Effect of Granisetron on Morphine Induced Pruritus in Cesarean Section

The study will be carried on 40 parturients scheduled for elective cesarean section (CS) under intrathecal anesthesia. They will be randomly allocated into two equal groups of 20 parturients each:

Group A: (placebo group) will receive 200 ug morphine sulphate will be injected intrathecally \& 2 mL of normal saline 0.9%.

Group B: (treatment group) will receive 200 ug morphine sulphate will be injected intrathecally \& 2 mL of 2 mg granisetron IV injection.

Preoperative assessment:

The day prior to surgery, all patients will undergo preanesthetic checkup including detailed history, thorough general, physical, systemic examination and weight of the patient. They will be kept NOP (nil per mouth) 6-8 hours for solids and 2 hours for water and clear fluids.

Preparation of the patients:

Written consent, coagulation profile, emergency resuscitation equipments including airway devices, advanced cardiac life support drugs. Parturients will be educated regarding the visual analogue scale (VAS).

Parturients in the holding area:

The patients will be positioned in the supine position, with uterine displacement to the left lateral side.

• Baseline monitoring readings of the maternal vital signs including Heart rate (HR), noninvasive systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), arterial oxygen saturation (SpO2) and respiratory rate (RR).
• Then IV cannula 18 G will be inserted into forearm vein and normal saline 0.9% solution 15 ml/kg will be infused for all women participating in the study over 20-30 minutes as a preload.
• The study drugs will be given 30 min before administration of intrathecal anesthesia.
• All patients will be premedicated with ranitidine 50 mg IV and then they will be transferred to the operating room.

Parturient in the operating room:

The previous monitoring data will be recorded again for the second time. Then subarachnoid block will be carried out under complete aseptic condition in the sitting position with the table in the horizontal level using 25 G pencil point spinal needle. Intrathecal block will be performed at the level of L 3-4 or L 4-5 vertebral interspaces; 12.5 mg (2.5 ml) of hyperbaric bupivacaine 0.5% and 200 ug morphine sulphate will be injected intrathecally at a rate of 1 ml/15 second after obtaining free flow of CSF. Immediately after end of injection of the drugs intrathecally, the parturient will be placed in the supine position with left lateral uterine displacement by putting a wedge under right hip (15ﹾ left-tilted supine position). All patients will receive supplemental oxygen 4 L/min via facemask until delivery of the baby. Sensory block will be assessed using loss of sensation in response to cold sensation (using ice cube). Surgery will start when the maximum height of sensory block reaches T6 or higher. Motor blockade will be assessed by modified Bromage scale (1 = unable to move feet or knees; 2 = able to move feet only; 3 = just able to move knees; 4 = full flexion of knees; 5 = no detectable weakness of hip flexion while supine; 6 = able to perform partial knee bend).

A third monitoring reading of the vital data will be taken immediately, 5 min and 10 min after spinal block and before the surgical operation (CS) starts.

Intraoperative assessment:

• After subarachnoid block parturients will be monitored for HR, NIBP, SpO2 and RR every 5 min till the end of the surgery. All parturients will be continuously monitored intraoperatively for any episodes of hypotension or bradycardia. Hypotension: defined as more than 20% decrease in maternal systolic blood pressure from the baseline. It will be treated with IV crystalloid fluid bolus and/or 3 mg IV ephedrine boluses when needed. Bradycardia defined as maternal heart rate < 60 beats/min. If occurred, it will be treated with IV atropine sulphate 0.5mg.
• After delivery of the baby, IV oxytocin 5 U will be administered slowly followed by an oxytocin infusion 0.03 U/mL at a rate of 200 mL/hr.

Study outcomes:

Primary outcome:

Incidence of pruritus during the first postoperative 24 hours.

Secondary outcomes:

1. Onset time of pruritus
2. Duration, location of pruritus and severity of pruritus according to the pruritus grading score The pruritus grading system (PGS) score for each patient is based on: distribution, frequency, severity of itch and quality of sleep. Pruritus Grading System Each patient's itch grade is calculated as the sum of the individual scores as:

• Distribution:Solitary site 1, Multiple sites 2, Generalized 3
• Frequency: Episodic 1, Frequent 3, Continuous 5
• Severity: Rubbing 1, Scratching 1, Localized excoriations 3, Generalized excoriations 5
• Sleep disturbance: Rare 0, Occasional 2, Frequent 4,Totally restless 6 Mild grade: if total score is between 0 and 5. Moderate grade: if total score is between 6 and 11. Severe grade: if total score is between 12 and 19. The onset of pruritus will be assessed and recorded every 15 min for 4 hours along with the complaint by the patient. Pruritus scores will then be evaluated at 4, 8 and 24 hours post-surgery. For patients with pruritus who request treatment, antihistamines such as pheniramine maleate and μ-opioid receptor antagonists such as naloxone will be used depending upon the severity assessed by the clinician, if required.

1. Postoperative pain assessment, by a blinded Post-Anesthesia Care Unit (PACU) nurse using VAS at 6, 12, 18 and 24 hours after intrathecal morphine injection. Visual analog scale (Fig. 1) is a validated approach to pain measurement (Wood, 2004). The most common VAS consists of a 10-cm line with one end labeled "no pain" and the other end labeled "worst pain imaginable." The patient marks the line at the point that best describes the pain intensity. The length of the line to the patient's mark is measured and recorded in millimeters. The main theoretical advantage of the VAS is that it does not limit pain to 10 discrete levels of intensity, permitting a more detailed rating of pain. Rescue analgesia will be given in the form of perfalgan (paracetamol) 1 gm/ 6 h (max 4 gm per day) IV infusion and/or pethidine (meperidine) 1 mg/ kg IM when VAS is greater than 4.
2. Perioperative adverse events will be recorded, including nausea, vomiting (treated with 10 mg IV metoclopramide), intraoperative shortness of breath and respiratory depression (RR < 8 breaths/ min), and postoperative headache in the first 24 hours postoperatively.
3. Participants' satisfaction after end of the delivery: 1) not satisfied or 2) satisfied and willing to take the same medication and procedure in the future when indicated.

Serum serotonin measurment:

Two blood samples (2 mL each) will be withdrawn from each parturient. One sample will be withdrawn in the holding area before preload infusion and granisetron injection (basal reading for serum serotonin) and the other one will be withdrawn 6 hours after intrathecal morphine injection in both groups. Repeated freezing and thawing of the samples should be avoided. Hemolytic and especially lipemic serum samples should not be used with this assay. Storage: up to 6 hours at 2 - 8ºC; for longer periods (up to 6 months) at - 20 ºC.

Intended use and principle of the test: Enzyme Immunoassay for the quantitative determination of serotonin in serum. In the first step, serotonin is quantitatively acylated. The subsequent competitive ELISA kit uses the microtiter plate format. The antigen is bound to the solid phase of the microtiter plate. The acylated standards, controls and samples and the solid phase bound analyte compete for a fixed number of antiserum binding sites. After the system is in equilibrium, free antigen and free antigen-antiserum complexes are removed by washing. The antibody bound to the solid phase is detected by an anti-rabbit IgG-peroxidase conjugate using TMB as a substrate. The reaction is monitored at 450 nm.

Quantification of unknown samples is achieved by comparing their absorbance with a reference curve prepared with known standard concentrations. Expected reference values in serum: Males: 80 - 450 ng/ml and females: 40 - 400 ng/ml