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Original Article

Comparative Study of Intranasal Midazolam and intravenous Diazepam Sedation for Procedures and Seizures

Panka j M i t t a l , R a m M a n o h a r a n d A . K . Rawat

Deparlment of Pediatrics, S.S. Medical College and G.M. Hospital, Rewa (M.P.)

ABSTRACT

Oblet;tive. 1 o evaiuate the salety and efficacy of intranasal midazolam for seizures and various procedures.

Methods. Prospective randomized study. Total 125 children of all ages of either sex, for seizure episode (n-76) and various invasive and non-invasive procedures (n-49) received either intranasal midazolam (0.2 mg/Kg) or intravenous diazepam (0.3 mg/Kg)

Results. Mean time from arrival at hospital to starting treatment was significantly shorter in midazolam group compared to diazepam group [2.34+0.90; minute vs 4.61_+1.08 minute p<0.001]. Mean time to control seizures after arrival in hospital was significantly shorter in midazolam group compared to diazepam group [5.25+0.86 minute vs 6.51+1.06 minute p< 0.001].

Conclusion. Midazolam by the intranasal route provides safe and equally effective non-invasive method of sedation for procedures and seizures. [Indian J Pediatr 2006; 73 (11) : 975-978] E-mai l - drakrawat01 @rediffmafl.com

Key words : Intravenous diazepam; Intranasal midazolam; Procedures, Seizures.

1 he sedation modalities for procedures and seizures in children have advacned substantially in the past 15 years. Procedural sedation is a technique of administering a .~edative or dissociative agent, with or without analgesic to induce a state that al low the pat ient to to lera te unp leasan t p rocedu re s with main ta ined a i rway independently and continuously? Benzodiazepines are commonly used drug for sedation and can be given by various routes like intravenous, intranasal, per-rectal and sublingual route. Disadvantage of these routes includes: training and painful administration (l.M. and l.V.), slow and variable absorption (oral and per-rectal), and delayed recovery (oral route). Drugs sprayed/inst i l led into the oIfactory mucosa are rapidly absorbed by the (a) olfactory neurons (b) supporting cells and surrounding capillary bed into cerebrospinal fluid and reach the systemic circulation z3. Midazolam has been used by the intranasal route for echocardiography in outpatient setting 4 and as an effective premedication in young children undergoing short surgical p rocedures . The present s tudy was

Correspondence and Reprint requests : Dr. A.K. Rawat, D-2 , Doctor's Colony, Rewa (M.P.) 486001. Fax No. 07662- 251167; Phone No. 07662 -256785.

undertaken to assess the efficacy and safety of intranasal midazolam as a sedative in pediatric procedures and seizures.

MATERIALS AND METHODS

Study design is p rospec t ive hospi ta l based and randomized, conducted from July 2003 to August 2004 in pedia t r ic d e p a r t m e n t of S.S. Medical College and Associated Gandhi Memorial Hospital, Rewa (M.P.). Prior to procedure, written consent from parents was obtained and they were encouraged to stay with the child during the procedure. The inclusion criteria were children of all ages and both sexes brought during seizure episodes or required therapeut ic and diagnost ic procedures . Commerc ia l ly available in t ravenous prepara t ion of midazolam was administered in dose of 0.2 m g /Kg as drops, half in each nostril by one or two ml syringe from which needle had been removed . Diazepam was administered after inserting an appropriate size of IV cannula in the dose of 0.3 mg/Kg after dilution. Sedation level was noted before and ten minutes after giving drugs, by the scale described by Wilton NCT, Leigh Rozen and Pandi t U. -~ H ea r t rate, r e sp i r a to ry rate and oxygen

