Dexmedetomidine for Cesarean Section
Condition: Cesarean Section, Affecting Fetus or Newborn
Study type: Interventional
Phase: Phase 1

Summary: 
      Current cesarean section often chooses spinal anesthesia. And in order to avoid the impact of
      drugs on the fetus, before the delivery, anesthesiologist generally don't use sedative or
      analgesic drugs. However, the majority of puerperas would appear nervous, anxiety, fear and
      other psychological reactions in cesarean section. Although the placental transfer and the
      foetal metabolism of dexmedetomidine have been reported and the result show no adverse
      effects on neonates, but the placental transfer of dexmedetomidine in intravertebral
      anesthesia area was lack of systematical research. This study intends to use of
      dexmedetomidine in the cesarean section under epidural anesthesia and investigate its effects
      on the parturients' haemodynamics and the neonates' placental transfer and metabolism.
    

Detailed description: 
      Current cesarean section in domestic and overseas often chooses spinal anesthesia. And in
      order to avoid the impact of drugs on the fetus, before the delivery, anesthesiologist
      generally don't use sedative or analgesic drugs. However, the majority of puerperas would
      appear nervous, anxiety, fear and other psychological reactions in cesarean section, and thus
      produced a series of stress reactions that not only cause the hemodynamic fluctuating in
      anesthesia and operation, but also lead to different degrees of personality and behavior
      changed. It causes serious injury to physical and mental health of patients. Dexmedetomidine
      is a highly selective α2 receptors agonist (α2-AR) ，it has sedation, analgesia,
      antisympathetic pharmacological effects and unique "conscious sedation" without respiratory
      depression. At present, dexmedetomidine has been widely used in patients in clinics and
      clinical anesthesia, it has been hailed as an"dvocate medicine in modern comfortable
      anesthesia."Experiments in animals have shown that dexmedetomidine had no adverse effects on
      pregnant rats. In addition, Dexmedetomidine has successful application in preterm infants,
      infants and children anesthesia, also has a few for caesarean patients sedation reports.
      Although the placental transfer and the foetal metabolism of dexmedetomidine have been
      reported and the result show no adverse effects on neonates, but the placental transfer of
      dexmedetomidine in intravertebral anesthesia area was lack of systematical research.

      The safety of the use of dexmedetomidine on neonatal outcome is a very important issue.
      Experimental study on acute exposure of rats to dexmedetomidine at the anticipated delivery
      time recorded absence of any adverse effects on perinatal morphology of pups, their birth
      weight, crown-rump length, physical growth and postnatal behavioural performances. Others
      studied the transfer of clonidine and dexmedetomidine across the isolated perfused human
      placenta. Dexmedetomidine disappeared faster than clonidine from the maternal circulation,
      while even less dexmedetomidine was transported into the fetal circulation. This was due to
      its greater placental tissue retention, the basis for which probably is the higher
      lipophilicity of dexmedetomidine.

      Umbilical cord blood gas analysis of umbilical vein and umbilical artery in this study was
      similar to the results of previous studies . The partial oxygen pressure (PO2) of the
      arterial blood gas in the umbilical vein was not significantly affected to the oxygen supply
      of the newborn infants. On the other hand, the umbilical arterial blood gas was the most
      reliable indicator of the oxygenation index and acid-base status of the fetus. Previous
      studies have indicated that the relationship between hydrogen ion concentration(PH), base
      excess（BE） and neonatal asphyxia was relatively large, and it was positively related to
      growth.

      Previous research of in vitro placental perfusion indicated that the transfer rate of
      dexmedetomidine through the placenta to foetus was 0.77, and the other study indicated that
      the rate of placental transfer of dexmedetomidine in cesarean section operation under general
      anesthesia was 0.76. It's indicated that dexmedetomidine can also easily pass through the
      placental barrier like other anaesthetic drugs. However, the placental transfer rate of
      dexmedetomidine is much lower than that of clonidine(0.85) and that of remifentanil(0.88),
      which may be caused by dexmedetomidine being more fat-soluble and easier to be retained in
      the placenta.

      Recently, there is a published interested case report about the successful use of
      dexmedetomidine 1 µg/kg followed with 1 µg/kg/h for 10 minutes before cesarean delivery to
      facilitate awake fiberoptic endotracheal intubation patient with spinal muscular atrophy type
      III with provided adequate sedation, without respiratory compromise. Although pharmacokinetic
      data cannot be determined, this case confirms existing in vitro data that dexmedetomidine has
      significant placental transfer. Nevertheless, serious neonatal effects were not detected.
      Similarly, others used, i.v. dexmedetomidine successfully as an adjunct to opioid-based PCA
      and general anesthesia for the respective provision of labor analgesia and cesarean delivery
      anesthesia in a parturient with a tethered spinal cord, with favourable maternal and neonatal
      outcome.

      Project Objectives:

      The investigators hypothesize that application of dexmedetomidine in cesarean section under
      epidural anesthesia was conducive to maintaining the stability of hemodynamics of the
      patients, reducing patients' anxiety and pain stress during the operations, which also had no
      adverse effects on newborns.

      The aims of the present study are:

      Our research efforts will focus on identifying the effects of 0.5 µg/kg/h dexmedetomidine for
      uncomplicated cesarean delivery on the followings.

      Hemodynamic [heart rate, systolic and mean blood pressure] changes. The rate of placental
      transfer of dexmedetomidine . Apgar score (1 and 5 minute) after delivery. The umbilical cord
      venous and arterial blood gases analyses. The sedation of Dexmedetomidine. The incidence of
      the major complications (respiratory, cardiovascular events, nausea, vomiting and other
      adverse reactions).

