Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01005433 |
| Other study ID # |
10/2009 |
| Secondary ID |
+966 (56) 937184 |
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
October 30, 2009 |
| Last updated |
March 22, 2012 |
| Start date |
December 2009 |
| Est. completion date |
December 2011 |
Study information
| Verified date |
March 2012 |
| Source |
King Faisal University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Saudi Arabia: Ethics Committee |
| Study type |
Interventional
|
Clinical Trial Summary
Regional anesthesia has become the anesthetic of choice for cesarean section in most
countries; however, some women still prefer general anesthesia techniques. There are many
trials for the pharmacological modifications of the sympathetic response to surgery,
including opioids, tenoxicam, ketorolac, lidocaine and paracetamol. However, opioid
administration to the mother before delivery has adverse neonatal effects. This research is
a novel trial on the use of dexmedetomidine for suppression of the hemodynamic and hormonal
responses of cesarean delivery.
Description:
Literature Review Regional anesthesia has become the anesthetic of choice for cesarean
section in most countries; however, some women still prefer general anesthesia rather than
regional techniques. There are many published controlled trials for the pharmacological
modifications of the sympathetic response to laryngoscopy, tracheal intubation, and surgical
stimulation, including opioids, tenoxicam, ketorolac, lidocaine and paracetamol.1-6 However,
opioid administration to the mother before delivery has adverse neonatal respiratory
depression.1
Dexmedetomidine, a specific [alpha]2-adrenoceptor agonist, has been approved for clinical
use for sedation of patients who need mechanical ventilation in the intensive care unit. 7
It has shown sedative, analgesic, and anxiolytic effects after intravenous (IV)
administration.8It is felt that the sedative effect of dexmedetomidine is safe and suited
for extubation under sedation because it has little effect on respiration.9
An older study tested the effects of preoperative administration of dexmedetomidine 10 min
prior to the induction of anesthesia on hemodynamic changes after intubation in 96 women
undergoing abdominal hysterectomy. They found that the increase in blood pressure and heart
rate was significantly less in the higher dexmedetomidine (0.6 µg/kg) group than in the
saline group (P < 0.01). Also, the postintubation increase in heart rate was significantly
less (P < 0.05) with the use of dexmedetomidine 0.6 µg/kg (increase of 18 ± 3 bpm) compared
to fentanyl (increase of 26 ± 3 bpm). In patients receiving dexmedetomidine 0.3 µg/kg, the
increase in blood pressure or heart rate did not differ from those receiving saline.10
Others found that a single pre-induction intravenous dose of dexmedetomidine 2 µg/kg in 50
patients undergoing minor orthopaedic and general surgery was associated with reduced the
hemodynamic response to tracheal intubation and extubation, intra-operative heart rate
variability, postoperative analgesic and anti-emetic requirements and lower peri-operative
serum catecholamine concentrations. However, there were more frequent episodes of
hypotension and bradycardia.11
Similarly, others reported that preoperative administration of a single dose of
dexmedetomidine 50 patients scheduled for elective minor surgery resulted in progressive
increases in sedation, blunted the haemodynamic responses during laryngoscopy, and reduced
opioid and anaesthetic requirements. 12
Recently, others found that a single dose of 0.5 µg/kg dexmedetomidine given before
induction of anesthesia in 40 ASA physical status I and II patients, aged 20 to 60 years,
who were scheduled for elective cholecystectomy, decreased thiopental requirements, lower
heart rate values, minimal effects on ejection fraction (EF), end-diastolic index (EDI),
cardiac index (CI), and stroke volume index (SVI), or any effect on recovery time.13
Esmaoglu and co'workers compared the use of midazolam loading dose of 0.05 mg/kg followed by
an infusion of 0.1 mg/kg/h and dexmedetomidine loading dose 1 µg/kg per 20 minutes, followed
by continuous infusion at 0.7 µg/kg/h in 40 women with eclampsia requiring termination of
pregnancy by caesarean delivery in intensive care unit (ICU). They concluded that
dexmedetomidine sedation in eclampsia patients is effective in reducing the demand for
antihypertensive medicine and duration of ICU stay.14
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.15 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.16
There are many published reports about the safety use of dexmedetomidine in neonates and
infants. Some authors described the successful use of dexmedetomidine as the sole anesthetic
for four infants requiring general anesthesia for direct laryngoscopy and bronchoscopy with
spontaneous ventilation with adequate surgical conditions and the hemodynamic and
respiratory profiles.17-18 Others suggested that invasive procedures can be successfully
performed in spontaneously breathing infants and toddlers with congenital heart disease
using dexmedetomidine 1-3 µg/kg alone or in combination with low dose ketamine.19Others
reported a case of an infant undergoing endoscopic repair of a laryngeal cleft where the
combination of dexmedetomidine and propofol infusions was successfully used as the
anesthetic technique.
