Table 2.

Studies of medications used to treat neonatal seizures without control or comparison groups (Tier II), but with electrographic confirmation of seizure diagnosis and response to therapy.

Study	Medications and doses studied	Study design	Study population	EEG monitoring	Key findings	Additional findings	Short-term Adverse effects	Study Limitations
Deshmukh et al, 198621	Lorazepam 0.05mg/kg IV 3rd line after phenobarbital (1st line) 15mg/kg, and phenytoin (2nd line) 15mg/kg	Uncontrolled, experimental (prospective)	N=7 total, But only N=3 with cEEG All infants with HIE 5 term, 2 preterm	cEEG, in only 3/7 infants. Does not state how long the EEG was continued after lorazepam dosing (implied by description of movements several hours later, that EEG was no longer ongoing)	3/3 (100%) on EEG monitored infants had seizure cessation within 5 min 4/4 (100%) clinically monitored infants with seizure cessation within 5 min	In EEG-monitored subjects- 1 of the 3 had bicycling movements recurring 8 hrs after lorazepam In clinically monitored kids, one had bicycling movements 8 hrs after lorazepam, 1 had recurrence of multifocal seizures 12 hrs after lorazepam, and 2 had occasional lipsmacking but no definite seizure recurrence	No significant side effects observed In two instances, following lorazepam administration, the serum phenobarbital level increased into the “toxic range”	No control/ comparison group Continuous EEG limited to only 3 patients, and unclear how long it was used. Lorazepam dose lower than typically used for seizure cessation in other age groups (e.g. 0.1mg/kg standard)
Connell et al, 198922	Clinical seizures treated, in this order: Phenobarbital- (1st line)- 20mg/kg Paraldehyde- (2nd line)- 0.3mL/kg rectally or 1–3mL/kg/hr IV Phenytoin- (3rd line)- 20mg/kg IV Diazepam- (4th line)- 0.25mg/kg IV	Prospective study of developmental outcomes in patients with neonatal seizures, treated (any antiepileptic drug) or untreated Partially blinded- neonatalogists were not given EEG results unless requested. Treatment decisions typically made on clinical basis without EEG info.	N=55 with EEG seizures, only 31 treated with anti-convulsants (untreated group = 24) Term and preterm (note- 22 were under 32 wks gestational age)	cEEG (but 2 channel only)	Complete response in 2/31 (6%) (with phenobarbital), equivocal response in 6/31 (19%) (2 phenobarbital, 4 paraldehyde). 13/31 (42%) had persistent EEG seizures, 10/31 (32%) showed no response (Definitions: Complete response: immediate and sustained cessation of EEG and clinical seizures Equivocal response = delayed response (but within 6 hrs) OR temporary response (recurred within 24hrs))	Neurologic outcome (range 6–24 months) of survivors- did not differ significantly between treated and untreated group. Outcomes: Normal: 2 treated, 2 untreated. Dystonia: 3 treated, 5 untreated Major abnormality: 6 treated, 7 untreated Death: 20 treated, 10 untreated Worse EEG background correlates with worse outcome- 27 infants with severe background EEG abnormalities died or had major neurologic abnormalities.	Not described	No control/ comparison group Untreated infants were not recruited and randomized as a formal control group- consisted mostly of patients WITHOUT clinical manifestations of EEG seizure activity
Bonati et al, 199023	Thiopental 10mg/kg IV 2nd line after phenobarbital 20mg/kg IV	Uncontrolled, experimental (prospective)	N=9 All ventilated, with severe HIE Term and preterm (>33wks)	cEEG duration not clear	9/9 (100%) with seizure cessation clinically and by EEG (“prompt and complete”)	All infants also kept on maintenance phenobarbital, with serum levels near 20. Recurrence of seizures in 1 infant 3 days later, stopped with a repeat dose.	Mild hypotension (mean systolic decrease of 27%) in 6/9 patients about 2 min after thiopental, requiring ethylephedrine dosing in all, dopamine in one, and volume explanion in two. Could not assess respiratory response, all infants mechanically ventilated	No control/ comparison group Did not use more phenobarbital than 20mg/kg- why not?
