Intrathecal Neostigmine for Prevention of PDPH
Condition: Post-Dural Puncture Headache
MeSH terms: Post-Dural Puncture Headache; Headache
Study type: Interventional
Phase: Phase 4

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).
    

Intervention name(s): Neostigmine Methylsulfate; Dextrose 5% in water
Intervention type(s): Drug; Drug
Intervention description(s): 20 µg Neostigmine Methylsulfate intrathecal in 0.2 ml of Dextrose 5% solution; intrathecal
Other intervention name(s): Neostigmine (0.5 mg); Dextrose 5% in Water (D5W)
Intervention MeSH terms: Neostigmine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: postural headache; intrathecal neostigmine for prevention of PDPH