25
`
`Original Article
`
`Comparative Study of Intranasal Midazolam and
`Intravenous Diazepam Sedation for Procedures and
`Seizures
`
`Pankaj Mittal, Ram Manohar and A.K. Rawat
`
`DepartmentofPediatrics, S.S. Medical College and G.M. Hospital, Rewa (M.P)
`
`ABSTRACT
`
`Objective. To evaluate the safety 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 [2.3440.90; 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 andseizures. [Indian J Pediatr 2006; 73 (11) : 975-978] E-mail - drakrawat01@rediffmail.com
`
`Key words: Intravenous diazepam; Intranasal midazolam; Procedures, Seizures.
`
`The sedation modalities for procedures and seizures in
`children have advacned substantially in the past 15 years.
`Procedural sedation is a technique of administering a
`sedative or dissociative agent, with or without analgesic
`to induce a state that allow the patient to tolerate
`unpleasant procedures with maintained airway
`independently and continuously.'! Benzodiazepines are
`commonly used drug for sedation and can be given by
`various routeslike intravenous, intranasal, per-rectal and
`sublingual route. Disadvantage of these routes includes:
`training and painful administration (I.M. and LV.), slow
`and variable absorption (oral and per-rectai), and delayed
`recovery (oral route). Drugs sprayed/instilled into the
`olfactory mucosaare rapidly absorbed bythe (a) olfactory
`neurons (b) supporting cells and surroundingcapillary
`bed into cerebrospinal fluid and reach the systemic
`circulation’’, Midazolam has been used by the intranasal
`route for echocardiography in outpatient setting’ and as
`an effective premedication in young children undergoing
`short surgical procedures. The present study 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.
`
`Indian Journal of Pediatrics, Volume 73—-November, 2006
`
`undertaken to assess the efficacy and safety of intranasal
`midazolam as a sedative in pediatric procedures and
`seizures.
`
`MATERIALS AND METHODS
`
`Study design is prospective hospital based and
`randomized, conducted from July 2003 to August 2004 in
`pediatric department 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 encouragedto stay with the child
`during the procedure. The inclusion criteria were children
`of all ages and both sexes brought during seizure episodes
`or required therapeutic and diagnostic procedures.
`Commercially available intravenous preparation of
`midazolam was administered in dose of 0.2 mg/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/Kgafter dilution. Sedation
`level was noted before and ten minutes after giving drugs,
`by the scale described by Wilton NCT, Leigh Rozen and
`Pandit U.5 Heart rate, respiratory rate and oxygen
`
`975
`
`AQUESTIVE EXHIBIT 1137 Page 0001
`AQUESTIVE EXHIBIT 1137 Page 0001
`
`

