Pharmacogenetics of Remifentanil in Patients With Hypertension Undergoing Cesarean Delivery Under General Anesthesia
Condition: Pregnancy; Cesarean Delivery; General Anesthesia
MeSH terms: Hypertension
Study type: Interventional

Summary: 
      Caesarean delivery under general anaesthesia (GA) carries nowadays still 25% risk of
      insufficient depth of anaesthesia in a time before the fetus delivery. The reason is the lack
      of opioid administration. Opioids easily cross placental barrier and negatively influence
      newborn postpartum adaptation by respiratory depression. Introduction to GA is thus
      accompanied by exaggerated autonomic stress reaction with hypertension and tachycardia. The
      use of ultra-short acting opioid remifentanil should suppress stress response in mother
      without increasing the risk for newborn. There are only a few clinical data available. This
      study will be the first one systematically studying the influence of remifentanil in pregnant
      women with hypertension on hemodynamic stability and newborns safety. This study will also
      identify potential pharmacogenetic factors of individual variability in remifentanil response
      with respect of drug efficacy and safety in mother and newborn.
    

Detailed description: 
      INTRODUCTION Even nowadays there is still a significant risk of insufficient depth of
      anesthesia during Cesarean delivery (CD) under general anesthesia (GA). The main reason in
      comparison to other surgeries is the lack of opioid administration due to risk of newborn
      respiratory depression.

      Opioids easily cross the placental barrier to the fetus circulation and may cause depression
      of respiration and deteriorate the overall newborns postpartum adaptation. This presents the
      main reason why according to contemporary recommendation is the use of opioids in CD
      restricted until the time of fetus delivery, and are given as far as after the navel wort
      ligation. Not to cause any depression of the newborn the premedication to GA is usually also
      omitted. The beginning of GA in common surgical operation is usually accompanied by the
      decrease in systemic blood pressure (BP) and heart rate (HR). However, in CD the
      investigators face the increase of BP and HR due to stress reaction of mother during the
      period before the fetus delivery and before full anesthesia application, including opioids.

      Generally, insufficient depth of anesthesia (assessed by patient's recollection) is reported
      in less than 1% of cases, but increases for up to 50% in GA during CD. However, this
      appraisal marginalized much more frequent cases when an insufficient depth of GA is
      accompanied by exaggerated autonomic reaction to the pain, especially the increase in
      systemic BP and heart rate as a reaction to the egestion of catecholamines, while total
      amnesia of the surgery is retained. In CD such type of anesthesia insufficiency was reported
      in 12-26% of patients! Current trend in CD anesthesia unequivocally prefers the use of
      regional techniques; GA remains indicated for emergency situations mainly and in those cases
      the stress reaction of mother tends to be much higher than in elective procedures.

      An independent remarkable risk factor to the pregnant women is the hypertension, both chronic
      and gestational including preeclampsia. This condition of preoperatively mostly hardly and
      insufficiently controlled hypertension may get dramatically worse during the first phase of
      CD, when blood pressure due to uncontrolled stress reaction enormously rises and elevates
      intracranial pressure with high risk of hemorrhagic stroke - a life threatening complication.

      Unfortunately there are only a few possibilities how to influence mother's stress response to
      intubation and laparotomy without increasing the risk of newborn depression. In absence of
      anesthetics not crossing placental barrier, the only possibility is the use of ultra-short
      acting anesthetics which should be eliminated from fetus circulation before his delivery. An
      important role might play remifentanil - µ-receptor agonist with rapid onset and ultra-short
      activity (biological half-life 3-10 min.). It's major advantage, beside fast onset, is also
      prompt and organs independent elimination.

      HYPOTHESIS Bolus administration of an ultra-short acting synthetic µ-opioid receptor agonist,
      remifentanil, in mothers with hypertension/preeclampsia before induction of general
      anesthesia attenuates egestion of stress catecholamines and development of stress autonomic
      reaction in response to laryngoscopy, intubation and subsequent laparotomy during CD. The
      remifentanil administration thus suppress the hypertensive and tachycardiac increase during
      the initial period of CD , but without negative influence on newborns postpartum adaptation,
      mainly breathing. On the contrary the prevention of uteroplacental blood flow reduction
      should improve the postpartum adaptation of the newborn. The project should also give pilot
      data, if genetic polymorphisms of target genes, important for remifentanil pharmacokinetic
      and pharmacodynamic, influence in Czech population drug efficacy and safety.

      As extrapolated result the investigators expect the reduction of complications attributed to
      severe BP increase, especially hemorrhagic stroke. The remifentanil administration should not
      have any negative influence on newborn, especially on postnatal adaptation and breathing
      activity. Prevention of uteroplacental insufficiency in response to hypertension and
      tachycardia may even lead to better newborn status.

      AIMS

      The aims of the project are:

        1. To assess newborn postnatal adaptation after cesarean delivery under general anesthesia
           with a remifentanil bolus 1 µg/kg prior to the induction of general anesthesia

        2. To demonstrate a stabilizing influence of remifentanil on circulation and depth of
           anesthesia in patients with hypertension/preeclampsia in the time of fetus delivery
           during CD

        3. To assess the influence of individual hereditary variability in MDR1 (multidrug
           resistance gene 1) and PXR (pregnane X receptor) on RMF pharmacodynamics.

