Dexmedetomidine for Cesarean Delivery
Dexmedetomidine for Cesarean Delivery
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.
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
Inclusion Criteria:

 -  80 women aged 18-45 years (ASA physical status II-III)with uncomplicated, singleton
 pregnancies of at least 36 weeks' gestation scheduled for elective cesarean delivery
 under general anesthesia.

 Exclusion Criteria:

 -  women with a history of cardiac, liver, or kidney diseases;

 -  women with allergy to amide local anesthetics;

 -  women with epilepsy;

 -  those taking cardiovascular medications;

 -  those with pregnancy-induced hypertension;

 -  women with evidence of intrauterine growth restriction or fetal compromise.