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Pankaj Mittal et al

saturat ion were noted before and ten minutes after giving drugs. Major negat ive behaviors du r ing procedures were eva lua t ed by a m o d i f i e d o b s e r v a t i o n b e h a v i o u r ra t ing scale. Lignocaine (2%) after sensitivity test ing was used as a local a n a e s t h e t i c for i nvas ive p r o c e d u r e s . D u r a t i o n from arr ival of pa t i en t in hosp i ta l to s t a r t ing t r ea tmen t and cessation of seizure were recorded. All pat ients were m o n i t o r e d u n t i l s co re one or t w o of s e d a t i o n . Resuscitat ion kit (Ambu bag, l a ryngoscope endotracheal tube, suc t ion ca the te r , o x y g e n sou rce and e m e r g e n c y d r u g s ) w e r e k e p t r e a d y . The d a t a g e n e r a t e d w a s tabulated and statist ically analyzed, us ing s tudent ' t ' test for con t inuous da ta and Ch i - square test for categorical data.

RESULTS

Total 125 chi ldren were enrol led for se izure episodes (n- 76) and for var ious invasive and noninvas ive procedures (n-49). The d i f f e r e n c e in m e a n a g e of c h i l d r e n in p r o c e d u r e s and se i zu re s was f o u n d to be s t a t i s t i ca l ly insignificant (p>0.05) be tween midazo l am and d iazepam

g r o u p s . Younges t p a t i e n t in w h o m a p r o c e d u r e was pe r fo rmed was 11-day-old and who had seizures was 6- day-o ld . There was a male p r e ponde ra nc e of pa t ien ts in bo th p r o c e d u r e s (65.3%) and se i zu res (63.2%). M e a n we igh t of chi ldren requi r ing sedat ion for p rocedure and s e i z u r e s for m i d a z o l a m a n d d i a z e p a m g r o u p w a s comparable . M i n i m u m weigh t was 2.5 Kg in p rocedure s and 2 Kg. in seizures g roup of patients. Max imum weight of 30 Kg was recorded for bo th p r o c e d u r e and seizure . T w e n t y f ive p e r c e n t of p a t i e n t s (19 o u t of 76) w e r e afebri le dur ing seizure episode. M a x i m u m t e m p e r a t u r e r e c o r d e d w a s 40.5~ M e a n t e m p e r a t u r e of f e b r i l e pat ients was comparab le in two groups.

Difference in score of sedat ion before and after g iv ing d r u g b e t w e e n IV-D a n d I N - M w a s f o u n d to be insignif icant (%2 = 0.15 and X2 = 5.63; p> 0.05) (Table 1). T h e r e w a s no s i g n i f i c a n t d i f f e r e n c e o b s e r v e d in cry, phys ica l restraint and moto r score be tween IN-M and IV- D du r ing invasive procedures . (X2 = 0.01, X2 = 0.01, X2 = 0.79 p>0.05). S i m i l a r l y in the n o n - i n v a s i v e p r o c e d u r e g r o u p no s igni f icant d i f fe rence was o b s e r v e d b e t w e e n two drugs for cry, physical restraint and motor score. (%2 =0.02, X2 = 0.03, X2 = 0.03; p>0.05) (Table 2).

A l though in the in t ranasal m i d a z o l a m group, t ime to

TABLE 1. Score of Sedation Before and After Giving the Drugs in Procedures

Score of Sedation IN-Midazolam (n-27) W-Diazepam (n-22) Before Drug After Drug Before Drug After Drug

I (Agitated) 15 (55.55%) 0 11 (50.0%) 0 P>0.05 II (Alert) 12 (44.45%) 2 (7.41%) 11 (50%) 0 P>0.05 III (Calm) 0 4 (14.81%) 0 2 (9.1%) P>0.05 IV (Drowsy) 0 21 (77.78%) 0 17 (77.27%) P>0.05 V (Asleep) 0 0 0 3 (13.63%) P>0.05

�9 Sedation Score before giving intranasal Midazolam and intravenous Diazepam Z2 = 0.15 p>0.05 �9 Sedation Score after giving intranasal Midazolam and intravenous Diazepam Z 2 = 5.63 p>0.05

"[ABLE 2. Behaviour During lnvasive and Non-invasive Procedures According to Drug Used

Score Invasive (n-25) Non-Invasive (n-24)