`

`Pankaj Mittal et a/
`
`26
`
`saturation were noted before and ten minutesafter giving
`drugs. Major negative behaviors during procedures were
`evaluated by a modified observation behaviourrating
`scale. Lignocaine (2%) after sensitivity testing was used as
`a local anaesthetic for invasive procedures. Duration
`from arrival of patient in hospital to starting treatment
`and cessation of seizure were recorded. All patients were
`monitored until score one or
`two of sedation.
`Resuscitation kit (Ambu bag, laryngoscope endotracheal
`tube, suction catheter, oxygen source and emergency
`drugs) were kept ready. The data generated was
`tabulated andstatistically analyzed, using student‘t’ test
`for continuous data and Chi-square test for categorical
`data.
`
`RESULTS
`
`Total 125 children were enrolled for seizure episodes (n-
`76) and for various invasive and noninvasive procedures
`(n-49). The difference in mean age of children in
`procedures and seizures was found to bestatistically
`insignificant (p>0.05) between midazolam and diazepam
`
`groups. Youngest patient in whom a procedure was
`performed was11-day-old and who had seizures was6-
`day-old. There was a male preponderanceofpatients in
`both procedures (65.3%) and seizures (63.2%). Mean
`weight of children requiring sedation for procedure and
`seizures for midazolam and diazepam group was
`comparable. Minimum weight was 2.5 Kg in procedures
`and 2 Kg. in seizures group of patients. Maximum weight
`of 30 Kg was recorded for both procedure andseizure.
`Twenty five percent of patients (19 out of 76) were
`afebrile during seizure episode. Maximum temperature
`recorded was 40.5°C. Mean temperature of febrile
`patients was comparable in two groups.
`Difference in score of sedation before and after giving
`drug between IV-D and IN-M was found to be
`insignificant (y2 = 0.15 and x2 = 5.63; p> 0.05) (Table 1).
`There was no significant difference observed in cry,
`physical restraint and motor score between IN-M and IV-
`D during invasive procedures. (y2 = 0.01, y2 = 0.01, x2 =
`0.79 p>0.05). Similarly in the non-invasive procedure
`group nosignificant difference was observed between
`two drugs for cry, physical restraint and motorscore. (x2
`=0.02, x2 = 0.03, 72 = 0.03; p>0.05) (Table 2).
`Althoughin the intranasal midazolam group,time to
`
`Taste 1. Score of Sedation Before and After Giving the Drugs in Procedures
`
`IN-Midazolam (n-27)
`Score of Sedation
`
` Before Drug After Drug
`
`IV-Diazepam (n-22)
`
` Before Drug After Drug
`
`P>0.05
`0
`11 (50.0%)
`0
`15 (55.55%)
`I (Agitated)
`P>0.05
`0
`11 (50%)
`2 (7.41%)
`12 (44.45%)
`II (Alert)
`P>0.05
`2 (9.1%)
`0
`4 (14.81%)
`0
`I (Calm)
`P>0.05
`17 (77.27%)
`0
`21 (77.78%)
`0
`IV (Drowsy)
`P>0.05
`3 (13.63%)
`0
`V (Asleep)
`0
`0
`
`p>0.05
`* Sedation Score before giving intranasal Midazolam andintravenous Diazepam x? = 0.15
`p>0.05
`* Sedation Score after giving intranasal Midazolam and intravenous Diazepam y? = 5.63
`Tas.e 2, Behaviour During Invasive and Non-invasive Procedures According to Drug Used
`Score
`
`Non-Invasive (n-24)
`
`Invasive (n-25)
`
`Midazolam (n-14)
`
`Diazepam (n-11)
`
`Midazolam (n-13)
`
`Diazepam (n-11)
`
`Cry Score
`
`I (Whimper)
`II (Cry)
`III (Scream)
`
`10 (71.4%)
`4 (28.6%)
`0
`
`Physical Restraint
`
`I (Minimal)
`II (Moderate)
`
`9 (64.3%)
`5 (35.7%)
`
`TI (Maximal)
`
`0
`
`MotorScore
`
`I (Squirmish)
`II (Kicking)
`III (Fail)
`
`8 (57.1%)
`5 (35.7%)
`1 (7.2%)
`
`*P> 0.05 Insignificant
`
`8 (72.7%)
`3 (27.3%)
`0
`
`7 (63.6%)
`4 (36.4%)
`
`0
`
`5 (45.4%)
`4 (36.4%)
`2 (18.2%)
`
`2=0.01*
`P>0,05
`
`x2 =0.01*
`P>0.05
`
`y2 = 0.79"
`x2 = 0.03
`
`12 (92.3%)
`1 (7.7%)
`0
`
`11 (84.6%)
`2 (15.4%)
`
`0
`
`11 (84.6%)
`2 (15.4%)
`0
`
`10 (90.9%)
`1 (9.1%)
`0
`
`9 (81.8%)
`2 (18.2%)
`
`0
`
`9 (81.8%)
`2 (18.2%)
`0
`
`x?=0.02*
`P>0.05
`
`x2 = 0.03*
`P>0.05
`
`P>0,05
`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
`
`976
`
`Indian Journal of Pediatrics, Volume 73—November, 2006
`
`AQUESTIVE EXHIBIT 1137 Page 0002
`AQUESTIVE EXHIBIT 1137 Page 0002
`
`