There is currently no FDA-approved usage in children. Despite this fact, there are more than
1,000 pediatric-aged patients reported in the literature who have received dexmedetomidine
for a variety of clinical applications in and out of the operating room. 20
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.21 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.22
There is an interested editorial report summarized that the practitioners of obstetric
analgesia would probably appreciate an additional agent for the provision of pain relief for
parturients who are unable or unwilling to receive neuraxial block. The role of low-dose
infusion of dexmedetomidine to maintain light sedation and haemodynamic stability with
minimal risk of respiratory depression could be advantageous, especially with proper patient
selection and monitoring. Its effects on the pregnant uterus, utero-placental unit and the
neonate must be rigorously examined.23
Project Objectives:
We hypothesize that the the preoperative use of different doses of i.v. dexmedetomidine ,
namely 0.2, 0.4 and 0.6 µg/kg/h from the preanesthesia period to the postoperative period
for uncomplicated cesarean delivery would reduce the maternal hemodynamic and hormonal
responses to endotracheal intubation, surgical stimulation and extubation with improved
quality of postoperative analgesia without harmful neonatal effects.
The aims of the present study are:
Our research efforts will focus on identifying the effects of 0.2, 0.4 and 0.6 µg/kg/h
dexmedetomidine for uncomplicated cesarean delivery on the followings.
1. Hemodynamic [heart rate, systolic and mean blood pressure] changes.
2. The perioperative changes in plasma cortisol concentrations.
3. The perioperative changes in plasma catecholamines concentrations, namely, epinephrine
and norepinephrine.
4. The neonatal outcome as regarding Apgar score, the neurologic and adaptive capacity
score (NACS), and umbilical cord venous and arterial blood gases analyses.
5. The quality of extubation conditions.
6. The quality of postoperative analgesia.
7. The incidence of the major complications (respiratory, cardiovascular events, and
neonatal adverse outcome).
Project Design:
Study Design:
This prospective randomized placebo-controlled double-blinded study will be carried out from
at the Maternity Unit - King Fahd University Hospital, after approval of the Local
Institutional Ethical Committee.
Study Phases: The project comprised of five phases as follow:
• Phase I: Literature review collection and writing which will spend 1 months.
• Phase II: Pilot Study for 1 months to determine the sample size required to detect
significant changes [Alpha error 0.05] in the hemodynamic responses [heart rate and blood
pressure] to intubation, surgical stimulation and extubation with the preoperative use of
dexmedetomidine for uncomplicated cesarean delivery to achieve an 85% power for that study.
• Phase III: (7 months) A. To test the primary effects of the preoperative use of different
doses of dexmedetomidine [0.2, 0.4 and 0.6 µg/kg/h] for uncomplicated cesarean delivery: on
perioperative hemodynamic responses, cortisol, epinephrine and norepinephrine changes B. To
test the secondary outcome variables included; the neonatal outcome as regarding Apgar
score, the neurologic and adaptive capacity score (NACS), and umbilical cord venous and
arterial blood gases analyses, the quality of extubation conditions and postoperative
analgesia and the incidence of the major complications (respiratory, cardiovascular events,
and neonatal adverse outcome).
Sampling Site:
The study will be conducted in the DR suite and maternity unit at the King Fahd Hospital of
the University - Al khobar Study period: For 9 months. I. Patient Selection: patients aged
18-60 years (ASA physical status II-III) scheduled for elective in about 80 women (American
Society of Anesthesiologists [ASA] I and II), with uncomplicated, singleton pregnancies of
at least 36 weeks' gestation, who will receive regional anesthesia and were scheduled for
elective cesarean delivery under general anesthesia. We 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.
I. Patient Groups and Study Protocol: All patients will be randomly assigned using sealed
envelopes included the computer generated randomized code into four groups; to receive
either placebo (saline) [group 1], dexmedetomidine [0.2, 0.4 and 0.6 µg/kg/h in groups 2, 3,
and 4 respectively, will started 10 minutes before induction of general anesthesia
II. Anesthesia and Surgery:
All parturients will receive oral ranitidine 150 mg on the night before and on the morning
of surgery and 30 mL of 0.3 mol/L sodium citrate 15 min before induction. Lactated Ringer's
solution (500 mL) will infused over 20 min. Left uterine displacement will be maintained
before induction.
The subjects will be allocated randomly to two groups,using a computer-generated
randomization code. The placebo group (n = 20) will receive an i.v. infusion of 0.1 mL/kg/h
saline 0.9%, at 20 min before induction of anesthesia. The dexmedetomidine groups (n = 20
for each) will receive i.v. infusion of 0.1 mL/kg/h of solution containing 2, 4, and 6 µg/mL
of dexmedetomidine, at 20 min before induction of anesthesia. The placebo and the
dexmedetomidine solutions will be looked identical and their infusions will be continued
until skin closure, when their infusion rate will be decreased by 50% until 20 min after
extubation. The test solution will be prepared by one anesthesiologist before induction of
anesthesia. Another anesthesiologist, who will be blinded to the study solution, will give
the anesthetic and will perform the assessments. All staff in the operating room will be
unaware of the randomization code.
