Comparison of Intranasal Midazolam and Rectal Diazepam as Anticonvulsant in Children

Introduction: Rectal diazepam is reputed as the gold-standard management of childhood seizures. Otherwise, intranasal (IN) midazolam has no first-pass metabolism and faster onset of action. The effectiveness and easier route of these drugs are important choices for faster seizure cessation. The aim of this study was to clarify the effectiveness of intranasal midazolam compared with rectal diazepam for seizure termination. Material and Methods: The children, one month until 18 years of age, presented with acute seizures. Patients were randomly classified into two groups with either received intranasal midazolam or rectal diazepam for seizure termination. Interval time of drug administration to cease seizure was compared. The log-rank analysis was used for statistical analysis. Side effect of both drugs were evaluated. Results: There were 60 patients enrolled the study, 30 in each group. The median time interval for seizures cessation with intranasal midazolam was 42 seconds, otherwise in rectal diazepam group was 180 seconds. There was statistically significant difference interval time between two groups (p<0.01). None of the both groups had any significant side effects statistically. Conclusion: Intranasal midazolam is effective to terminate a seizure in children. It can be used as an alternative treatment for seizures in patients with intravenous or rectal route difficulties.


Introduction
S eizures are the well-known most common pediatric neurologic disorder, with 4% to 10% of children will experience minimum one seizure in the fi rst 16 years of life 1 .Most childhood convulsions are short dura on and resolve without treatment.Recommenda ons for early use of eff ec ve medica on that could reduce seizure dura on has been suppor ng to decrease morbidity and mortality 2 .Most pa ents with forcefull seizures will require pharmacologic medica on to terminate the symptoms.Benzodiazepines are the recommended chosen drugs for the acute management of seizures.Diazepam is a benzodiazepine that has short dura on of ac on and a rapid onset of ac on.Rectal diazepam is reputed as the goldstandard of prehospital medica on of acute childhood convulsions.
Because diazepam can accumulates in fat stores, repeated doses can precede to a prolonged stage of seda on.Hypotension and cardio-respiratory depression may also occur.Administra on of rectal diazepam might be embarrassing, and absorp on is variable.Rectal diazepam has some disadvantages, slow drug absorp on, dura on and rela vely short half-life, the drug o en comes out with feces 3,4 .The use of intravenous (IV) access is diffi cult, thus requiring more me 3,5,6 .
Midazolam is imidazobenzodiazepine with seda ve, muscle relaxant, anxioly c, amnesic, and an seizure proper es.It is more powerful than diazepam.It could be administered intramuscularly, intravenously, intranasally as well buccally.Intranasal Midazolam route can go through the blood-brain barrier and reach the central nervous system biophase quickly 7,8 .Wermeling found some of the advantages of IN; no fi rst-pass metabolism, more rapid absorp on, faster onset of ac on, good bioavailability 9 .It is short-ac ng, and at physiological pH is a highly soluble in fat so fast penetra on into the central nervous system, ioniza on stable 7,10,11 .Wermeling found that IN midazolam can be absorbed quickly, high bioavailability 12 .Haschke study of intravenous administra on of midazolam compared with intranasal showed good pharmacokine c, absorbed quickly, averaging 72-92% bioavailability with minimal side eff ects 10 .
The aim of this study was to fi nd out the effi cacy and safety of intranasal (IN) midazolam compared with rectal diazepam in pediatric acute onset seizure.

