COMPARATIVE STUDY ON THE EFFICACY OF INTRANASAL MIDAZOLAM VERSUS INTRAVENOUS MIDAZOLAM AND INTRAVENOUS DIAZEPAM IN CONVULSING NEONATES AND CHILDREN
Richa Sharma, Rekha Harish
Department of Pediatrics, Government Medical College, Jammu, India.
Address for Correspondence
Dr Richa Sharma, Sai valley hospital, Sundernagar, Mandi (HP) 174402.
Email
richa32@yahoo.com
Abstract
Aim: To compare the clinical efficacy of two routes of midazolam intranasal vs. intravenous, in relation to intravenous diazepam for control of seizures.

Methods: A prospective randomized study conducted on 150 convulsing patients of 0-19 years of age hospitalized in pediatric emergency ward and neonatal intensive care unit (NICU). Group-I was given intranasal midazolam at 0.3 mg /kg, Group-II was given intravenous midazolam at 0.3mg/kg and Group-III was given intravenous diazepam at 0.3 mg /kg. Outcome was measured in terms of time taken from physician contact to drug administration and the time taken from drug administration to cessation of seizures.

Results: Mean time from physician contact to drug administration was significantly shorter with intranasal midazolam as compared to intravenous midazolam and intravenous diazepam (0.40±0.10min vs. 1.06±0.40 min and 1.06±40 min) (p-0.03). Mean time from drug administration to cessation of seizures was lesser in midazolam (1.6 ± 0.3mins(IN) and 1.6±0.3min(IV) as compared to diazepam (2.26±0.6 min) (p-0.06). However this difference was statistically insignificant. The vital parameters or oxygen saturation did not reveal any statistically significant difference between the three groups.

Conclusion: Seizure control was most prompt with intranasal midazolam.
Keywords
Midazolam, Diazepam, Intranasal, Intravenous, Seizures.
Introduction
Seizure is defined as paroxysmal change in motor activity and or behavior that results from abnormal electrical activity in the brain. (1) It constitutes about 70% of pediatric neurological disorders. It is a life threatening event and longer duration is associated with higher mortality and morbidity. Till date short acting anticonvulsants like benzodiazepines have mainly been used to control seizures. Benzodiazepines cross the blood brain barrier promptly achieve peak cerebrospinal (CSF) concentration within minutes of administration. Conventionally short acting benzodiazepines (Diazepam, Midazolam) are given by parental routes (IV or IM) for acute management of seizures. However intravenous (IV) line is often difficult to establish in a convulsing child and requires expertise. Intramuscular (IM) route cannot be relied upon as it has erratic absorption and delayed central nervous system (CNS) effects.(2) Thus various alternative routes of administration are under evaluation. Currently emphasis is being laid not only to control an acute episode in hospital setting but also for management of seizures at home. Various alternative routes of administration are intranasal, rectal, sublingual and buccal. Buccal and sublingual routes are difficult because of frothing and clenching associated with seizures. (3) Rectal route is socially less acceptable (especially in an adolescent. (4) Therefore intranasal (IN) route assumes more relevance as far as its convenience in drug administration is considered.

Midazolam is a water-soluble triazole- benzodiazepine. It has imidizole ring different from other benzodiazepines. At a pH less than 4 it is water soluble but at physiological pH it is highly lipophilic which accounts for its rapid absorption by rich vascular nasal mucosa reaching peak plasma and CSF concentrations within minutes of administration. It has shorter duration of action and rapid clearance twenty times faster than diazepam. (5) Thereby making it ideal for intranasal administration. We conducted this study to evaluate the efficacy of intranasal midazolam vs. intravenous midazolam and intravenous diazepam in convulsing neonates and children.
Methods & Materials
A prospective randomized study was conducted on 150 children over a period of one year in the Department of Pediatrics SMGS hospital Government Medical College, Jammu. One hundred and fifty patients between the age of 0-19 years hospitalized in pediatric emergency and neonatal intensive care unit (NICU) in a convulsing state were included in the study. The trial was permitted by the Ethical Committee of the institution. A written informed prior consent was taken from parents/guardians. Neonates were administered the drug only after excluding the metabolic causes. Neonates were given midazolam only as diazepam is known to interfere with bilirubin metabolism. Patients were randomized into three groups by serially numbered 150 opaque envelops. Treatment was then allocated by permuted block randomization to keep number equal in all the groups. The groups and drug administration are depicted below:

GROUP-I:- Administered commercially available preparation of midazolam @ 0.3 mg / kg as drops in each nostril through a syringe without needle .

