Evaluation of the Analgesic Effect of Midazolam and Ketamine as an Additive to Intrathecal Bupivacaine in Patients Undergoing Cesarean Section

Study Overview
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Brief Summary
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Objective :To compare the analgesic effect of intrathecal midazolam and ketamine as an additive to bupivacaine in patients undergoing cesarean section . Methods:Following Ethics Committee approval and informed patients consent, Ninety patients 18-45 yr old ASA physical status I or II, scheduled for cesarean section under spinal anesthesia, were studied in a prospective, double-blinded, randomized way. The patients were randomly allocated to one of three groups of 30 each. The ketamine group (groupK) received bupivacaine 10mg combined with 0.1 mg/kg ketamine preservative free ,the midazolam group (group M) received bupivacaine 10mg combined with0.02 mg/ kg midazolam and the placebo group (group P) received bupivacaine 10mg combined with 0.5ml distilled water intrathecally . Time to first requirement of analgesic supplement, Sensory block onset time, maximum sensory level , onset of motor block, duration of blockade, hemodynamics variables, the incidence of hypotension, ephedrine requirements, bradycardia ,hypoxemia [Saturation of peripheral oxygen (SpO2)<90], postoperative analgesic requirements and Adverse events, such as sedation, dizziness , Pruritus and postoperative nausea and vomiting were recorded. Patients were instructed preoperatively in the use of the verbal rating scale (VRS) from 0 to 10 (0no pain, 10maximum imaginable pain) for pain assessment. If the VRS exceeded four and the patient requested a supplement analgesic, diclofenac Na supp 100 mg was to be given for post-operative pain relief as needed . For breakthrough pain(VRS >4) if time of administration of diclofenac Na less than 8h,Pethidine 25 mg IV was given.

Detailed Description
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The patients were randomly allocated to one of three groups of 30 each. The ketamine group (groupK) received bupivacaine 10mg combined with 0.1 mg/kg ketamine preservative free ,the midazolam group (group M) received bupivacaine 10mg combined with0.02 mg/ kg midazolam and the placebo group (group P) received bupivacaine 10mg combined with 0.5ml distilled water intrathecally .

Conditions
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Post Operative Pain

Intervention / Treatment
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* Drug: placebo(distilled water
* Drug: Ketamine
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with American Society of Anesthesiologists(ASA) physical status I and II, undergoing elective cesarean section Exclusion Criteria: significant coexisting disease such as hepato-renal and cardiovascular disease any contraindication to regional anesthesia such as local infection or bleeding disorders allergy to ketamine or midazolam long-term opioid use or a history of chronic pain.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ketamine<br>The ketamine group (groupK) received bupivacaine 10mg combined with 0.1 mg/kg ketamine preservative free intrathecally . | Drug: Ketamine<br>* The ketamine group (groupK) received bupivacaine 10mg combined with 0.1 mg/kg ketamine preservative free intrathecally<br>|
| Active Comparator: midazolam<br>The midazolam group (group M) received bupivacaine 10mg combined with0.02 mg/ kg midazolam intrathecally | Drug: Midazolam<br>* The midazolam group (group M) received bupivacaine 10mg combined with0.02 mg/ kg midazolam intrathecally<br>|
| Placebo Comparator: placebo<br>The placebo group (group P) received bupivacaine 10mg combined with 0.5ml distilled water intrathecally . | Drug: placebo(distilled water<br>* The placebo group (group P) received bupivacaine 10mg combined with 0.5ml distilled water intrathecally .<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first requirement of analgesic supplement | analgesic administration was initiated by patient request(verbal rating scale[ VRS]>4) | participants will be followed for the duration of 24 hours after intratechal injection (Time from the injection of intrathecal anesthetic solution to first requirement of analgesic supplement will be recorded.) | 
| Postoperative analgesic requirements | postoperative analgesic requirements will be assessed by verbal rating scale (VRS) from 0 to 10 (0no pain, 10maximum imaginable pain).Each administration was initiated by patient request( VRS>4) | 24 hours postoperative(Time from the injection of intrathecal anesthetic solution to 24 hours postoperative) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory block onset time will be assessed by a pinprick test | The onset of sensory block was defined as the time between the end of injection of the intrathecal anesthetic and the absence of pain at the T10 dermatome | sensory block will be assessed by pinprick test every 10 seconds following intrathecal injection | 
| duration of sensory block will be assessed by a pinprick test | The duration of sensory block was defined as the time for regression from the maximum block height sensory block to T10 dermatom will be assessed by pinprick test every 5 minuts following intrathecal injection | sensory block will be assessed by pinprick test every 5 minuts following intrathecal injection | 
| the onset of motor block will be assessed by the modified Bromage score | The onset of motor block was defined as the time between the end of injection of the intrathecal anesthetic to Bromage block 1 | every10 seconds following intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 5min before the intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 2minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 4minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 6minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 8minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 10 minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 15minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 20 minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 25 minutes after intrathecal injection | 
| hemodynamic variables are assessed by noninvasive automatic blood pressure measurement and electrocardiogram monitoring |  | 30 minutes after intrathecal injection | 
| duration of motor block will be assessed by the modified Bromage score | duration of motor block was defined the time from intrathecal injection to Bromage score0 | every 5 minutes following intrathecal injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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midazolam, ketamine, intrathecal, pain