Maytal et al, 199124	Lorazepam 0.05–0.15mg/kg IV 2nd line after phenobarbital 40mg/kg IV	Prospective observational, no comparison group. Bolus doses of 0.05mg/kg given, repeated q 15 min up to total of 3 doses if still seizing	N=7 All but 1 were term Only 3 with EEG during lorazepam administration	cEEG only in 3 subjects, for a short duration after lorazepam given- 17–46 min. Duration of response to lorazepam determined clinically.	Complete cessation of seizures in 1–3 min in all but 1 patient (86%), who did have reduction of frequency and duration of seizures. “All patients responded clinically or on EEG recordings within 5 minutes”.	Duration of clinical seizure freedom: recurred after 12–16 hrs in 2 pts; no recurrence for >24hrs in 4 pts though 1 of these had lip-smacking at 6 hrs and 1 had occasional myoclonic jerks. EEG amplitude attenuation seen in some, after lorazepam given	No significant side effects observed	No control/ comparison group Small numbers, and did not really have consistent cEEG monitoring to determine full seizure cessation
Bye and Flanagan 199525	Series of anticonvulsants: Phenobarbital (1st line) 20mg/kg IV, if failure then up to cumulative dose of 40mg/kg or level of 40. Phenytoin (2nd line), 15–20mg/kg Clonazepam (3rd line)-intermittent 50ug/kg	Prospective, no comparison group for efficacy. Main purpose of study was to characterize the EEG seizures.	N=32 22 with seizure cessation during the monitoring period (data are unclear in 10- some died, 7 with seizure cessation but unclear if due to an anticonvulsant response). Term and preterm	cEEG. Monitoring continued for 12 hrs after achieving seizure control. Strength- Defined seizure cessation as within 120 min (if >120 min, unsure if could attribute to the drug)	Overall, seizure cessation in 15/22 (68%) within 120min. (12 within 30 min = 54%). 2 of these with <=20mg/kg phenobarbital, 6 with 21–30mg/kg phenobarbital, none with >30mg/kg phenobarbital, 5 with addition of phenytoin, 2 with addition of clonazepam. Amount of anticonvulsant required for an individual infant could not be predicted. 7 patients had seizures temporarily suspended after anticonvulsant doses but not completely controlled.	Clinical manifestations decreased after sequential anticonvulsant doses (highest correlation of clinical to EEG seizure was BEFORE anticonvulsants given). Inadequacy of relying on clinical observation to tell if seizure free. Some neonates with very long interictal periods. Anticonvulsants affected seizure characteristics: reduced seizure duration, increased interictal periods, and reduced EEG spread.	Not described	No control/ comparison group
Sheth et al, 199626	Midazolam 0.15mg/kg IV load, then 0.1–0.4mg/kg/hr 3rd line after 20–40mg/kg phenobarbital and usually 20mg/kg phenytoin	Retrospective, observational, no control group	N=6 mechanically ventilated infants 5 term and one 30week preterm	cEEG	6/6 (100%) seizure free within 1 hr (4/6 = 67% had seizure cessation immediately after loading dose)		No significant side effects observed, but all infants were already mechanically ventilated	No control/ comparison group Very small number Risk factors and illness severity different in infants who got long-term continuous EEG
Boylan et al, 200227	Phenobarbital, 20mg/kg IV then additional loads up to 40mg/kg as needed	Secondary analysis of a prospective observational investigation	N=14 Term and preterm	cEEG for at least 1 hr pre-treatment and continued at least 1–2 hrs post treatment, plus intermittent or continuous monitoring in subsequent days	4/14 (29%) “responded” to 1st phenobarbita load Of the responders- 2 remained seizure free completely, 1 with a single seizure the next day then no others, and the last had 2 seizures (1 clinical, 1 electrographic) later after the phenobarbital. 2 additional babies had initial dramatic response but seizures were recurring by 24 hrs.	Responders tended to be those with low seizure burden and normal or mildly abnormal EEG background Responders had normal neurologic outcome at 1 year in 2 subjects, moderate hearing impairment in another, and 1 died. Nonresponders had mostly moderate to severe neurologic outcomes or died. None normal.	Not described	No control/ comparison group Potential for selection bias- only 14/33 infants with seizure in a 3 yr period had sufficient video-EEG data to meet inclusion criteria If electrographic seizures persisted, additional treament was not given until the following day
