RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES …



6. BRIEF RESUME OF THE INTENDED WORK

6.1 Need for the Study

Convulsions or seizures are one of the most common neurological disease seen in neonate and preschool children with incidence of upto 60 per 1000. 85% of status epilepticus occur in neonate and preschool children age group. Seizures lead to unrelenting muscular activity leading to anaerobic metabolism and tissue breakdown as well as increase the cerebral metabolic rate exceeding the oxygen and glucose supply to brain leading to brain ischaemia and neuronal death. Thus it is important to control seizure rapidly to minimize the systemic as well as brain damage.

Diazepam is most widely used drug for acute management of all types of seizures in both adults and children. However, it has a short duration of action and can be administered intravenous and rectal route but cannot be given intramuscular as it is a lipophilic agent with erratic absorption and tends to accumulate if repeated doses are given with the possible rare complication of brain stem depression leading to bradyapnoea or even respiratory arrest. In a convulsing child precious time is spent on introduction of IV line and it is difficult to secure in a child with generalised tonic clonic seizures.

Midazolam, new benzodiazepine is the first water soluble agent widely accepted as parenteral anxiolytic and premedication agent. Its safety and efficacy as a intramuscular anticonvulsant drug has been shown in several studies in animals and humans (adults and children). Midazolam is 3-4 times more potent than diazepam on a milligram to milligram basis, and can be given by intravenous or intramuscular route. The dose of midazolam is 0.1 mg/kg to 0.3 mg/kg via intramuscular route with 90% bioavailability.

Thus this study is chosen to compare the safety and efficacy of intramuscular midazolam with intravenous diazepam in control of seizures in children.

6.2 Review of Literature

1. In 1979, Knudsen FU conducted prospective study in children, aged 6 months to 5 years, admitted to hospital with febrile convulsion epilepsy were treated with rectal diazepam during 59 generated attacks and concluded that diazepam is rapid reliable anticonvulsant with few side effects when given rectally in emergency which makes this treatment a valuable alternative to intravenous diazepam in control of childhood seizures.1

2. In 1992, Lahat et al. studied the antiepileptic properties of first water soluble benzodiazepine midazolam in 48 children in age group of 4 months to 14 years with 69 episodes of various type of seizures and results suggested that intramuscular midazolam is efficacious, safe in variety of seizures in childhood specially when attempt to intravenous access is difficult in convulsing child.2

3. In 1996, Hung OR et al. studied the absorption kinetics of intramuscular midazolam and diazepam and concluded that mean peak absorption rate was shorter and onset of action was rapid following intramuscular midazolam compared to diazepam.3

4. In 1997, Chamberlain et al. conducted the randomized comparative study on intramuscular midazolam versus intravenous diazepam in 24 patients of which 22 patients had good effective control of seizures and concluded that intramuscular midazolam has good rapid absorption rate and more rapid cessation of seizures. The intramuscular route of administration was particularly effective in pre-hospital settings and for children with difficult intravenous access.4

5. In 1999, Towne AR et al. conducted study on use of intramuscular midazolam for status epilepticus as alternative to diazepam and lorazepam during difficult venous access and showed that pharmacodynamic effect of midazolam was within seconds of administration and seizures arrest within 5-10 min with good local tolerability.5

6. In 2000, Lahat et al. studied use of intranasal midazolam in 47 children aged 6 months to 5 years with prolonged febrile seizures and showed that midazolam was safe antiepileptic drug and overall time of cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam.6

7. In 2004, Mohamoudian T et al. studied 70 children aged 2 months to 15 years with acute seizures and compared use of intranasal midazolam versus intravenous diazepam and showed that intranasal midazolam is safe and effective as intravenous diazepam in treatment of acute childhood seizures in medical centres but also in general practice and at home after appropriate instruction are given to families of children with recurrent seizures.7

8. In 2005, Shah Ira et al. conducted prospective trial on 115 children in age group of 1 month to 12 years on use of intramuscular midazolam and concluded that intramuscular midazolam is safe and effective in control of acute seizures, irrespective to type of convulsion and age of the child and suggested that intramuscular midazolam can be used as first line of agent in management of acute convulsion in whom intravenous access is difficult.8

9. In 2006, Bhattacharya M et al. conducted random trial on 180 seizures episodes in 46 children when rectal diazepam (0.3 mg/kg) and intranasal midazolam (0.2 mg/kg) was used and concluded that intranasal midazolam is preferable to rectal diazepam in treatment of acute seizures in children because of ease of administration, rapid onset of action and no significant effect on respiration, oxygen saturation and socially acceptable.9

10. In 2006, Galdames-Contreras D et al. conducted prospective open clinical trial that included 43 status epilepticus in 38 adult patients aimed for faster control of seizures where initial dose of 15 mg intramuscular midazolam with simultaneous oral dose of phenytoin (15-20 mg/kg dose) or carbamazepine (15 mg/kg) was given and results suggested that intramuscular midazolam can be used as initial treatment in status epilepticus in adults especially in a low complexity settings due to its effectiveness, quick action and safety.10

11. In 2007, Riaz Ahmed conducted study on 28 children with tonic clonic seizures with mean age of 4.6 years received low dose buccal midazolam in a dose of 0.2 mg/kg for control of seizures of various types and concluded that low dose midazolam given by buccal route is often sufficient to control seizures effectively.11

12. Buccal or nasal midazolam (0.5 mg/kg) is another option when IV access is not available and can be safely administered in emergency medical seizures crew prior to the hospital. Respiratory depression and hypotension are known to occur with barbiturates. Diazepam is effective in management of tonic-clonic status, but the drug has a short half life and seizures thus recur unless a longer acting anticonvulsant is administered simultaneously.12

6.3 Objectives of the Study

1. To compare efficacy of intramuscular midazolam with intravenous diazepam in control of seizures in children.

2. To study the adverse effects associated with administration of intramuscular midazolam in control of acute seizures in children.

