Pregnancy Clinical Trial
Official title:
Pharmacogenetics of Remifentanil in Patients With Hypertension Undergoing Cesarean Delivery Under General Anesthesia
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Investigator, Outcomes Assessor), Primary Purpose: Prevention
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