Material and Methods
A randomized controlled clinical design experiment was conducted from October 2012 to January 2013.The research was set at the Emergency department (ED) and paediatric inpa ent ward at Dr. Soetomo Hospital.
Children with acute all type of seizures admi ed to the emergency department and inpa ent pediatric ward with one month ll 16 years of age at Dr. Soetomo Hospital were enrolled in the study.The pa ents were excluded if they had respiratory depression, history of allergy to benzodiazepines, status epilep cus and history of acute diarrhea.If seizures did not cease for fi ve minutes a er IN midazolam or rectal diazepam administra on, it was categorized as treatment failure criteria.The parents obtained informed consent to follow the study.The randomiza on series list was produced using a computerized random number system.Par cipants were allocated to one of the two treatment groups using an equal alloca on ra o.The alloca on sequence was obscured from the inves gators enrolling the pa ents in sequen ally numbered and sealed envelopes.The envelopes were then opened a er the par cipants completed all baseline assessments, and that was me to allocate kind of interven on.The randomized codes were kept secure un l all data entry was complete.A er randomiza on, pa ents were randomly assigned to receive intranasal midazolam or rectal diazepam.The pa ents received IN midazolam at dose 0.2 mg/ kgBW into the anterior nares using a mucosal atomizer device (MAD).The Mucosal Atomiza on Device was an applicator placed on the syringe hub that distributed liquid for nasal administra on in a 30-μ par cle size, coa ng the mucosa.It would enhance rapid nasal absorp on, reach eff ec ve plasma and cerebrospinal fl uid concentra ons.The other interven on was rectal diazepam at doses of 0.5 mg/kgBW administrated into the restora on posi on, lying on their side and gently insert the nozzle of the applicator into the back then poin ng it downwards.
Time measurement was immediately performed by using a stopwatch (seconds) when an convulsants had been given un l the seizures ceased.The pa ents were observed for one hour a er seizures.The seizure was categorized by clinical observa on of the physician.The eff ec veness of the drug was defi ned by observa on of the cessa on of the convulsive ac vity within fi ve minutes.A history of previous convulsions and an epilep c medica on were obtained from family members.
All data were analyzed in a parametrical sta s c.Normality data was tested using Kolmogorov Smirnov test.Median me comparison of seizure cessa on between groups was analyzed using log-rank test.Sta s cal analysis was supported by SPSS 17 for Windows.A p value of <0.05 was considered sta s cally signifi cant.
The ethical clearance cer fi cate had been issued and tested by the Commi ee on Human Health Research and Ethics Dr. Soetomo Hospital.

Results
There were 64 subjects appropriate with the study criteria.Four subjects were excluded because of status epilep cus and diarrhea.The baseline characteris cs of the subjects before receiving treatment such as variables of age, sex, nutri onal status, history of previous seizures, type of seizures were presented in Table 1.The youngest age was two months, and the oldest was 13 years.The baseline characteris cs are homogeneous between the two groups.
Ten subjects had me to seizure cessa on more than fi ve minutes, and then they received other an convulsants and me to seizure cessa on was counted as a sensor that was 300 seconds.Median of me to seizure cessa on for IN midazolam group was 42 (12.29 -54.88) seconds and for rectal diazepam group was 180 (72.8 -287.1)seconds with signifi cance p <0.001.There was sta s cally signifi cant diff erence me to seizure cessa on between two groups.IN midazolam had a shorter me to stop seizures than rectal diazepam.This study also evaluated the tolerability of IN midazolam, and rectal diazepam administra on observed within 24 hours a er ini a on.It was observed no signifi cant diff erence in side eff ects incidence and complica ons between two groups.Hypoxia occurred in one subject who received IN midazolam, and in two subjects who received rectal diazepam, and they had an improvement in oxygen delivery.