7. MATERIALS AND METHODS

7.1 Source of Data

The proposed study in a hospital based prospective randomized study on children with active seizures brought to the emergency ward of Cheluvamba hospital attached to Mysore Medical College and Research Institute, Mysore during the term period between December 2007 to May 2009.

7.2 Method of Collection of Data

Sample size: Minimum of 100 cases meeting the criteria are included for the present study and are randomized into two groups: 50 cases in midazolam group and 50 cases in diazepam group.

Sampling method: Simple random sampling

Inclusion Criteria

Patients in age group of one month to 12 years brought to emergency department with acute convulsion and those patients admitted in paediatric ward and PICU who developed acute seizures were included in the study.

Exclusion Criteria

Patients who had received other anticonvulsants for treatment of acute seizures were excluded from the study.

A total of 100 children in age group of 2 months to 12 years are included in the present study and are further randomized into two groups of 50 each. In group I, children are treated with intravenous diazepam (0.2 mg/kg) and in group II the children in whom intravenous access will be difficult are treated with intramuscular midazolam (0.2 mg/kg) for control of seizures in emergency ward. Because the route of administration is different for each drug those administering the drug and assessing the outcome will be aware of the specific drug used. Informed consent will be obtained with parents or guardians.

The intravenous preparation of midazolam (5 mg/ml) is taken in a syringe with needle and administered to convulsing child by intramuscular route and intravenous preparation of diazepam is pushed intravenous slowly. The heart rate, cardiac rhythm, respiratory rate, respiratory rhythm, and oxygen saturation will be monitored at 5 min, 10 min, 20 min, 30 min and every hour for 6 hours. Only single dose of both drugs will be given and dose will not repeated.

The therapeutic success is defined as cessation of visible signs of seizure activity within 10 minutes of administration of drug and without any other seizure within one hour. If child is having seizures at 10 minutes further management is done as per standard protocol. The requirement of another anticonvulsant at this stage is concluded as failure.

The duration of seizure prior to admission to emergency ward, time taken from arrival to emergency room for administration of drug, time taken for control of seizures after administration of drug are noted. The total number of seizures in first 24 hours is recorded and any other adverse events that could be attributed to these drugs administered will also be documented. Once patient has been stabilised details of the case will be recorded in predesigned proforma.

Statistical methods used: Analyzed by ‘t’ table and compared using Chi-square test for proportions.

7.3 Does the study require any investigation/intervention to be conducted on

patients/humans/animals ? If so, please describe briefly.

No

7.4 Has ethical clearance been obtained from your institution in case of 7.3 ?

Yes (copy enclosed)

8. REFERENCES

1. Knudsen FU. Rectal administration of diazepam in solution in the acute treatment of convulsion in infants and children. Arch Dis Child 1979 Nov;54(11):855-7.

2. Lahat E, Aladjem M, Eshel G, Bistritzer T, Katz Y. Midazolam in treatment of epileptic seizures. Pediatr Neurol 1992 May-Jun;8(3):215-6.

3. Hung OR, Dyck JB, VArvel J, Shafer SL, Stanski DR. Comparative absorption kinetics of intramuscular midazolam and diazepam. Can J Anaesth 1996; 43(5):45-5.

4. Chamberlain JM, Altieri MA, Futterman C, Young GM, Ochsenchlager DW, Waisman Y. A prospective, randomised study, comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997 Apr;13(2):92-4.

5. Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for status epilepticus. J Emerg Med 1999 Mar-Apr;17(2):323-8.

6. Lahat E, Goldman M, Barr J, Bistritzer T, Berkovitch M. Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: Prospective randomised study. BMJ 2000 Jul 8; 321(7253):83-6.

7. Mahmoudian T, Zodeh MM. Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children. Epilepsy Behav 2004 Apr;5(2):253-5.

8. Shah I, Deshmukh CT. Intramuscular midazolam vs intravenous diazepam for acute seizures. Indian J Pediatr 2005;72(8):667-70.

9. Bhattacharyya M, Kalra V, Uulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol 2006 May;34(5):355-9.

10. Galdames-Contreras D, Carrasco-Poblete E, Aguilera-Olivares L, Fabres-Oyarzo L, Galdames-Poblete D. Intramuscular midazolam in the initial treatment of status epilepticus. Rev Neurol 2006 May 16-31;42(6):332-5.

11. Riaz Ahmed. Low-dose buccal midazolam for aborting seizures in children. J Pediatr Neurol 2007;5(4).

12. Johnston MV. Seizures in childhood. 18th ed. In: Kliegman, Behrman, Jenson, Stanton, editors, Nelson Textbook of Pediatrics. Vol. 2. Philadelphia: WB Saunders Company; 2007. p. 2474.

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