Sublingual Misoprostol & Isoflurane During Caesarean Section
Condition: Pregnancy; Cesarean Delivery
Study type: Interventional
Phase: Phase 2

Summary: 
      Misoprostol would reduce the uterine bleeding after caesarean delivery, without harmful
      effects on either mother or baby. The investigators postulated that the use of sublingual
      misoprostol during isoflurane anaesthesia for uncomplicated caesarean delivery would reduce
      maternal haemorrhage, uterine atonic effects, and the need for additional uterotonic agents,
      without harmful effects on either mother or baby. Therefore, the present study was designed
      to evaluate the effects of preoperative sublingual misoprostol on maternal blood loss,
      uterine tone, the need for additional oxytocin and neonatal outcome after elective caesarean
      delivery under isoflurane anaesthesia.
    

Detailed description: 
      Volatile anaesthetics including sevoflurane, desflurane, and isoflurane are often used during
      general anaesthesia for caesarean delivery. The cost effectiveness of isoflurane anaesthesia1
      for caesarean delivery is widely used at many centres including the authors' centre, where
      general anaesthesia is commonly used for caesarean deliveries than did regional anaesthesia
      because of the refusal of many ladies for the later, especially in the light of
      evidence-based equivocal maternal or neonatal outcomes of both techniques. 2 However,
      isoflurane in similar to other inhalational anaesthetics have been shown a dose-dependent
      (from 0.5 to 2.35 minimum alveolar concentration (MAC)) induced myometrial relaxation in 25%
      of parturients with added risks of postpartum haemorrhage, 3-5 which may be mediated through
      the inhibition of the oxytocin-induced contraction,6 decrease in intracellular concentration
      of free calcium,7 inhibition of voltage-dependent calcium channels activity,8 and activation
      of adenosine triphosphate-sensitive potassium channels (K (ATP))9 of pregnant uterine smooth
      muscle.

      Several uterotonics such as oxytocin reduce postpartum haemorrhage by inducing uterine
      contraction, but with added risks of haemodynamic adverse effects. 10 Sublingual or rectal
      misoprostol, a prostaglandin E1 analogue, in doses of 100 to 800 µg is safe and as effective
      as intravenous infusion of oxytocin in reducing blood loss and the need for additional
      oxytocin after caesarean delivery under either spinal or general anaesthesia, with occurrence
      of transient side effects such as nausea, shivering and pyrexia. 11-17 Misoprostol possess
      several advantages over oxytocin, including long shelf life, stability at room temperature,
      and possible buccal, rectal and sublingual administration. 11, 16The later has many
      advantages such as rapid uptake, long-lasting duration of effect, and greatest
      bioavailability, compared with other routes of misoprostol administration. 18 Up to our best
      knowledge, this trial was the first one studied the inhibitory effects of misoprostol on the
      uterine atonic effects of inhalational anaesthetics.

      Based upon previous published data, 19 blood loss after caesarean delivery was normally
      distributed with standard deviation 560 ml. A priori power analysis indicated that 174
      patients in each group would be sufficient to detect a 20% reduction in blood loss after
      caesarean delivery, with a type-I error of 0.05 and a power of 90%. The investigators added
      10% more patients to account for patients dropping out during the study.

      Patients were randomly allocated to receive sublingual 400 µg of misoprostol or identical
      placebo two tablets after tracheal intubation before surgery.

      Anaesthetic management was standardized in all studied patients. Oral ranitidine 150 mg was
      given the night before and on the morning of surgery, with 0.3 mol/L sodium citrate (30 mL)
      given 15 min before induction. In the operating theatre women were positioned supine on the
      operating table with 15° firm rubber wedge under the right hip to effect left uterine
      displacement. A slow 500-mL i.v. infusion of lactated Ringer's solution was given to all
      subjects over 20 min.

      Subjects were monitored with electrocardiography, non-invasive blood pressure, pulse oximetry
      (SpO2), and end-tidal carbon dioxide concentration (EtCO2). After pre-oxygenation for 5 min,
      rapid-sequence induction was performed with propofol 1.5-2 mg/kg followed by suxamethonium
      1.5 mg/kg after loss of verbal response. Cricoid pressure was applied after loss of
      consciousness and was released after correct placement of the tracheal tube had been
      confirmed.

      After tracheal intubation, subjects were allocated randomly to two groups by drawing
      sequentially numbered sealed opaque envelopes containing a software-generated randomisation
      code (Random Allocation Software, version 1.0.0, Isfahan University of Medical Sciences,
      Isfahan, Iran). The parturients in the placebo group (n = 183) received sublingual two
      moistened white coated placebo tablets which looked identical in size, colour, and packing to
      misoprostol tablet. In the misoprostol group (n = 183), sublingual misoprostol was given by
      putting two moistened tablets of misoprostol (400 µg) under the tongue and allowing them to
      dissolve (Misotac®, Sigma Pharmaceutical Industries, Egypt) (200 µg/tablet). The
      anaesthesiologists who gave the anaesthetics and study tablets were blinded to the study
      randomization and were not involved in collecting of the patients' data. All staff in the
      operating room were unaware of the randomization code.

      Anaesthesia was maintained with 0.5-1 MAC of isoflurane with nitrous oxide 50% in oxygen to
      maintain the heart rate and blood pressure within 20% of baseline values. Neuromuscular block
      was maintained with vecuronium 0.06 mg/kg. The lungs were ventilated using a tidal volume of
      8 mL/kg, an inspiration-expiration ratio of 1: 2, and at a respiratory rate necessary to
      maintain an EtCO2 of 30-35 mm Hg. An infusion of lactated Ringer's solution 800 mL was given
      to all subjects during the procedure. Induction to delivery (I-D) times was recorded using a
      stopwatch.

      After the umbilical cord was clamped, a 10-unit infusion of oxytocin in 500 mL of 5% glucose
      was started. Intravenous midazolam 0.05 mg/kg and fentanyl 2.0 µg/kg were given and end-tidal
      concentration of the nitrous oxide was increased to 70%.

      The obstetrician who was blinded to the study group, assessed the uterine tone by palpation
      every three minutes after delivery of the placenta and rated the degree of uterine
      contraction on a 10-cm VAS (0: well contracted; 10: completely relaxed). If uterine tone
      remained unsatisfactory after 3 min, an additional 5-unit bolus of oxytocin was administered.

      All neonates were assessed by a paediatrician unaware of the randomisation code as regarding
      their Apgar scores at 1 and 5 min, arterial blood pressure, heart rate, temperature and
      arterial oxygen saturation.

      At the end of surgery, isoflurane and nitrous oxide were discontinued, residual neuromuscular
      block was antagonised and the patients were extubated. Postoperative analgesia was achieved
      with morphine, tramadol and paracetamol.
    

Intervention name(s): Placebo; Misoprostol
Intervention type(s): Drug; Drug
Intervention description(s): received sublingual two moistened white coated placebo tablets which looked identical in size, colour, and packing to misoprostol tablet.; sublingual misoprostol was given by putting two moistened tablets of misoprostol (400 µg) under the tongue and allowing them to dissolve (Misotac®, Sigma Pharmaceutical Industries, Egypt) (200 µg/tablet).
Other intervention name(s): Group A; Group M
Intervention MeSH terms: Misoprostol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Full term pregnancy > 36 weeks; Cesarean delivery; General anesthesia