Van Leuven et al 200428	Midazolam 0.05mg/kg IV load, then 0.15mg/kg/hr 3rd line after phenobarbital 20mg/kg and then lidocaine	Uncontrolled, experimental (prospective) aEEG reader blinded to final patient outcome	N=15 Term infants with HIE	aEEG	11/15 (73%) with seizure cessation within 24 hrs 1/15 with reduced seizure frequency	Brief, moderate aEEG background suppression × about 2 hours, in 4/15 patients	No significant side effects observed	No control/ comparison group 3 patients also received clonazepam during the midazolam infusion due to severe ongoing seizures
Malingre et al, 200629	Lidocaine 2mg/kg IV over 10 min, then 6mg/kg/hr × 12 hrs, then 4mg/kg/hr × 12 hrs, then 2mg/kg/hr × 12 hrs 3rd line after Phenobarbital (1st line), and midazolam or clonazepam (2nd line in term vs preterms)	Uncontrolled, experimental (prospective) aEEG assessed blindly Second confirmatory study – 2nd group of 15 patients with slightly different dosing (6mg/kg/hr maintenance for 6 hours rather than 12)	N=20 infants (21 treatments- one infant treated twice due to seizure recurrence) Term and preterm Followup study N=15, with 16 treatments)	aEEG	11/21 (52%) achieved seizure cessation, 5/21 (24%) had diminished seizure activity or cessation with later recurrence. So overall-76% with some effect. Secondary confirmatory study- some effect in 78% (similar)	Main focus of manuscript was the development of an optimal dosing strategy without cardiac toxicity	No significant side effects observed	No control/ comparison group Time to seizure cessation not described in detail
Abend et al, 201130	Levetiracetam (1st, 2nd, or 3rd line) 10mg/kg IV then maintenance (mean 45mg/kg/day) divided BID Phenobarbital 1st line then phenytoin in some.	Retrospective, observational, no control group	N=23 (2 as first line, 13 as 2nd line, 3 as 3rd line, 1 as 4th line) Term and late preterm	cEEG EEG usually continued for 24hrs after seizure cessation	8/23 (35%) with seizure improvement (>50% reduction) within 24 hrs (7/8 with termination of seizures). Another 4 had improvement in 24–72 hrs. Note that only 35% response is similar to what we get with phenobarbital or phenytoin, but many of these patients had already received at least a first line agent	First-line: ½ with seizure cessation 2nd line: 4/13 (31%) with cessation in <24hrs, 2/13 with cessation in >24hrs, 1/13 with 50% reduction within 24 hrs, 1/13 with reduction > 24 hrs, and 5/13 with no improvement	States that no serious cardio-pulmonary adverse events were recorded, and no serious or intolerable adverse effects	Observational, no comparison group, wide range in dosage, varies as to which other anticonvulsants had previously been received (1st, 2nd or 3rd line levetiracetam usage)
Khan et al 201131	Levetiracetam 10–50mg/kg IV load (usually 2nd line to phenobarbital but sometimes 1st line), then maintenance.	Retrospective, observational, no control group	N=22 20 of the 22 got loading dose of 50mg/kg (one got 10, one 20mg/kg) 19 of these maintained on 50mg/kg/day Term only	cEEG “seizures were clinical at onset and then electroclinical on followup prolonged continuous EEG monitoring”. All patients had EEG correlation at time of seizure cessation.	19/22 (86%) had immediate seizure cessation at 1 hr 7/22 (32%) with complete seizure cessation after loading dose, 14 (64%) by 24 hrs, 19 (86%) by 48 hrs, all (100%) by 72 hrs. (Most had already received phenobarbital and not completely responded). Defined seizure response at 1 hr after loading dose, and time to complete cessation.	Of those followed til 6 mo (17)– 71% had achieved complete seizure freedom off anticonvulsants, 24% while still on levetiracetam were seizure free, and 1 with recurrence even on levetiracetam	No significant side effects observed One patient with irritability, improved on pyridoxine	No control/ comparison group Half were receiving other anticonvulsants concomitantly with levetiracetam- though usually just for a few days

Abbreviations: cEEG= continuous electroencephalography, aEEG= amplitude-integrated electroencephalography, hr=hour, min=minute, F/U = follow-up, IV = intravenous, HIE = hypoxic-ischemic encephalopathy