Ayesha Kazmi  ( Children Hospital and The Institute of Child Health, Multan, Pakistan. )
Ghulam Abbas  ( Government College University Faisalabad, Pakistan. )
Asim Khurshid  ( Children Hospital and The Institute of Child Health, Multan, Pakistan. )
Shahid Shah  ( Government College University Faisalabad, Pakisan. )
Tauqeer Hussain Mallhi  ( Department of Clinical Pharmacy, College of Pharmacy, Jouf University, Sakaka, Kingdom of Saudi Arabia )
Muhammad Hanif  ( Bahauddin Zakariya University, Multan, Pakistan. )
Uzma Saleem  ( Government College University Faisalabad, Pakistan. )
Abid Shah  ( Children Hospital and The Institute of Child Health, Multan, Pakistan. )
Nabeel Riaz  ( Government College University Faisalabad, Pakistan. )

Objective: To compare the efficacy of intravenous midazolam and diazepam in the management of status epilepticus seizures in children.

Method: The comparative study was conducted in the paediatric neurological emergency unit of The Children's Hospital and the Institute of Child Health, Multan, Pakistan, from December 15, 2018, to May 14, 2019, and comprised paediatric patients of status epilepticus seizures which were divided into Diazepam and Midazolam groups. Data was analysed using Graph-Pad Prism 5.

Results: Of the 164 patients, 82(50%) were in each of the two groups. There was no significant difference between the groups in terms of weight, age, residence area of patients and mean duration of seizures (p>0.05). Status epilepticus seizures subsided after intravenous midazolam administration in 77(93.90%) cases, while success in the diazepam group 64(78.05%) (p<0.05). Mean time taken by midazolam to halt seizures was significantly shorter than diazepam (p<0.05) and less cases of treatment failure were observed with intravenous midazolam (p<0.05). Somnolence was observed after diazepam administration in 47(57.3%) cases (p=0.0001).

Conclusion: Intravenous midazolam was found to be superior in efficacy than intravenous diazepam in controlling status epilepticus seizures.

Keywords: Diazepam, Midazolam, Status epilepticus, Seizures. (JPMA 71: 640; 2021)

DOI: https://doi.org/10.47391/JPMA.843

 

Introduction

 

The word epilepsy is derived from a Greek word meaning "to take court, to grab or to seize".¹ It is a chronic non-communicable disease that affects people of all ages, and seizures can be acute in nature.² Epilepsy may be generalised or focal. If electroencephalogram (EEG) abnormalities and seizures are generalised, it is generalised epilepsy. It may be partial, or focal, if EEG and clinical presentation suggest focal onset. But this classification is not always clear.³ Sudden excessive electrical discharge in brain cells cause seizure episodes.⁴ Depending on clinical presentation, guidelines of the International League against Epilepsy classify seizures as generalised convulsive or non-convulsive or as focal.^5,6 Generalised seizures occur if abnormal electrical activity affect both cerebral hemispheres.⁷ Generalised seizures affects most or all parts of brain. Generalised seizures are of many types, including atonic, tonic, clonic, absence, myoclonic and tonic-clonic. Most violent type of seizures are tonic-clonic because they commonly involve the whole body.⁸ Partial seizures affect a portion of one cerebral hemisphere of the brain.⁹ Status epilepticus is a central nervous system (CNS) emergency that comprises one or a series of seizures persisting for more than 30min without complete retrieval of consciousness.^10,11 If a seizure extends beyond 5min, it will often last at least 30min unless anticonvulsants are given. Patients who have seizures continuing for 5min or longer are expected to be in the initial stages of convulsive status epilepticus and must be treated rapidly.¹² Globally, every year about 2.4 million individuals are diagnosed with epilepsy.¹³ Worldwide, about 10.5 million children below 15 years have active epilepsy. It is about 25% of the worldwide epilepsy population. Every year about 3.5 million individuals are developing epilepsy. From these, more than 80% are living in developing countries and 40% are <15 years.³

Status epilepticus is a frequently encountered neurological disorder in the emergency of paediatric neurology department of hospitals. Intravenous (IV) anticonvulsant drugs are suitable in the initial stage treatment used for the management of this disorder.¹⁴ Immediate management of recurrent seizures follow the fundamental principles of emergency care that a drug should terminate the seizures safely and promptly. Ideally, the given drug should be safe and effective. It must be easy to administer and have a prolonged anti-seizure action.³ To control convulsive seizure quickly, the drug should reach the brain rapidly without serious untoward effects. IV injection of anticonvulsants might be the route of choice for this purpose.^15,16 Benzodiazepines are used as first-line treatment of recurrent seizures via IV or rectal route.^3,16

Midazolam is an effective water-soluble anticonvulsant drug which belongs to the benzodiazepine class.^17,18 It can be given through rectal, intramuscular (IM), IV and nasal routes of drug administration.¹⁹ Midazolam, like diazepam, is lipophilic in nature at physiological potential of hydrogen (pH) 2.8-3.6. Lipophilic nature aids in quick diffusion into the CNS.²⁰ On the other hand, diazepam can be administered rectally, orally, or via IM and IV.²¹ IV diazepam is used as the standard acute treatment for status epilepticus.^16,22 Accumulation of diazepam can cause prolonged sedation in newborn.²³ Both drugs produce anticonvulsant action by enhancing inhibitory activity of gamma-aminobutyric acid receptor.²⁰

The current study was planned to compare the efficacy of IV midazolam and diazepam.

