Clinical trial NCT03587441: Intrathecal Neostigmine for Prevention of PDPH
Official title: The Efficacy of Neostigmine as an Adjuvant to Bupivacaine for Intrathecal Block in Reducing the Incidence and Severity of Post-Dural Puncture Headache for Parturients Scheduled for Elective Caesarean Section
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Post-Dural Puncture Headache
Keywords: postural headache
intrathecal neostigmine for prevention of PDPH
Lead sponsor: Fayoum University Hospital
Sponsor class: OTHER
First posted: 2018-07-16
Enrollment: 240
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Neuraxial blocks continue to be the cornerstone of anesthesia and postoperative analgesia for normal vaginal delivery and elective caesarean section due to its approved safety and efficiency for decades. Post-dural puncture headache (PDPH) is still one of the most common complications of neuraxial anesthetic techniques. The headache could be severe and limit the activities of the new mother to care for her baby, prolong hospital stay.

PDPH is defined as a headache that develops within five days of dural puncture and can't be attributed to any other types of headache and mostly is postural in character.

Neostigmine methylsulfate is a synthetic carbamic acid ester which reversibly inhibits the enzyme Acetylcholine esterase (AChE) that makes more Acetylcholine molecules available at cholinergic receptors. Neostigmine is used in anesthesia mainly as a reversal for non-depolarizing neuromuscular agents.

Intrathecal (IT) neostigmine was tried as an adjuvant to local anesthetics in IT block for elective cesarean sections to decrease local anesthetic consumption and to prolong postoperative analgesia. Side effects of IT neostigmine are dose-dependent with doses more than 25 µg especially nausea and vomiting and could be decreased by increasing the baricities of the local anesthetic solutions and by early head up position after IT injection. However, its effect on PDPH was not investigated before in literature.

Parturients will be randomly assigned into one of two groups: the intervention group will receive 20 µg with IT Bupivacaine and the control group will receive an equivalent volume of dextrose 5% with the IT Bupivacaine.

The objective of the current study is to evaluate the efficacy and safety of IT neostigmine as an adjuvant to bupivacaine in reducing the incidence and severity of post-dural puncture headache in parturients scheduled for an elective cesarean section.

Detailed description: The study will be performed from July 2018 to July 2019 at Fayoum University hospital after approval of the local institutional ethics committee and local institutional review board. The study design will be prospective, randomized, double-blind, parallel groups, placebo-controlled clinical trial. A detailed informed consent will be signed by the eligible participants before recruitment and randomization.

Randomization will be done by using computer-generated random numbers that will be placed in separate opaque envelopes that will be opened by study investigators just before IT block. Neither the participants, the study investigators, the attending clinicians, nor the data collectors will be aware of groups' allocation until the study end. The Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting randomized, controlled clinical trials will be followed.

Preoperative preparations and Premedication:

The study solutions will be prepared in a one milliliter syringe as following: For the intervention group (N), it will contain 20 µg of Neostigmine® (0.5 mg/ml ampules manufactured by Amriya for pharmaceutical industries in Alexandria, Egypt) neostigmine ampule will be diluted in 4 ml dextrose 5% to make a solution of 100 µg/ml, 0.2 ml of this solution will be used, while in the control group an equal volume (0.2 ml) of dextrose 5% will be prepared. The syringes used will be labeled as A and B per their content. The identical coded syringe will be prepared by trained anesthesia technicians who will not be included in the study.

All parturients will receive 150 mg Ranitidine oral tablet on the night before and on the morning of the operation as a premedication.

Intraoperative technique and management:

Upon arrival to the operating room standard monitors (Pulse oximeter, Noninvasive blood pressure monitoring, and Electrocardiogram) will be applied and continued all over the operation, an eighteen gauge (18G) peripheral intravenous (IV) cannula will be inserted, and 10 ml/kg of Ringer lactate solution warmed to 37°C will be infused over 15 minutes as a preload.

IT block will be performed via a midline approach into the L4-5 interspaces in sitting position with complete aseptic condition using a 25 gauge Quincke spinal needle after giving 3 ml of lidocaine 2% (60 mg) as a subcutaneous infiltration. After confirming free cerebrospinal fluid (CSF) flow through the needle a 2.5 ml of hyperbaric bupivacaine 0.5 % in addition to the content of the prepared study syringe will be slowly injected. Then, the parturient will be immediately placed in the supine position with 15° left tilt, and an oxygen mask will be applied at 2 l/min.

After ensuring sufficient anesthesia level, the surgical procedure will start with continuous hemodynamics monitoring and recording. If the systolic blood pressure (SBP) decreased to 20% below the baseline or less than 90 mmHg, ephedrine 5 mg will be administered intravenously. Also, if heart rate (HR) will be less than 50 beats/min, atropine sulfate 0.5 mg will be administered intravenously. Any intraoperative or postoperative nausea or vomiting will be managed with 10 mg of metoclopramide Upon delivery of the fetus, ten units of oxytocin will be given by IV infusion, and if the uterus is not well contracted, additional increments of 5 units will be added accordingly. One gm of Ceftriaxone will be also given after delivery of the fetus by IV infusion.

Postoperative monitoring, Pain control and follow up:

At the end of surgery, Participant will be transferred to postoperative anesthesia care unit (PACU) with standard monitoring applied. All Participants will receive 75 mg diclofenac sodium intramuscular every 12 hours as a pain management per institution policy, 1,23 4 mg of morphine will be given IV if rescue analgesia is needed postoperatively every 10 minutes with a maximum of 20 mg in 6 hours or 32 mg in 24 hours. The participant will be transferred to obstetrics ward after fulfilling the criteria of modified Aldrete scoring system. 24 Assessment for post-dural puncture headache and other associated symptoms will be done from day 0 to day five postoperatively and if the participant will be discharged home, follow up will be done by a phone call. If there will be a complaint of a headache, the participant will be asked to come back to the hospital for proper assessment and management either on an outpatient or inpatient bases per the headache severity.