Midazolam ( n - 1 4 ) Diazepam (n-11) Midazolam (n-13) Diazepam (n-11)

Cry Score I (Whimper) 10 (71.4%) 8 (72.7%) 12 (92.3%) 10 (90.9%) II (Cry) 4 (28.6%) 3 (27.3%) 1 (7.7%) 1 (9.1%) III (Scream) 0 0 0 0

X2=0.01 * X2---0.02 *

P>0.05 P>0.05 Physical Restraint I (Minimal) 9 (64.3%) 7 (63.6%) 11 (84.6%) 9 (81.8%)

lI (Moderate) 5 (35.7%) 4 (36.4%) 2 (15.4%) 2 (18.2%)

Motor Score

llI (Maximal) 0 0 0 0

*P> 0.05 Insignificant

Z2 = 0.01" Z2 = 0.03* P>0.05 P>0.05

I (Squirmish) 8 (57.1%) 5 (45.4%) 11 (84.6%) 9 (81.8%) II (Kicking) 5 (35.7%) 4 (36.4%) 2 (15.4%) 2 (18.2%) 1II (Flail) 1 (7.2%) 2 (18.2%) 0 0

Z2 = U.79" I'>0.05 Z2 = 0.03* P>0.05

There is no significant difference observed in the behaivor score between IN-M and IV-D during invasive and non-invasive procedures

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"I'Ai~L.L: 3.

Comparative Study of Intranasal Midazolam and Intravenous Diazepam Sedation

Duration of time intervals (in minutes) for giving drugs, seizure control, and response to treatment in study groups (values are Mean+S.D. and 95% confidence interval)

IN-Midazolam IV-Diazepam

m

Time to giving drug after arrival in hospital 2.34• (4.26 to 4.96)

Time to cessation of seizures after giving drug 2.97• (1.77 to 2.07)

[ime to cessation of seizures after arrival in hospital 5.25• (6.16 to 6.86)

P<O.O01 Highly Significant for all groups

4.61+1.08 (2.06 to 2.62)

1.92_+0.45 (2.81 to 3.13)

6.5I_+1.06 (4.98 to 5.52)

cessation of seizures after giving drug was longer in c o m p a r i s o n to i n t r a v e n o u s d i a z e p a m (2.97+_0.53 vs 1.92+_0.45 minute) the time to cessation of seizures after arrival in hospital was significantly shorter with IN-M than IV-D (5.25+_0.86 vs 6.51+_0.5 minute) ; because adminis t ra t ion of d rug was sooner in the midazo lam group than the d iazepam group (2.34+_0.90 vs 4.61+1.08 minute); (p< 0.001; Highly significant in all the groups). (Table 3). No significant difference was observed in heart rate, respiratory rate and oxygen saturation before and ten minutes after administration of both drugs for procedures and seizures.

DISCUSSION

Midazolam is a newer water soluble Benzodiazepine absorbed via the intranasal route, which provides an easy and painless method of sedation. Intravenous diazepam (IV-D) is the most frequently used method of sedation but administration is painful, takes time and requires more material and training. The objective of this study was to compare the efficacy and safety of intranasal midazolam (IN-M) with intravenous d iazepam (IV-D) for var ious pediatric procedures and seizures.

Out of 125 children of all ages and either sex, attending ou tdoor or indoor pedia t r ic emergency depa r tmen t , various procedures were performed in 49 children and 76 children required treatment for seizures. There was no statistically significant difference in the duration of non- invasive and invasive procedures between IN-M and IV- D groups. In the present study fever was not an inclusion or exclusion criteria for selection of patients. Lahet E et aP con lpared IN-M with IV-D for t rea t ing only febri le seizures in children.