Maternal monitoring will include electrocardiography, noninvasive blood pressure, pulse
oximetry, end-tidal sevoflurane and carbon dioxide (EtCO2) concentrations, neuromuscular
blockade, and response entropy (RE) and state entropy (SE) using the Datex-Ohmeda S/5
Entropy Module (M-EntropyTM) (Datex-Ohmeda Division, Instrumentarium Corporation, Helsinki,
Finland).. After preoxygenation for 5 min, a rapid-sequence induction will be performed with
propofol 1.5-2.5 mg/kg and suxamethonium 1.5 mg/kg. Cricoid pressure will be applied,
laryngoscopy will be performed after the 1-min blood pressure recording, and tracheal
intubation will be completed before the 2-min reading. Anesthesia will be maintained with a
45% of oxygen with 0.5-1 MAC of sevoflurane based on entropy reading where the end-point was
SE 50 and SE-RE difference less than 10. Rocuronium 0.6 mg/kg will be given for muscle
relaxation to maintain suppression of the second twitch using a train-of-four stimulation.
. The patients'lungs will be ventilated to maintain an EtCO2 of 4-4.6 kPa. After the
umbilical cord will be clamped, infusions of 10 U oxytocin and fentanyl 2 μg/kg will be
given. Sevoflurane will be discontinued and study drug infusion rate will be decreased by
50% at the start of skin closure. At the end of surgery, residual neuromuscular block will
be antagonized with neostigmine 50 μg/kg and atropine 20 μg/kg, and the trachea will be
extubated. The study drug infusion will be discontinued 20 min after extubation.
III. The Investigators who will be involved with subsequent postoperative patient assessment
will be blinded of the patient group.
IV. Clinical Examination: will include times for induction to delivery (I-D), extubation
(time from discontinuation of sevoflurane to extubation), and spontaneous ventilation (time
between beginning of spontaneous breathing and extubation) will be recorded. The quality of
tracheal extubation will be was evaluated using a 5-point rating scale: 1, no coughing or
straining; 2, very smooth, minimal coughing; 3, moderate coughing; 4, marked coughing or
straining; and 5, poor extubation, very uncomfortable.25 Heart rate and mean arterial
pressure (MAP) will be recorded before and 15 min after bolus infusion; at 1, 2, 3, 4, 5, 6,
7, 8, 9, and 10 min after induction; 15 and 30 min after delivery; and 0, 1, 5, 15, 30, and
60 min after extubation.
The obstetrician will be assessed uterine tone by palpation every 5 min after delivery of
the placenta, using a 10-cm visual analogue score (VAS; 0, well contracted; 10, completely
relaxed). If uterine tone remained unsatisfactory after 3 min, an additional 5-U bolus of
oxytocin will be administered.
All neonates will be assessed by a pediatrician unaware of the mothers' randomization. Apgar
scores at 1 and 5 min, and newborns' blood pressure, heart rate, temperature, arterial
oxygen saturation, and the neurologic and adaptive capacity score (NACS) will be recorded at
15 min and at 2 and 24 h after delivery. NACS gives a total score: the maximum is 40, and a
score of 35-40 denotes vigor.26 The percentages of infants scoring 35 or less will be
determined.
The presence of perioperative side effects, including bradyarrhythmia, hypotension,
sedation, nausea and vomiting, neonatal hypothermia, bradycardia or respiratory depression
will be reported.
V. Blood Biochemistry: will include the neonatal umbilical artery (UA) and umbilical vein
(UV) samples collection from a double-clamped segment of umbilical cord for the measurement
of blood pH, gas tensions, and base excess.
VI. Samples Collection and Analysis For the hormonal assays: Maternal venous blood samples
(MV) will be collected for assay of cortisol, epinephrine and norepinephrine concentrations,
at five points: preoperatively, immediately after bolus infusion, 5 min after intubation, 1
h after delivery, and 1 h after continuous infusion.
1. . Type of samples: centrifuged stored aliquots of serum at -70°C.
2. . Laboratory Analysis:
1. Plasma cortisol levels will be determined using a radioimmunoassay technique
(Gamma Coat Cortisol 125IRIA; Nihon Sheering, Chiba, Japan).
2. Plasma catecholamines [epinephrine and norepinephrine] levels will be determined
using a radioimmunoassay technique.
IV. Statistical Analysis: 1month Statistical analysis will be performed using the
Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). Data will be tested
for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis of variance will
be used for analysis of serial changes in the hemodynamic data at different times after
administration of dexmedetomidine . Chi-square test will be used for categorical data.
Parametric variables will be analyzed by one way ANOVA comparisons among the four groups and
will be followed by the post hoc Tukey's HSD (honestly significant difference) test. The
Kruskal-Wallis one-way ANOVA will be performed for intergroup comparisons for the
non-parametric hormonal values and post hoc pairwise comparisons will be done using the
Wilcoxon rank sum t test. Data will be expressed as mean (SD), number (%), or median
[range]. A value of p < 0.05 will be considered to represent statistical significance.
V.Report Writing:2 months