 

Patients and Methods

 

1) The comparative study was conducted in the paediatric neurological emergency unit of The Children's Hospital (TCH) and the Institute Of Child Health (ICH), Multan, Pakistan, from December 15, 2018, to May 14, 2019. After approval from the ICH ethics review board, the sample size was determined using Open-Epi calculator.²⁴ The sample was raised using non-probability sampling technique, approaching all paediactirc patients with status epilepticus visiting the emergency department (ED). Those included were patients of either gender aged 1-14 years having status epilepticus of duration >5min. Those excluded were patients who had received prior anticonvulsant treatment other than benzodiazepine; patients on assisted ventilation; patients diagnosed with metabolic fits due to hypoglycaemia treated in emergency with glucose; chronic liver disease assessed through history and medical record; known patients of chronic renal disease; those with hypertensive encephalopathy detected on blood pressure reading done in ED; and those with history of head injury.

Data was collected after permission for the respective hospital managements and written informed consent from parents/guardians of the subjects enrolled. Baseline demographic characteristics, including age and gender as well as type and duration of seizure were noted.

The patients were randomly allocated using the lottery method into two equal groups A and B, with the former receiving IV diazepam 0.3mg/kg and the latter receiving IV midazolam 0.15mg/kg. All patients were monitored and timing of cessation of seizures was recorded. Treatment was considered successful if seizures stopped within 10 minutes of dose dispensensation. If seizures did not stop within 10 minutes, second-line drug was administered as per the institutional protocol.

Supportive treatment was provided according to the hospital emergency protocol. Emergency resuscitation equipment was available to manage any untoward reaction, like respiratory depression, hypotension and cardiac arrhythmia. Data was collected on pre-designed proforma.

Data was analyzed using Graph-Pad Prism version 5. Descriptive statistics were used for quantitative Variables, while frequencies and percentages were calculated for qualitative variables. Fisher's exact test was used to compare the efficacy of the two drugs. P<0.05 was taken as significant.

 

Results

 

Of the 164 patients, 82(50%) were in each of the two groups. Tonic-clonic seizure was the most common type 105(64%). There was no no significant differences in baseline characteristics (Table-1).

The seizures subsided after IV midazolam administration in 77(93.90%) cases, while success in the diazepam group was 64(78.05%) (p<0.05). In the diazepam group, 1(1.2%) patient expired due to respiratory depression Mean time from drug administration to stoppage of seizures was significantly lower for midazolam compared to diazepam group (p<0.05). Somnolence was observed after diazepam administration in 47(57.3%) cases (p=0.0001) (Table-2).

There was no significant difference in the vital signs between the groups (Table-3).

 

Discussion

 

The current study is novel in comparing intravenous benzodiazepines in children. Treatment with benzodiazepines have potential risks, like cardiovascular events and respiratory depression, as well as benefits, like prevention from life-threatening convulsive seizures.²⁵ Buccal and nasal spray of midazolam is safe and effective in seizure control, but these routes are not of choice. When patient is in a state of seizure, it is difficult to open the mouth of the patient or nasal congestion may render these routes ineffective.^16,26,27 Midazolam acts rapidly than diazepam.²⁸ Generally, IV diazepam is given for cessation of acute life-threatening seizures.²⁹ Convulsive status epilepticus seizures can be managed by rectal diazepam efficiently, but plasma concentration of rectally-administered diazepam varies and it also fails in controlling seizures in 30% patients.^30,31 Moreover, the rectal route is not convenient, and parents are reluctant to have medication administered by this route.¹²

The current study demonstrated that IV midazolam was more efficacious in controlling status epilepticus seizures. Mean time from IV injection to stoppage of seizures was shorter for midazolam group and there were fewer cases of treatment failure. The results are in line with previous findings, like studies in Western countries  have led to guidelines suggesting use of midazolam in cases of status epilepticus seizures.^32,33 An investigational study reported 85.7% efficacy of continuous midazolam comparable with diazepam infusion.³⁴ Midazolam may be a drug of choice in the management of refractory status epilepticus.³⁵ IV midazolam is quick in its action compared with IV diazepam. It took 2.58min to stop epileptic seizures while IV diazepam took 4min in the current study. Midazolam is very efficacious if administered shortly after the onset of seizures.¹⁴

The current study found that IV midazolam was less like to cause somnolence in children. Midazolam is safe to be administered to children. It caused no significant side effect; similar to observations in studies comparing IV diazepam versus buccal midazolam, rectal diazepam versus buccal midazolam, rectal diazepam verses buccal midazolam and buccal midazolam alone.^12,36-38 Studies in Japan have reported less incidences of cardiovascular events and respiratory depression with midazolam.¹⁴ One study reported 5% incidence of adverse effects due to midazolam which is almost similar to the finding of the current study.³⁹

The sample size of the current study is one of its limitations. Besides, the patients were monitored for 6h in ED which is not long enough to monitor adverse drug events and interactions effectively.

 

Conclusion

 

IV midazolam was more effective and safe in managing paediatric status epilepticus patients in ED than IV diazepam. It was quick in action and less likely to cause adverse reactions.

 

Disclaimer: None.

Conflict of Interest: None.

Source of Funding: None.

 

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