Valproic Acid in Treating Cyanotic Breath Holding Spells

The Effectiveness of Valproic Acid in Treating Frequent Cyanotic Breath Holding Spells

Breath holding spells (BHS) are common non-epileptic paroxysmal behavioral involuntary episodes occurring in up to 5.9% of healthy children. The attacks occur in early childhood (0.5-3 years) but are self-limited by school age (4-5 years old) (90%). Classically, BHS were classified as cyanotic (blue), pallid (pale) and mixed based on the color change of the child during the spell. In general, cyanotic spells have been classically described in a toddler with excessive temper tantrums [stubborn, easily frustration or annoyed. The mechanisms of BHS are controversial. The most suggested cause of BHS is instability of the autonomic nervous system, inhibition of respiratory effort and cyanosis in cyanotic BHS and bradycardia or a brief asystole and cerebral hypoperfusion in pallid BHS. Iron deficiency anemia (IDA) has been widely regarded as a risk factor for BHS in nearly 50% of children due to reduced brain oxygenation [4]. It is generally agreed that the long-term prognosis is considered good [1]. There is no definite therapy for BHS. In children with low frequency spells, parental reassurance are just enough; however, high frequency spells may result in anxiety to the parents or fear from sudden death of the child or development of mental subnormality. Treatment of iron has been reported to result in reduction of the frequency of spells or its stoppage. Some reported improvement of BHS with piracetam [a nootropic drug known to increase brain oxygenation]. We did not find systematized published reports evaluating the effectiveness of antiepileptic drugs (AEDs) in reduction of spells frequency of cyanotic BHS or their stoppage.

Study Overview

• Status: Completed
• Conditions: Breathhold
• Intervention / Treatment: Drug: Valproic Acid

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Assiut, Egypt, 71516
    • Assiut University Hospitals, Faculty of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

1. Children with high frequency spells (≥ 4/week) of CBHS.
2. Children with parents who were wishing to provide treatment to their children.
3. Failure of alternatives modalities of treatment (e.g. iron supplements, piracetam, non-specific vitamins, etc) (tried for ≥ 3 months) to reduce the frequency of spells or stop them.
4. Follow-up for 6 months after starting treatment with valproic acid.

Exclusion criteria:

1. Primary neurologic disease, history of epilepsy or febrile convulsions, abnormal neurological examination and abnormal EEG.
2. Primary cardiac disease or presence of long QT syndrome in the ECG.
3. Presence of a hematologic (other than IDA) or other medical disease, electrolyte disturbance, hypoglycemia, hypocalcemia, impaired kidney or liver function tests.
4. Those with a doubtful diagnosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
OTHER: cyanotic breath holding spells; drug, valproic acid: 5mg/kg/d for 6 months	Drug: Valproic Acid; Treatment of children with frequent cyanotic breath holding spells (at least 4 spells per week) with 5 mg/kg/day for 6 months.; Other Names: sodium valproate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
frequency of spells after starting treatment with valproic acid	The parents or legal guardians are the sources of information about the frequency of spells.	6 months

Collaborators and Investigators

• Sponsor: Assiut University

Publications and helpful links

General Publications

• Hamed SA, Elhadad AF, Farghaly HS. Evaluation of the effectiveness of valproic acid for treating cyanotic breath holding spells: A Pilot prospective study. Expert Rev Clin Pharmacol. 2020 Nov;13(11):1263-1270. doi: 10.1080/17512433.2020.1828059. Epub 2020 Nov 1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 30, 2017
• Primary Completion (ACTUAL): January 30, 2018
• Study Completion (ACTUAL): December 30, 2018

Study Registration Dates

• First Submitted: October 3, 2017
• First Submitted That Met QC Criteria: July 18, 2020
• First Posted (ACTUAL): July 23, 2020

Study Record Updates

• Last Update Posted (ACTUAL): July 23, 2020
• Last Update Submitted That Met QC Criteria: July 18, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: valproic acid; Breath holding spells; cyanosis
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: BHS-VPA-SH-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No