`

`27
`
`Comparative Study of Intranasal Midazolam and Intravenous Diazepam Sedation
`
`TABLE 3. Duration of time intervals (in minutes) for giving drugs, seizure control, and responseto treatmentin study groups(values are
`Mean+S.D. and 95% confidence interval)
`
`IN-Midazolam
`IV-Diazepam
`
`
`Timeto giving drugafter arrival in hospital
`
`Timeto cessation of seizures after giving drug
`
`Timeto cessation of seizures after arrival in hospital
`
`2.34+0.90
`(4.26 to 4.96)
`2.97+0,53
`(1.77 to 2,07)
`5.2520.86
`(6.16 to 6.86)
`P<0,001 Highly Significantfor all groups
`
`4,.61+1.08
`(2.06 to 2.62)
`1,92+0.45
`(2.81 to 3.13)
`6.51+1.06
`(4.98 to 5,52)
`
`cessation of seizures after giving drug was longerin
`comparison to intravenous diazepam (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
`administration of drug was sooner in the midazolam
`group than the diazepam 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
`andseizures.
`
`DISCUSSION
`
`Midazolam is a newer water soluble Benzodiazepine
`absorbedvia the intranasal route, which provides an easy
`and painless methodof sedation. Intravenous diazepam
`(IV-D) is the most frequently used methodof sedation but
`administration is painful, takes time and requires more
`material and training. The objective of this study was to
`comparetheefficacy and safety of intranasal midazolam
`(IN-M) with intravenous diazepam (IV-D) for various
`pediatric procedures and seizures.
`Out of 125 childrenof all ages and either sex, attending
`outdooror indoor pediatric emergency department,
`various procedures were performedin 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 alé
`compared IN-M with IV-D for treating only febrile
`seizures in children.
`The assessment of sedation was performedafter 10
`minute of drug instillation. This interval was also chosen
`by Wilton NCTet al5 and SloverR et al’, In the present
`study in the midazolam group (n-27), 55.55% of children
`wereagitated (Score-I) and 44.45% werealert before
`giving drug. Most ofthe children (n-21; 77.78%) became
`drowsyafter giving IN-M (Score-IV). The findings ofthis
`study are consistent with that of Wilton NCTet al’, who
`found most patients become either calm or drowsy
`
`Indian Journal of Pediatrics, Volume 73—November, 2006
`
`(sedation scale III or IV). Slover R et al’also found that
`majority of patients (80%) were in the calm and/or
`drowsy category. There is no significant difference
`observed in the cry, physical restraint and motor score
`between IN-M and IV-D during invasive procedures. (y2
`=0.01, ¥2=0.01, y2=0.79 p>0.05). Similarly in non-invasive
`procedures nosignificant differences were observed
`between the two drugsfor cry, physical restraint and
`motorscore. (y2=0.02, ~2=0.03, ~2=0.03; p>0.05) (Table 2).
`M.Fishben et al’ evaluated IN-M in children undergoing
`esophagogastrodudenoscopy and noted fewer incidence
`of crying and screaming and other major negative
`behavior during separation from parents after
`administration of the drug. Major negative behavior
`scores were the highest for the invasive procedures. The
`present study showsnodifference in theefficacy of these
`drugs (IN-M and IV-D) during procedures.
`In the use of IN-M controlof seizures after arrival of
`patients in hospital was achieved sooner than with
`diazepam given intravenously. Mean timeto 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 drugafter arrival
`in hospital being more in younger than older age groups
`of children.
`In the present study there were no significant
`differences observed in heart rate, respiratory rate and
`oxygen saturation before and after giving IN-M or IV-D in
`proceduresandseizures.
`Key Message: Midazolam byintranasal route provides
`| a rapid, safe and effective non-invasive method of
`| sedation for procedures andfortreating seizures.
`
`Acknowledgements
`
`The authorssincerely acknowledge Dr. C.B. Shukla , Superintendent
`of G.M. Hospital and Dr, P.K. Baijal Dean, S.S. Medical College,
`Rewafor their kind permission and support to carry outthis study
`in G.M. Hospital and S.S. Medical College, Rewa (M.P.)
`
`REFERENCES
`
`1. Krauss Baruch, Steven M Green. Sedation and analgesia for
`
`977
`
`AQUESTIVE EXHIBIT 1137 Page 0003
`AQUESTIVE EXHIBIT 1137 Page 0003
`
`

`

`Pankaj Mittal et a/
`
`28
`
`proceduresin children New England J Med 2000; 342 (13): 938-
`945.
`. Gopinath PG, Gopinath G, Kumar TCA. Targetsite of
`intranasally sprayed substances andtheir transport across the
`nasal mucosa:a new insightinto the intranasal 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
`Neuropathology and Applied Neurobiology 1993; 19: 480-488.
`Latson Larry A, Chaetham JP, Gumbiner CH, Kingler JD,
`Danford DA, Hofschire PJ. Midazolam Nose Drops for
`Outpatients Echocardiographic Sedation in Infants. Am Heart
`J 1991; 121: 209,
`
`Wilton NCT, Leigh J, Rosen DR, Pandit U. Preanesthetic
`sedation of preschool children using intranasal midazolam.
`Anesthesiology 1988; 69: 972-975.
`Lahet Eli, Micheal G, Joseph B, Tzvi B, Matithyahu B.
`Comparison of intranasal Midazolam with intravenous
`Diazepam fortreating febrile seizures in children-prospective
`randomized study. British Med J 2000; 321: 83-86.
`Slover R, Schlesinger T. Use of intranasal midazolam in
`preschool children. Anaseth Analg 1990; 70 : 51-54.
`Fishbein Mark, Lugo Ralph A woodlandJennifer, Lininger
`Barbara and Linscheid Tom. Evaluation of intranasal
`midazolam in children undergoing esophagogastro-
`duodenoscopy. J Pediatr Gastroenterol Nutr 1997; 23(3): 261-266.
`
`978
`
`Indian Journal of Pediatrics, Volume 73—November, 2006
`
`AQUESTIVE EXHIBIT 1137 Page 0004
`AQUESTIVE EXHIBIT 1137 Page 0004
`
`