      Project Design:

      Study Design:

      The study was approved by the first affiliated hospital ethics committee of Nanjing Medical
      University, and the puerperas and their families signed informed consent.

      Sampling Site:

      I. Patient Selection: patients aged 23-41 years (ASA physical status I-II) scheduled for
      elective in about 40 women (American Society of Anesthesiologists [ASA] I and II), with
      uncomplicated, singleton pregnancies, who will receive epidural anesthesia. The investigators
      will exclude women with a history of cardiac, liver, or kidney diseases; allergy to amide
      local anesthetics; epilepsy; those taking cardiovascular medications; and those with
      pregnancy-induced hypertension, evidence of intrauterine growth restriction, or fetal
      compromise.

      II. Anesthesia method

      Routine monitoring such as electrocardiogram(ECG), heart rate(HR), saturation of pulse
      oxygen(SpO2) were monitored after patient arrived at the operation room. Selected the forearm
      vein to open venous access, infused sodium lactate Ringer's solution before anaesthesia. Then
      began to epidural anesthesia: The patients were at left side lying position, the L2,3 gap was
      chosen for puncture. After determined the success of puncture, inserted the epidural catheter
      into the head side, the length of the epidural space is 4cm. By intraductal injection of 2%
      lidocaine 3ml, signs of spinal anesthesia were excluded. Additional 0.75% ropivacaine 10 ~
      20ml was injected to control the level of pain disappear on thoracic4(T4) or thoracic6(T6) to
      satisfy the operation needs. After the level of anesthesia completed, Dex group:
      dexmedetomidine was continuously infused by 0.5 μg/kg in 10 min, followed with 0.5 μg/kg/hr
      continuous infusion until the closure of the abdominal. normal saline(NS)group: Pumped in the
      same volume of normal saline. In the operation, if the blood pressure was lower than 70%
      before anesthesia given ephedrine 10 ~ 15mg, and 0.5mg atropine was used when the heart rate
      was lower than 60 beats per minute. All operations were performed by the same group of
      maieutologists.

      III. The Investigators who will be involved with subsequent postoperative patient assessment
      will be blinded of the patient group.

      IV. Observational information

      Systolic pressure(SBP) and diastolic blood pressure(DBP), heart rate(HR) were recorded at
      four time points: before anesthesia(T0), infused 10 min(T1), at the delivery of the baby(T2),
      at the end of the operation(T3). Ramsay sedation scales were evaluated at three time points:
      before anesthesia (T0), skin incision (T1) and 10min after delivery (T2). (Ramsay standard
      for evaluation: 1 point: anxious or restless or both; 2 point: cooperative, orientated and
      tranquil; 3 point: responding to commands; 4 point: brisk response to stimulus; 5 point:
      sluggish response to stimulus; 6 point: no response to stimulus. The Apgar scores were
      evaluated at 1 and 5 minute after the delivery. The urinary volume, the bleeding volume and
      the infusion volume during the operation were measured. Adverse effects such as nausea and
      vomiting in 24 hour after the operation were recorded. Postoperative analgesic formula: 12mg
      butorphanol tartrate, 9mg granisetron hydrochloride, diluted with normal saline to 100ml.
      Background dose: 2 milliliter per hour, patient controlled analgesia (PCA): 0.5 milliliter,
      locking time:15 minutes.

      V. Samples Collection and Analysis For blood gas analysis and the plasma dexmedetomidine
      concentrations:

      Maternal venous blood samples (MV), umbilical artery(UA) and umbilical vein(UV) will be
      collected for blood gas analysis, plasma dexmedetomidine concentrations. concentrations at
      points: When the baby was born.

        1. Type of samples: centrifuged 3500 revolutions per minute for 5 minutes and separated of
           plasma to -20℃ frozen preservation.

        2. Laboratory Analysis:

      High-performance liquid chromatography-mass spectrometry(HPLC-MS/MS) was then used for
      measuring the plasma dexmedetomidine concentrations [concentration of umbilical vein(CUV),
      concentration of umbilical artery(CUA) and concentration of maternal vein(CMV)]..

      VI. Statistical Analysis: The statistical analysis was performed with SPSS 22.0. The
      measurement data are shown as mean ± standard deviation (x±s), the t-test was used for
      comparison between the groups, and repeated measures analysis of variance was performed for
      comparison within the group; chi-square test was used for comparison of the count data, and
      rank-sum test was used for comparison of the level information. p < 0.05 was considered as
      statistically significant.

      VII. Report Writing: 2 months
    

Intervention name(s): Dexmedetomidine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The dexmedetomidine groups (n = 20 ) will receive i.v. infusion of 0.5 μg/kg of solution containing 5 µg/mL of dexmedetomidine, at 10 min after the level of anesthesia completed. Followed with 0.1ml/kg/hr continuous infusion until the closure of the abdominal.The placebo and the dexmedetomidine solutions will be looked identical and their infusions will be continued until skin closure.; The placebo group (n = 20) will pumped in the same volume of saline 0.9% as calculated by patients' weight in 10 min, then will receive an i.v. infusion of 0.1 mL/kg/h saline 0.9%, until the closure of the abdominal. The placebo and the dexmedetomidine solutions will be looked identical and their infusions will be continued until skin closure.
Other intervention name(s): Dexmedetomidine Hydrochloride Injection
Intervention MeSH terms: Dexmedetomidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Epidural Anaesthesia; Cesarean Section; Dexmedetomidine