Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache

A Randomized Controlled Trial

Ahmed Abdelaal Ahmed Mahmoud, MD, FCAI; Amr Zaki Mansour, MD; Hany Mahmoud Yassin, MD; Hazem Abdelwahab Hussein, MD; Ahmed Moustafa Kamal, MD; Mohamed Elayashy, MD, FCAI; Mohamed Farid Elemady, MD; Hany W. Elkady, MD; Hatem Elmoutaz Mahmoud, MD; Barbara Cusack, LRCP&SI, MB MCh, NUI, MCAI; Hisham Hosny, MD; Mohamed Abdelhaq, MD

Disclosures

Anesth Analg. 2018;127(6):1434-1439.

Abstract and Introduction

Abstract

Background: Postdural puncture headache (PDPH) lacks a standard evidence-based treatment. A patient treated with neostigmine for severe PDPH prompted this study.

Methods: This randomized, controlled, double-blind study compared neostigmine and atropine (n = 41) versus a saline placebo (n = 44) for treating PDPH in addition to conservative management of 85 patients with hydration and analgesics. The primary outcome was a visual analog scale score of ≤3 at 6, 12, 24, 36, 48, and 72 hours after intervention. Secondary outcomes were the need for an epidural blood patch, neck stiffness, nausea, and vomiting. Patients received either neostigmine 20 μg/kg and atropine 10 μg/kg or an equal volume of saline.

Results: Visual analog scale scores were significantly better (P< .001) with neostigmine/atropine than with saline treatment at all time intervals after intervention. No patients in the neostigmine/atropine group needed epidural blood patch compared with 7 (15.9%) in the placebo group (P< .001). Patients required no >2 doses of neostigmine/atropine. There were no between-group differences in neck stiffness, nausea, or vomiting. Complications including abdominal cramps, muscle twitches, and urinary bladder hyperactivity occurred only in the neostigmine/atropine group (P< .001).

Conclusions: Neostigmine/atropine was effective in treating PDPH after only 2 doses. Neostigmine can pass the choroid plexus but not the blood–brain barrier. The central effects of both drugs influence both cerebrospinal fluid secretion and cerebral vascular tone, which are the primary pathophysiological changes in PDPH. The results are consistent with previous studies and clinical reports of neostigmine activity.

Introduction

Postdural puncture headache (PDPH) is a complication of spinal anesthesia or lumbar puncture and is an unpleasant experience for the patient as well as the anesthetist. It is thought to result from meningeal traction related to low cerebrospinal fluid (CSF) pressure or cerebral vasodilation as an indirect effect of decreased CSF pressure.^[1] We encountered a case of PDPH in a patient who had failed conservative management and was scheduled for an epidural blood patch (EBP) procedure. However, the EBP was cancelled following resolution of the PDPH within an hour of receiving neostigmine and atropine for the management of postoperative ileus.^[2] The dramatic response to neostigmine in the patient with PDPH and postoperative ileus are in line with the central effects of neostigmine, which can pass through the choroid plexus but not the blood–brain barrier, and atropine on CSF secretion and cerebral vascular tone that are the primary pathophysiological changes associated with PDPH.^[3–17] The clinical experience with neostigmine prompted this comparison of the efficacy of neostigmine and conservative management for the treatment of PDPH. The decision was supported by the well-known pharmacologic profile, safety, and ready availability of neostigmine.

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Abstract and Introduction
Methods
Results
Discussion
References
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Table 1. Demographic Characteristics and Headache Onset in Participants Treated With N or P
	N Group (n = 41)	P Group (n = 41)	Standardized Difference
Age (y)	30.22 ± 6.03	28.7 ± 6.15	0.25
Weight (kg)	80.63 ± 12.61	83.86 ± 14.95	−0.23
Height (m)	1.63 ± 0.07	1.64 ± 0.08	−0.13
Body mass index (kg/m²)	30.2 ± 5.34	31.33 ± 6.15	−0.2
Onset of headache (h)	23.24 ± 8.15	26.02 ± 12.85	−0.26

Values are mean ± SD. Unpaired Student t test was used to compare group means (all P > .05).
Abbreviations: n, number of patients; N, neostigmine/atropine; P, placebo.

Table 2. VAS Scores for PDPH in N and P Group Participants Before and at 6, 12, 24, 36, 48, and 72 h After Intervention
	N Group (n = 41)	P Group (n = 41)	Median Difference (95% CI)^a
Before intervention	8 (8–9)	9 (7–9)	0 (−1 to 1)
6 h after intervention	3 (2–4)	6 (4–7)	3 (2 to 4)
12 h after intervention	2 (1–3)	5 (4–6)	3 (2 to 3)
24 h after intervention	2 (0–3)	5 (4–6)	3 (2 to 4)
36 h after intervention	1 (0–2)	5 (4–6)	4 (3 to 4)
48 h after intervention	1 (0–2)	5 (4–6)	4 (3 to 4)
72 h after intervention	1 (0–2)	5 (4–6)	4 (3 to 4)

Values are median (interquartile range).
Abbreviations: CI, confidence interval; N, neostigmine/atropine; P, placebo; PDPH, postdural puncture headache; VAS, visual analog scale.
^aHodges–Lehmann estimate was used to derive median differences (95% CI) between the 2 groups.