The participants who will be diagnosed to have PDPH per the criteria of the International Headache Society (HIS) will be treated by using oral medications Panadol extra™ (paracetamol 1gm + caffeine 130 mg) (Manufactured by: Alexandria company for pharmaceuticals \& chemical industries under license: GlaxoSmithKline Consumer Healthcare Ltd. Ireland) at 6-hour interval in addition to hydration and bed rest. Severe Intractable headache (VAS ≥ 40) persistent for more than 48 hours with no response to conservative measures will be managed with an epidural blood patch after participant approval and consent signing.

Statistical analysis and sample size estimation:

Continuous variables will be tested for normal distribution by the Shapiro-Wilk test (P ≤ 0.05). Parametric data will be expressed as mean and standard deviation (SD) and analyzed by using the independent t-test. Data with kurtosis or skewness will be depicted as median and interquartile range and compared for significant difference by implementation of Mann-Whitney U test. Categorical variables will be presented as numbers and frequencies and the chi-square test or Fisher exact test will be used to analyze the significant differences between the two arms. A P value ≤ 0.05 will be considered statistically significant. Data will be analyzed using SPSS (SPSS 16.0, SPSS Inc., Chicago, II, USA).

The sample size calculation based on that a 15 % reduction in the incidence of PDPH between the two arms could be of clinically important relevance. The reported incidence of PDPH with the use of 25 gauge Quincke needle is 25 %. Sample size of 100 participants per group were found sufficient assuming (two tail) α = 0.05, β = 0.2 (80 % power), and 1:1 allocation ratio. We will plan to recruit 120 participants per group to account for data loss or protocol violation. The sample size calculation performed with G\*Power software version 3.1.9.2 (Institute of Experimental Psychology, Heinrich Heine University, Dusseldorf, Germany).

Eligibility criteria: Inclusion Criteria:

* American society association (ASA) physical status II parturients who will be scheduled for an elective caesarean section by IT anesthesia

Exclusion Criteria:

* significant renal, hepatic, and cardiovascular diseases
* pre-eclampsia
* any contraindication to regional anesthesia such as local infection or bleeding disorders
* allergy to neostigmine
* long-term opioid use
* a history of chronic pain, migraine, cluster headache
* digestive problems with nausea or vomiting
* cognitive or memory disorders
* history of urinary retention; bronchial asthma
* perioperative blood transfusion

Primary outcomes:
measure: incidence of post-dural puncture headache
timeFrame: At day 5 from intrathecal block
Secondary outcomes:
measure: Visual analog score of post-dural puncture headache (PDPH) at presentation
timeFrame: At 24 hours after headache onset
measure: Visual analog score of post-dural puncture headache (PDPH) after medical treatment
timeFrame: At 48 hours after starting medical treatment
measure: highest Visual analog score of post-dural puncture headache
timeFrame: At 48 hours after starting medical treatment
measure: Percent of participants with neck stiffness
timeFrame: At 48 hours after headache onset
measure: Percent of participants in need for epidural blood patch
timeFrame: After 48 hours from onset of headache
measure: Percent of participants complained from intraoperative nausea and vomiting
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: Percent of participants complained from postoperative nausea and vomiting
timeFrame: AT 48 hours after PDPH
measure: incidence of urine retention
timeFrame: At 48 hours from intrathecal block
measure: incidence of memory and cognitive disorders
timeFrame: At 48 hours from intrathecal block
measure: incidence of hypotension
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: ephedrine requirements
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: incidence of desaturation
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: incidence of respiratory depression
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: incidence of bradycardia
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: atropine requirements
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: incidence of shivering
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: time to the first requirement of analgesic supplement
timeFrame: From intrathecal block until discharge from PACU, assessed up to 24 hours
measure: total analgesic consumption
timeFrame: At 24 hour after intrathecal block
measure: the assessment of duration of sensory blockade
timeFrame: From intrathecal block until the first appearance of pain at the T10 dermatome, assessed up to 24 hours
measure: the assessment of duration of motor blockade
timeFrame: From intrathecal block until the modified Bromage score will be zero, assessed up to 24 hours
measure: Age
timeFrame: 6 hours before intervention
measure: Weight
timeFrame: 6 hours before intervention
measure: Height
timeFrame: 6 hours before intervention
measure: Body mass index
timeFrame: 6 hours before intervention
measure: Headache onset
timeFrame: After intrathecal block for five days till appearance of PDPH
measure: Duration of surgical procedures
timeFrame: After completion of surgical procedures, within about two hours of intervention
Other outcomes:
Locations:
city: Madīnat al Fayyūm
country: Egypt
facility: Fayoum University hospital
state: Faiyum Governorate
Study officials:
affiliation: Faculty of medicine, Fayoum university
name: Hany M Yassin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808. doi: 10.1177/0333102413485658. No abstract available.
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citation: Cossu AP, De Giudici LM, Piras D, Mura P, Scanu M, Cossu M, Saba M, Finco G, Brazzi L. A systematic review of the effects of adding neostigmine to local anesthetics for neuraxial administration in obstetric anesthesia and analgesia. Int J Obstet Anesth. 2015 Aug;24(3):237-46. doi: 10.1016/j.ijoa.2015.05.002. Epub 2015 May 19.