GROUP II:- Administered commercially available preparation of midazolam @ 0.3 mg/kg through IV route by placing an IV cannula of appropriate size.

GROUP III:- Administered IV diazepam @ 0.3mg/kg.

After administering the drugs, vital parameters and oxygen saturation (saO2) was monitored for 30 minutes. Outcome was measured in terms of time consumed from physician contact to drug administration and from drug administration to cessation of seizures . The results were statistically analyzed using analysis of variance followed by post hoc comparisons by Bonferroni test. All analysis were performed using intention to treatment principle.
Results
All the three groups were comparable in terms of age, sex, prior history of seizure and intake of anticonvulsants (Table 1). Mean time from physician contact to drug administration was significantly shorter in Group-I (0.40±0.1 min) as compared to Group-II (1.06±0.40mins) and Group-III (1.06±0.40mins) (p=0.03). Time from drug administration to cessation of seizures was lesser in Group-I (1.6+ 0.3 mins) and Group-II (1.6±0.3mins) as compared to Group-III (2.26±0.3mins) (p-0.06). Effect of drugs on heart rate, respiratory rate, blood pressure and oxygen saturation is depicted in Table-2. Twelve (24%) had uncontrolled seizures and required another anticonvulsant to control seizures of which 3 (6%) are in group I, 4 (8%) in group II and 5 (10%) in group III.

Table 1: Baseline profile of patients in each group
Parameters Group I GP II Group III P value
Age
< 1 month
1month-1year
1-6 years
6-12 years
12-18 years

4 (8%)
12 (24%)
24 (48%)
8 (16%)
2 (4%)

3 (6%)
14 (28%)
22 (44%)
8 (16%)
3 (6%)

0
10 (20%)
24 (48%)
12 (24%)
4 (8%)
0.31
Gender
Male
Female
Prior seizure
Prior anticonvulsant usage

30 (60%)
20 (40%)
13 (26%)
12 (24%)

25 (50%)
25 (50%)
14 (28%)
14 (28%)

26 (52%)
24 (48%)
18 (36%)
16 (32%)

0.43

0.51
0.80
Type of seizure
GTC
Partial
Atonic
Multifocal

31 (62%)
11 (22%)
2 (4%)
6 (12%)

34 (68%)
12 (24%)
1 (2%)
3 (6%)

35 (70%)
10 (20%)
2 (4%)
3 (6%)


Table 2: Comparison of vital parameters in various groups.
Vital Parameters Group-I MEAN+SD Group-II MEAN+SD Group-III MEAN+SD p value
Hear rate/min 114 + 27.54 110 + 25.65 103 + 21.32 0.06
Respiratory rate/min 39.68 + 15.46 34.66 + 16.07 31.1 + 14.56 0.31
Blood pressure (mm Hg) 110/86 102/84 104/88 0.06
Oxygen saturation (%) 94.68 + 5.69 94.58 + 5.08 93.54 +4.20 0.06