Table 3. Secondary Outcomes of N and P Groups Treatment of PDPH
	N Group (n = 41)	P Group (n = 44)	P Value
Need for EBP, n (%)	0 (0)	7 (15.9)	.008
Neck stiffness (yes/no), n (%)
Before intervention	15 (36.6)	12 (27.3)
6 h after intervention	15 (36.6)	12 (27.3)
12 h after intervention	13 (31.7)	12 (27.3)
24 h after intervention	13 (31.7)	9 (20.5)
36 h after intervention	12 (29.3)	8 (18.2)
48 h after intervention	10 (24.4)	8 (18.2)
72 h after intervention	10 (24.4)	8 (18.2)	.48
Nausea and vomiting (yes/no), n (%)
Before intervention	7 (17.1)	11 (25)
6 h after intervention	6 (14.6)	8 (18.2)
12 h after intervention	5 (12.2)	5 (11.4)
24 h after intervention	5 (12.2)	4 (9.1)
36 h after intervention	4 (9.8)	4 (9.1)
48 h after intervention	4 (9.8)	4 (9.1)
72 h after intervention	4 (9.8)	4 (9.1)	.92

χ² Test was used to compare the 2 groups at 72 h.
Abbreviations: EBP, epidural blood patch; N group, neostigmine/atropine group; P group, placebo group; PDPH, postdural puncture headache.

Table 4. Neck Stiffness and Nausea and Vomiting in the N and P Groups 72 h After Treatment
	N Group (n = 41)	P Group (n = 44)	Odds Ratio (95% CI)	P Value
Neck stiffness (yes/no), n (%)
72 h after intervention	10 (24.4)	8 (18.2)	2.33 (0.33–16.18)	.391
Nausea and vomiting (yes/no), n (%)
72 h after intervention	4 (9.8)	4 (9.1)	1 (0.199–5.01)	>.99

P > .05, binary logistic regression with baseline covariate adjustment. Abbreviations: CI, confidence interval; N, neostigmine/atropine; P, placebo.

Table 5. Treatment-Associated Side Effects in the N and P Groups
	N Group (n = 41)	P Group (n = 44)
Diarrhea, n (%)	None	None
Abdominal cramps, n (%)	8 (19.5)	None^a
Muscle cramps, n (%)	2 (0.05)	None
Muscle twitches, n (%)	6 (14.6)	None^a
Bronchospasm, n (%)	None	None
Urinary bladder hyperactivity, n (%)	5 (12.2)	None^a

χ² or Fisher exact test was used.
Abbreviations: N, neostigmine/atropine; P, placebo.
^a P < .05.

Authors and Disclosures

Ahmed Abdelaal Ahmed Mahmoud, MD, FCAI*^†, Amr Zaki Mansour, MD^‡, Hany Mahmoud Yassin, MD^§, Hazem Abdelwahab Hussein, MD*, Ahmed Moustafa Kamal, MD^‡, Mohamed Elayashy, MD, FCAI^‡, Mohamed Farid Elemady, MD^‡, Hany W. Elkady, MD^‡, Hatem Elmoutaz Mahmoud, MD*, Barbara Cusack, LRCP&SI, MB MCh, NUI, MCAI^†, Hisham Hosny, MD^‡ and Mohamed Abdelhaq, MD^‡

*Faculty of Medicine, Department of Anesthesiology, Beni-Suef University, Beni Suef, Egypt; †Department of Anaesthesia, Tallaght University Hospital, Dublin, Ireland; ‡ Faculty of Medicine, Department of Anesthesiology, Cairo University, Giza, Egypt; and §Faculty of Medicine, Department of Anesthesiology, Fayoum University, Faiyum, Egypt.

Address correspondence to
Ahmed Abdelaal Ahmed Mahmoud, MD, FCAI, Department of Anaesthesia, Tallaght University Hospital, Tallaght, Dublin 24, D24 NR0A, Ireland. Address e-mail to carnitin7@yahoo.com.

The authors declare no conflicts of interest.

Disclosures
Name: Ahmed Abdelaal Ahmed Mahmoud, MD, FCAI.
Contribution: This author helped search the database, design the study, and write the primary and final manuscript.
Name: Amr Zaki Mansour, MD.
Contribution: This author helped invent the main idea of research.
Name: Hany Mahmoud Yassin, MD.
Contribution: This author helped in clinical cases and statistical analysis and search database.
Name: Hazem Abdelwahab Hussein, MD.
Contribution: This author helped in clinical cases, collect the data, and search the database.
Name: Ahmed Moustafa Kamal, MD.
Contribution: This author helped in clinical cases and collect the data.
Name: Mohamed Elayashy, MD, FCAI.
Contribution: This author helped in clinical cases, collect the data, and search database.
Name: Mohamed Farid Elemady, MD.
Contribution: This author helped in clinical cases and collect the data.
Name: Hany W. Elkady, MD.
Contribution: This author helped in clinical cases and collect the data.
Name: Hatem Elmoutaz Mahmoud, MD.
Contribution: This author helped in clinical cases and collect the data.
Name: Barbara Cusack, LRCP&SI, MB MCh, NUI, MCAI.
Contribution: This author helped search the database and revise the final manuscript.
Name: Hisham Hosny, MD.
Contribution: This author helped in statistical analysis and revise the final manuscript.
Name: Mohamed Abdelhaq, MD.
Contribution: This author helped in statistical analysis and revise the final manuscript.
This manuscript was handled by: Richard Brull, MD, FRCPC.