        4. To assess the influence of individual genetic variability in µ-opioid receptor gene on
           drug effects in newborn.

      Extrapolated result should be both the reduction of complications in mother associated with
      serious increase in systemic blood pressure and improved postpartum newborn adaptation.
      Patients with hypertension/preeclampsia are at high risk of insufficient depth of anesthesia
      during CD and this may lead to uncontrolled hypertension with the risk of intracranial
      bleeding. To avoid this complication represents one of current obstetrician anesthesia
      priorities. Optimal introduction to GA in this clinical situation has not been yet
      identified.

      METHODS AND RESEARCH SAMPLE Type of study: prospective, randomized, double-blinded for the
      assessment of neonatal adaptation and single-blinded for the evaluation of haemodynamic
      changes.

      Patient file: 160 pregnant women undergoing CD under GA; 80 patients with
      hypertension/preeclampsia - 40 in the REMIFENTANIL group and 40 in the STANDARD (placebo)
      group; 80 patients without hypertension/preeclampsia - 40 in the REMIFENTANIL group and 40 in
      the STANDARD (placebo) group.

      Randomization: Will be performed before CD using the envelope method. Randomization and
      preparation the appropriate study bolus (remifentanil 1 µg/kg) will be performed by
      supervising anesthesiologist. The randomization for the neonatologist will be broken in the
      case of medical complication, e.g. when respiratory depression in infant occurs and opioid
      antagonist may be administered. Supervising anesthesiologist will not otherwise interfere
      with the course of CD or evaluation of the data.

      Conduct of anesthesia: Thirty seconds prior to GA induction bolus of study drug solution is
      given intravenously. Afterwards anesthesia will be conducted in a standard way: induction to
      GA with combination of thiopentone 5 mg/kg and suxamethonium 1.25 mg/kg; subsequent
      intubation and inhalation of oxygen/nitrous oxide (1:1) and sevoflurane 0.7%. Following the
      intubation neuromuscular relaxant Atracurium is administered 0.35 mg/kg. After delivery of
      the newborn and umbilical cord clamping opioid analgesia with sufentanil 0.3-0.5 µg/kg and
      inhalation of oxygen/nitrous oxide (2:3) + sevoflurane 0.7-1.0% will be administered. If
      required, additional bolus of sufentanil 10 µg intravenously will be given.

      Intraoperative monitoring: All the patients will be monitored according to guidelines with
      respect to risk associated with hypertension/preeclampsia and GA for CD - ECG (including V4-5
      thoracic lead, ST analysis), SatO2, ETCO2, % of oxygen, % of volatile anesthetics,
      ventilation parameters (PIP, MV, TV, F).

      For evaluation of anesthesia depth continuous bispectral EEG analysis (BIS) and sympathetic
      skin reflex response (SSRR) will be used. BIS is electrophysiological method reflecting the
      inability to perceive stimuli from environment using mathematical analysis of EEG curve; SSRR
      is unique method measures changes of skin conductivity that with high sensitivity and delay
      of only 1-2 sec. reflects immediate changes in sympathetic system to nociceptive stimuli
      (Stress Detector; Med-Storm, Norway).

      DATA COLLECTION Demographics: age, height, weight, BMI, gestational age, previous pregnancy,
      associated medical conditions.

      Preoperative laboratory values (haematology, liver and kidney function, total protein).
      Hemodynamics (BP, MAP, HR, ST analysis), ventilation (MV, SatO2, ETCO2), depth of anaesthesia
      (BIS, SSRR). Time course of CD (study drug administration, induction to GA, intubation,
      beginning of surgery, hysterotomy, delivery). Measurement of blood loss, complications.

      Clinical examination and assessment of newborn status (Apgar score + acid-base measurement
      from umbilical cord, clinical evaluation and scoring).

      Biological material sampling To assess genotype of MDR1 gene and PXR (Pregnane X Receptor) 8
      ml of umbilical blood and 8 ml of venous blood from mother will be collected.

      Pharmacogenomic analysis: Validated methods for PXR and MDR1 polymorphism analysis are
      available at our workplace. In both genes five polymorphisms with possible functional impact
      will be analyzed in every sample. Method for assessment of opioid receptor polymorphism
      (A118G) will be implemented during the first year of the study.

      EVALUATION Level of anesthesia depth will be evaluated by BIS and SSRR values and by
      hemodynamic response to intubation and incision, especially by changes of BP (systolic,
      diastolic, mean) and heart rate.

      Evaluation of newborn status will be assessed by Apgar score and acid-basis measurement of
      umbilical cord blood and by clinical assessment and scoring performed by experienced
      neonatologist.
    

Intervention name(s): Remifentanil
Intervention type(s): Drug
Intervention description(s): bolus of remifentanil 1 µg/kg will be given 30 sec before induction to general anesthesia
Other intervention name(s): Ultiva
Intervention MeSH terms: Remifentanil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: remifentanil; Caesarean operation; general anaesthesia; hypertension; newborn's adaptation; pharmacogenetics