Discussion
Intranasal administration of midazolam has been area of tremendous interest in recent years. The ability of rich vascular nasal mucosa to absorb drug readily reaching peak plasma and CSF concentrations within minutes of administration make it the prime route for fast and easy drug delivery. (6, 7) Our study included subjects from 0-18 years of age which is also similar to reported in other studies. (8) Majority of authors have studied children between 1-15 years of age excluding the neonatal period citing physiological differences and dissimilarity in seizure type. (9,10) Seizure control with midazolam has ranged from 75%-100% (11,12) which is similar to our study. In our study we observed that intranasal midazolam is a safe and effective anticonvulsant for acute management of seizures as time required from physician contact to drug administration was considerably shorter. Such situations where seconds matter, saving time can have significant impact on clinical outcome of a critically ill convulsing child and helps emergency physician to look into other aspects of critical care management. Reducing the duration of seizure also decreases the associated mortality and morbidity. Mean time from drug administration to cessation of seizures was similar in both the groups. The results obtained are in concordance with other studies. (13) No adverse cardio respiratory effect was noted. These observations were comparable to other studies. (14-16) Thus, we conclude that intranasal midazolam is a rapid, efficacious, socially more acceptable route of drug administration. It can be used not only in hospital setting but also for home management of seizures with proper education of the parents and caregivers.
References :
  1. Johnston MV. Seizures in childhood. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Text Book of Pediatrics. 18th edn. Thomsom Press. Pennsylvania. 2008: 2457-2475.
  2. Rey E, Delaunay L, Pons G, Murat I, Richard MO, Saint-Maurice C, Olive G. Pharmacokinetics of midazolam in children : comparative study of intranasal and intravenous administration . Eur J Clin Pharmacol. 1991 ; 41: 355-357  [Google Scholar]  [Pubmed]  [CrossRef]
  3. Scheepers M Scheepers B, Clarke M, Comish S, Ibitoye M. Is intranasal midazolam an effective rescue medication for adolescent with severe epilepsy? Seizure. 2000; 9: 417-422.  [Google Scholar]  [Pubmed]  [CrossRef]
  4. Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs. rectal diazepam in acute childhood seizures. Pediatr Neurol. 2006; 34: 355-359  [Google Scholar]  [Pubmed]  [CrossRef]
  5. Blumer JL. Clinical pharmacology of midazolam in infants and children. Clin Pharmacokinet 1998; 35: 37-47  [Google Scholar]  [Pubmed]  [CrossRef]
  6. Jawad S, Oxley J, Wilson J, Richens A. A pharmacodynamic evaluation of midazolam as anti-epileptic compound. J Neurol Neurosurg Psychiatry. 1986; 49: 1050-4.  [Google Scholar]  [Pubmed]
  7. Ever AS, Michel C, Balser JR. Benzodiazepines. In: Goodman and Gilman`s The Pharmacological Basis of Therapeutics, 11th edn. 2003:,403-411.
  8. Mittal P, Manohar R, Rawat AK, Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr. 2006 ; 73 : 75-78.  [Google Scholar]  [Pubmed]  [CrossRef]
  9. Lahat E, Goldman M, Barr J, Eshel G, Berkovitch M. Intranasal midazolam for childhood seizures. Lancet. 1998: 352: 620  [Google Scholar]  [Pubmed]  [CrossRef]
  10. Kutlu NO, Yakinci C, Dogrul M, Durmaz Y. Intranasal Midazolam for prolonged convulsive seizures in children. Brain Dev. 2000; 22: 359-361  [Google Scholar]  [Pubmed]
  11. Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children : prospective randomized study . BMJ. 2000; 321 : 83-86  [Google Scholar]  [Pubmed]  [CrossRef]
  12. McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children : a randomized controlled trial. Lancet 2005; 366 : 205-210  [Google Scholar]  [Pubmed]  [CrossRef]
  13. Holsti M, Sill B, Firth SD, Filloux FM, Joyce SM, Furnival RA. Prehospital intranasal midazolam for treating pediatric seizures. Pediatr Emerg Care. 2007; 23:148-53.  [Google Scholar]  [Pubmed]
  14. Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenschlager DW, Waisman Y. A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997; 13 : 92-94.  [Google Scholar]  [CrossRef]
  15. Fisgin T, Gürer Y, Senbil N, Teziç T, Zorlu P, Okuyaz C, Akgün D. Nasal midazolam effects on childhood acute seizures. J Child Neurol 2000;15 (12) 833-835.  [Google Scholar]  [Pubmed]  [CrossRef]
  16. Mahoudian T, Zadeh MM. Comparison of Intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav 2004; 5: 235-255.  [Google Scholar]
Last Updated : Wednesday, January 01, 2014 Vol 11 Issue 1 Art #13
DOI: 10.7199/ped.oncall.2014.13
How to Cite URL :
Sharma R, Harish R. COMPARATIVE STUDY ON THE EFFICACY OF INTRANASAL MIDAZOLAM VERSUS INTRAVENOUS MIDAZOLAM AND INTRAVENOUS DIAZEPAM IN CONVULSING NEONATES AND CHILDREN . Pediatric Oncall [serial online] 2014[cited 2014 January-March 1];11. Art #13. Available From : http://www.pediatriconcall.com/Journal/Article/FullText.aspx?artid=678&type=J&tid=&imgid=&reportid=404&tbltype=
Disclaimer: The information given by www.pediatriconcall.com is provided by medical and paramedical & Health providers voluntarily for display & is meant only for informational purpose. The site does not guarantee the accuracy or authenticity of the information. Use of any information is solely at the user's own risk. The appearance of advertisement or product information in the various section in the website does not constitute an endorsement or approval by Pediatric Oncall of the quality or value of the said product or of claims made by its manufacturer.