Ignite Creation Date:
2024-05-06 @ 11:18 AM
Last Modification Date:
2024-10-26 @ 12:43 PM
Study NCT ID:
NCT03483870
Status:
COMPLETED
Last Update Posted:
2021-09-09
First Post:
2018-03-22
Brief Title:
Effect of Granisetron on Morphine Induced Pruritus in Cesarean Section
Sponsor:
Assiut University
Organization:
Assiut University
Study Overview
Official Title:
Effect of Intravenous Granisetron on Incidence and Severity of Intrathecal Morphine Induced Pruritus in Elective Cesarean Section
Status:
COMPLETED
Status Verified Date:
2021-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Neuraxial anesthesia which includes epidural anesthesia and intrathecal anesthesia is a frequent anesthetic approach for caesarean delivery and other lower abdominal and lower limb anesthetic procedures The addition of neuraxial morphine to local anesthetics provides an effective and prolonged postoperative analgesia Neuraxial administration of morphine which is considered as a gold standard for analgesia has been associated with a frequent incidence of pruritus and postoperative nausea and vomiting
The incidence of neuraxial opioid induced pruritus varies widely from 30 - 60 after orthopedic surgery with intrathecal morphine injection and from 60 - 100 in pregnant women after neuraxial opioid administration Parturients appear to be the most susceptible to neuraxial opioid-induced pruritus which probably might be due to the interaction of estrogens with opioid receptors
Although the exact mechanism of neuraxial opioid induced pruritus is unclear the postulated mechanisms include the presence of an itch center in the central nervous system CNS medullary dorsal horn activation antagonism of inhibitory transmitters modulation of 5-hydroxytryptamine subtype 3 5-HT3 or serotonergic pathways and the involvement of prostaglandins
There is dense concentration of opioid receptors and 5-HT3 receptors in the dorsal part of the spinal cord and the nucleus of the spinal tract of the trigeminal nerve in the medulla Activation of these receptors by neuraxial opioid administration or by circulating estrogen in parturients results in neuraxial opioid induced pruritus which is usually localized to the face neck or upper thorax Nalbuphine propofol and ondansetron have been used effectively in the treatment of pruritus associated with neuraxial morphine in surgical patients
Granisetron is a potent and highly selective 5-HT3 receptor antagonist that has little or no affinity for other 5-HT receptors or dopaminergic adrenergic benzodiazepine histaminic or opioid receptors Its onset of action is 1-3 min peak plasma level 30 min plasma half-life is 4-6 h and duration of action up to 24 h Its longer duration of action than that of ondansetron may coincide with the peak incidence of pruritus after intrathecal morphine 6-9 h In contrast other 5-HT3-receptor antagonists have affinities for various receptor-binding sites For example ondansetron has detectable binding to 5-HT1B 5-HT1C α1-adrenergic and μ-opioid receptor sites Although not proven the binding of these agents to additional receptor subtypes other than their target receptor may underlie the inferior adverse event profile seen with ondansetron compared with granisetron
The incidence of neuraxial opioid induced pruritus varies widely from 30 - 60 after orthopedic surgery with intrathecal morphine injection and from 60 - 100 in pregnant women after neuraxial opioid administration Parturients appear to be the most susceptible to neuraxial opioid-induced pruritus which probably might be due to the interaction of estrogens with opioid receptors
Although the exact mechanism of neuraxial opioid induced pruritus is unclear the postulated mechanisms include the presence of an itch center in the central nervous system CNS medullary dorsal horn activation antagonism of inhibitory transmitters modulation of 5-hydroxytryptamine subtype 3 5-HT3 or serotonergic pathways and the involvement of prostaglandins
There is dense concentration of opioid receptors and 5-HT3 receptors in the dorsal part of the spinal cord and the nucleus of the spinal tract of the trigeminal nerve in the medulla Activation of these receptors by neuraxial opioid administration or by circulating estrogen in parturients results in neuraxial opioid induced pruritus which is usually localized to the face neck or upper thorax Nalbuphine propofol and ondansetron have been used effectively in the treatment of pruritus associated with neuraxial morphine in surgical patients
Granisetron is a potent and highly selective 5-HT3 receptor antagonist that has little or no affinity for other 5-HT receptors or dopaminergic adrenergic benzodiazepine histaminic or opioid receptors Its onset of action is 1-3 min peak plasma level 30 min plasma half-life is 4-6 h and duration of action up to 24 h Its longer duration of action than that of ondansetron may coincide with the peak incidence of pruritus after intrathecal morphine 6-9 h In contrast other 5-HT3-receptor antagonists have affinities for various receptor-binding sites For example ondansetron has detectable binding to 5-HT1B 5-HT1C α1-adrenergic and μ-opioid receptor sites Although not proven the binding of these agents to additional receptor subtypes other than their target receptor may underlie the inferior adverse event profile seen with ondansetron compared with granisetron
Detailed Description:
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 09
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 09 solution 15 mlkg 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 125 mg 25 ml of hyperbaric bupivacaine 05 and 200 ug morphine sulphate will be injected intrathecally at a rate of 1 ml15 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 Lmin 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 andor 3 mg IV ephedrine boluses when needed Bradycardia defined as maternal heart rate 60 beatsmin If occurred it will be treated with IV atropine sulphate 05mg
After delivery of the baby IV oxytocin 5 U will be administered slowly followed by an oxytocin infusion 003 UmL at a rate of 200 mLhr
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 patients itch grade is calculated as the sum of the individual scores as
DistributionSolitary 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 4Totally 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
3 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 patients 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 andor pethidine meperidine 1 mg kg IM when VAS is greater than 4
4 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
5 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 ngml and females 40 - 400 ngml
Group A placebo group will receive 200 ug morphine sulphate will be injected intrathecally 2 mL of normal saline 09
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 09 solution 15 mlkg 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 125 mg 25 ml of hyperbaric bupivacaine 05 and 200 ug morphine sulphate will be injected intrathecally at a rate of 1 ml15 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 Lmin 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 andor 3 mg IV ephedrine boluses when needed Bradycardia defined as maternal heart rate 60 beatsmin If occurred it will be treated with IV atropine sulphate 05mg
After delivery of the baby IV oxytocin 5 U will be administered slowly followed by an oxytocin infusion 003 UmL at a rate of 200 mLhr
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 patients itch grade is calculated as the sum of the individual scores as
DistributionSolitary 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 4Totally 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
3 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 patients 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 andor pethidine meperidine 1 mg kg IM when VAS is greater than 4
4 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
5 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 ngml and females 40 - 400 ngml
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None