapid sequence induction will be performed using propofol
      1.5-2.5 mg/kg and suxamethonium 1 mg/kg with the application of cricoid pressure from the
      time of loss of the consciousness until the inflation of the cuff of the endotracheal tube.
      Laryngoscopy will be performed after the 1-min blood pressure recording, and tracheal
      intubation will be completed before the 2-min reading. Correct placement of the endotracheal
      tube will be confirmed with direct visualization of the passage of its tip between the vocal
      cords, auscultation of equal breath sounds on both sides of the chest and capnography
      waveform. The patient's lungs will be mechanically ventilated to maintain (ETCO2) at
      30-35mmHg. Anaesthesia will be maintained with a 0.5-0.7% minimum alveolar concentration of
      sevoflurane in oxygen. Atracurium 0.5 mg/kg will be given for muscle relaxation to maintain
      suppression of the second twitch using a train-of-four stimulation. The Induction-to-delivery
      time will be recorded using a stopwatch.

      After the umbilical cord is clamped, a 5-10 IU infusion of oxytocin in 500 mL of lactated
      Ringer's solution will be started and morphine 0.1 mg/kg will be given. After peritoneal
      closure, study solution will be discontinued.At the end of surgery, sevoflurane will be
      discontinued, residual neuromuscular block will be antagonized and the trachea will be
      extubated.

      Postoperative analgesia will be achieved according to the authors' hospital protocol with
      12-hourly IM diclofenac (75 mg), 6-hourly IVI paracetamol (1 g), and rescue doses of IV
      meperidine (25 mg).

      Statistical analysis:

      Data will be tested for normality using the Kolmogorov-Smirnov test. X2 test will be used for
      categorical data. Repeated-measures analysis of variance will be done to test the serial
      changes in hemodynamic and cortisol data. Student-t- and Mann Whitney U tests will be used to
      compare the parametric and nonparametric data between the two studied groups. Data will be
      expressed as mean (SD), number (%), or median [range]. p < 0.05 will be considered to
      represent statistical significance.

      In a previous study, Yoo et al have demonstrated that the mean (SD) values of MAP at 1 min
      after tracheal intubation in those received remifentanil bolus were 118 (20) mm Hg. A priori
      power analysis revealed that 16 patients would be needed in each group to detect a 20%
      difference in MAP values, 1 min after intubation, after the administration of remifentanil
      with a type I error of 0.05 and a power of 90%. We assumed that the detection of 20%
      differences in the mean MAP would be of clinically importance. We increased the sample size
      by 10% to compensate for patients dropping out during the study.
    

Intervention name(s): Remifentanil; Dexmedetomidine
Intervention type(s): Drug; Drug
Intervention description(s): Remifentanil (0.1 µg/kg/min) starting 5 min before induction of anaesthesia and continued until peritoneal closure.; dexmedetomidine (0.4 µg/kg/h) starting 20 before induction of anaesthesia and continued until peritoneal closure
Intervention MeSH terms: Dexmedetomidine; Remifentanil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Caesarean delivery; severe pre-eclampsia; remifentanil; dexmedetomidine; cardiovascular response