Discussion
During acute convulsions, the purpose is the immediate termina on of the convulsion without physical harming the pa ent.The proven fi rst choice of drug to be administra on is benzodiazepine intravenously.It is diffi cult to establish intravenous access during the seizure, so noninvasive methods like rectal diazepam are preferred 13 .Some author observed that the parents did not prefer rectal administra on 3 .There are physical and social constraints to the use of the rectal route.Rectal diazepam works slower in the onset of ac on and other disadvantages include the lower social acceptability.When all of these are considered, nasal administra on is a simple way without any complica on, and the nasopharyngeal mucosa surface is moderately large and well vascularized, tolera ng for a rapid absorp on of midazolam 14 .It is easier to use midazolam in the nasal drop and spray forms, but these are not available in our country.The only commercially available, undiluted parenteral fl uid containing 5 mg/ml midazolam in Indonesia has been used for this study.This intravenous midazolam formed was administered for a nasal route for acute childhood seizures.
The recent study proved that there was a signifi cant diff erence in seizure cessa on me between IN   administra on to a cessa on of seizure was signifi cantly less in the midazolam group than the diazepam group 16 .Lahat et al., tried to randomize 52 children with prolonged seizure to receive intravenous diazepam or intranasal midazolam.Good control was achieved equally in both groups, but the mean me from pa ent arrival to seizure termina on was signifi cantly shorter in the pa ents receiving midazolam.The authors assumed the more rapid eff ect in the nasal group was determinable to the me saved by excluding the need to insert an intravenous line 17 .
Intranasal midazolam was also found to be a good op on for home administra on by parents.Wilson et al., stated that 33 of 40 parents ques oned reported intranasal midazolam to be eff ec ve, and 83% preferred it to rectal diazepam 18 .
The nasal mucosa provides a large, highly vascular absorp ve surface adjacent to the brain.Together with neighboring olfactory mucosa, it off ers a direct pathway for drug absorp on into the bloodstream and cerebrospinal fl uid.At physiological PH, the ring formed by the molecule closes, making it highly lipophilic.Then, as a result, it overpasses the blood-brain barrier and fl ows into the central nervous system.Therefore, the nasal route is a good possibility for medica on that undergo massive fi rst-pass hepa c metabolism, and drugs with erra c absorp on pa ern 19 .When intranasal midazolam is administered, it is available in the cerebral cortex in 2 to 5 minutes, and beta ac vity increases in the electroencephalogram (EEG).It takes a maximum of eight minutes to achieve a posi ve response 20 .
The dose of intranasal midazolam for termina ng seizure is based on body weight.According to Knoester et al., the dose recommended is 0.2 mg/kg for children 14 .This study used the similar dose appropriate for those previous study.When engaging the intranasal route for benzodiazepines, it is essen al that the drug be highly intensifi ed and that it be distributed directly to the surface of the mucosa.Too abundant an amount or over rapid administra on may result in subop mal absorp on and loss of drug into the pharynx, rendering it ineff ec ve 19 .
The intranasal route appears to be equally safe to intravenous and intramuscular routes, which have not been observed to be associated with respiratory changes.Tolerability that was assessed in this study is the appearance of the side eff ects of the administra on of benzodiazepines.There were three subjects who suff er from hypoxia with oxygen satura on was below 80%.Moreover, there was a subject with pneumonia whose satura on was 70%.In this case, probably hypoxia was not caused by medica on given but from the underlying disease of the subject.Two other subjects with a diagnosis of cerebral abscess, oxygen satura on improved a er the therapy was given, in this situa on hypoxia, appeared due to benzodiazepine administra on, which was immediately improved a er administra on of oxygen.There were no subjects who experienced any side eff ects such as respiratory depression, hypotension, cough and allergic reac ons.Lahat et al., administered intranasal midazolam to 20 children aged six months to fi ve years with acute seizures.In 19 children, control was accomplished within 3.5 minutes of drug distribu on, and none of the children had clinical symptoms of respiratory distress or bradycardia 21 .These fi ndings have important implica ons, as the specifi c emergency treatment used may be part of the many issues responsible for respiratory depression 19 .In spite of the existence of an upper respiratory tract infec on might help drug absorp on by enhancing blood fl ow to the nasal mucosa, nasal secre ons can dilute the midazolam solu on and interfere with its contact with the absorbing surface.Lahat et al., reported most of the 21 children followed the instruc on had an upper respiratory tract infec on; otherwise only three children revealed ineff ec ve absorp on of midazolam and subsequent poor seizure termina on 17 .Lugo et al., reported pain and irrita on during nasal administra on 22 .However, we did not observe that kind of side eff ects.
This study limits to small sample size due to diffi cul es of fi nding seizing children in emergency room and pediatric ward.Although there was seizing child, the evident just only took a few seconds and ended itself.The seizure type was also unclassifi ed because of a technical problem of tes fying the incident.

Conclusion
In conclusion, IN midazolam was found to be more eff ec ve than rectal diazepam to terminate acute seizures in children.Its an convulsant route eff ect is reasonably safe and easy to be administered.This study is indica ng that intranasal midazolam may be used not only in medical centers but also in general prac oner's offi ce as well as at home by parents and families of seizure-prone children, a er appropriate instruc on.Future studies with electroencephalographic recording are recommended to ensure the effi cacy of intranasal midazolam as an alterna ve route in the treatment of pediatric seizures.

Table 2 :
15me to seizure cessa on IN midazolam group was smaller than the control group.IN midazolam tends to work faster than rectal diazepam to stop seizures.Midazolam and diazepam are both benzodiazepines group with a similar onset of ac on, but the determina on of the pathways will aff ect the bioavailability of midazolam through the drug provision10.Study from Fisgin et al reported that intranasal midazolam is easy and eff ec ve for acute childhood seizures.The study used 16 children at the age of two months to 14 years with a diagnosis of acute seizures.The seizures of three pa ents terminated within one minute, of seven pa ents in one to two minutes and three pa ents in two to fi ve minutes.However, three pa ents did not respond to treatment15.Another research by Bha acharyya reported the effi cacy of intranasal midazolam compared to rectal diazepam.The study used 188 seizure episodes in 46 children, three months to 12 years of age, which randomly assigned.Mean me from arrival of a medical prac oner to drug administra on was 68.3 ± 55.12 seconds in diazepam group and 50.6 ± 14.1 in seconds in the midazolam group.Mean me from drug the