The assessment of sedation was per formed after 10 minute of drug instillation. This interval was also chosen by Wilton NCT et aY and Slover R et a l l In the present study in the midazolam group (n-27), 55.55% of children were agi tated (Score-I) and 44.45% were alert before giving drug. Most of the children (n-21; 77.78%) became drowsy after giving IN-M (Score-IV). The findings of this study are consistent with that of Wilton NCT et al 5, who found mos t pa t i en t s becom e ei ther calm or d r o w s y

(sedation scale III or IV). Slover R et al;also found that major i ty of pa t ien ts (80%) were in the calm a n d / o r d r o w s y ca tegory . There is no s ignif icant d i f ference observed in the cry, physical restraint and motor score between IN-M and IV-D during invasive procedures. (X2 =0.01, Z2=0.01, Z2=0.79 p>0.05). Similarly in non-invasive procedures no significant differences were observed between the two drugs for cry, physical restraint and motor score. (Z2=0.02, Z2=0.03, Z2=0.03; p>0.05) (Table 2). M. Fishben et al 8 evaluated IN-M in children undergoing esophagogastrodudenoscopy and noted fewer incidence of c ry ing and sc r eaming and o ther major nega t ive behav io r d u r i n g separa t ion f rom pa ren t s af ter adminis t ra t ion of the drug. Major negat ive behav ior scores were the highest for tile invasive procedures. The present study shows no differencc in the efficacy of these drugs (IN-M and IV-D) during procedures.

In the use of IN-M control of seizures after arrival of pa t ients in hospi ta l was ach ieved sooner than with diazepam given intravenously. Mean time to control the seizure by intravenous diazepam, after arrival in hospital was maximum in the age group 0-1 year and minimum in the age group > 6 year. This difference is due to difficulty in establishing intravenous access in younger age groups as evident from the mean time to giving drug after arrival in hospital being more in younger than older age groups of children.

In the p r e sen t s t udy there were no s ignif icant differences observed in heart rate, respiratory rate and oxygen saturation before and after giving IN-M or IV-D in 9rocedures and seizures.

K e y M e s s a g e : MidazoIam by intranasaI route provides a rapid, safe and effective non- invas ive method of sedation for procedures and for treating seizures.

A c k n o w l e d g e m e n t s

The authors sincerely acknowledge Dr. C.B. Shukla, Superintendent of G.M. Hospital and Dr. P.K. Baijal Dean, S.S. Medical College, Rewa for their kind permission and support to carry out this study in G.M: ttospita] and S.S. Medical College, Rewa (M.P.)

REFERENCES

1. Krauss Baruch, Steven M Green. Sedation and analgesia for

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procedures in childreq Nea~ England ] Med 2000; 342 (13): 938- 945. Gopinath PG, Gopinath G, Kumar TCA. Target site of intranasally sprayed substances and their transport across the nasal mucosa: a new insight into the intranasaI route of drug- delivery. Curr Ther Res 1978; 23 : 596-607. Kida S, Pantazis A, Weller R.O. CSF Drains Directly from the Subarachnoid Space into Nasal Lymphatics in the Rat- Anatomy, Histology and Immunological Significance. J .\'europathology and Applied Neurobioh~gy 1993; 19: 480-488. l,atson Larry A, Chaetham Jp, Gumbiner CH, Kingler JD, Danford I)A, t lofschire PJ. Midazolam Nose Drops for Outpatients Echocardiographic Sedation in Infants. Am Heart ! 1991; 121: 209.

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5. Wilton NCT, I..eigh J, Rosen DR, Pandit U. I 'reanesthetic sedation of preschogl children using intranasal midazolam. Anesthesiology 1988; 69: 972-975.

0. Lahet Eli, Micheal G, Joseph B, Tzvi B, Mati thyahu B. Comparison of intranasal Midazolam with intravenous Diazepam for treating febrile seizures in children-prospective randomized study. British Med J 2000; 321 : 83-86.

7. Slover R, Schlesinger T. Use of intranasal midazolam in preschool children. Anaseth Analg 1990; 70 : 51-54.

8. Fishbein Mark, Lugo Ralph A woodland Jennifer, Lininger Barbara and l,inscheid Tom. Evaluation of intranasal midazolam in children undergoing esophagogastro- duodenoscopy. J Pediatr Gastroenterol Nutr 1997; 23(3): 261-266.

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