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ORIGINAL ARTICLE
Year : 2015  |  Volume : 4  |  Issue : 4  |  Page : 232-236

Comparative efficacy of phenobarbital, phenytoin and lorazepam for the treatment of neonatal seizures: A†randomized Trial


Department of Pediatrics, Government medical college and Sir T general Hospital , Bhavnagar - 364001, Gujarat, India

Date of Web Publication16-Oct-2015

Correspondence Address:
Alpesh P Patel
Department of Pediatrics, Sir T Hospital, Bhavnagar, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2249-4847.161696

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  Abstract 

Aims: To compare efficacy of phenobarbital (PB), phenytoin (PHT) and lorazepam (LZP) for neonatal seizures. Settings: Medical College Hospital. Design: Prospective block design randomized trial (registration-CTRI/2012/12/003255). Subjects and Methods: Of 121 neonates with convulsions, 106 were grouped to receive PB (20 mg/kg), PHT (20 mg/kg) or LZP (0.05 mg/kg) intravenously over 5 min. The primary end point was clinical control of seizures within 2.5 min of starting single dose anti-epileptic drug (AED). Treatment was considered to have failed if the seizures lasted longer than 5 min, or a total of 2.5 min of seizure activity within 5 min period after a single dose. Statistical Analysis: Chi-square, Fisher's exact test, t-test, ANOVA. Results: Seizures subsided in 78 (74%) neonates within 2.5 min with a single dose, recurred in 55 (52%) and other AED was required in 30 (28%) neonates. 11% (10/89) required AED beyond discharge. The complete control of neonatal seizures within 2.5 min was similar with PB and PHT, but significantly more seizure control (89%) in the LZP group (P < 0.05). Adverse events (19%) were: PB - drowsiness 11; PHT - thrombophlebitis 3, nystagmus 1; LZP - drowsiness 2, hypotonia 3. 22 neonates expired (phenobarbitone 12, PHT 3, LZP 7). Conclusion: The complete control of 1st neonatal seizures within 2.5 min was similar with PB and PHT, but LZP had less treatment failure and less response time to control seizures. For control of recurrence and persistent seizure, none of the three drugs was better than the other. PB had the worst outcome as far as the deaths were concerned, followed by LZP and PHT.

Keywords: Lorazepam, neonatal seizures, phenobarbital, phenytoin


How to cite this article:
Solanki DI, Gohil JR, Patel AP. Comparative efficacy of phenobarbital, phenytoin and lorazepam for the treatment of neonatal seizures: A†randomized Trial. J Clin Neonatol 2015;4:232-6

How to cite this URL:
Solanki DI, Gohil JR, Patel AP. Comparative efficacy of phenobarbital, phenytoin and lorazepam for the treatment of neonatal seizures: A†randomized Trial. J Clin Neonatol [serial online] 2015 [cited 2019 Sep 19];4:232-6. Available from: http://www.jcnonweb.com/text.asp?2015/4/4/232/161696


  Introduction Top


There is increasing evidence that neonatal seizures have an adverse effect on neurodevelopment progression and may predispose to cognitive, behavioral, or epileptic complications later in life. The incidence of neonatal seizures ranges from 1 to 5:1000 live births.[1] The treatment is usually with phenobarbital (PB), phenytoin (PHT), or lorazepam (LZP), but the efficacy of the three drugs has not been compared directly. There is a pressing need for consistent, evidence-based guidelines in the management of neonatal seizures by pediatrics neurologists and neonatologists.[2] Standardized approaches to the treatment of neonatal seizures remain undeveloped. Seizures are an early sign of brain injury in newborns. Seizures have often been diagnosed on the basis of clinical findings in the emergency department. Nevertheless, despite concern about diagnosis, most physicians choose to treat neonates who have seizures, most commonly with PB, PHT, or LZP primarily because of the experience with these drugs in older children and adults. These drugs are thought to be effective in neonates, but there are few data about their efficacy in relation to the clinical and physiologic characteristics of the seizures, and the three drugs have not been compared directly.


  Subjects and Methods Top


This prospective randomized trial study was conducted in Neonatal Intensive Care Unit (NICU) of Tertiary Care Hospital and Medical College for 1-year from August 2013 to July 2014. The protocol was approved by the Hospital's Institutional Review Board and Clinical Trial Registry of India (CTRI/2012/12/003255).

Inclusion criteria

All neonates, who developed clinicallyfirst seizure, before 28 days of life, were enrolled in the study.

Exclusion criteria

Neonates was already on ventilator support, or neonates with hypoglycaemia, hypocalcaemia and hypo/hypernatremia, who responded to specific treatment (e.g., with glucose, calcium, etc.) were not assigned to treatment with either of PB, LZP and PHT.

Clinical details of each seizure episode as reported by the staff sisters on duty, by the mother, and then confirmed by a physician on duty, type of convulsion and age at onset of seizure were recorded. Seizures were classified according to Volpe's [3] classification into subtle, clonic, tonic, and myoclonic seizures. Initial screening laboratory tests seek to identify the underlying etiology and include a complete blood count, glucose, sodium, potassium, ionized calcium, sepsis screen. A lumbar puncture to exclude intracranial infections, meningitis, and encephalitis, is usually undertaken, cranial sonography and a cranial computerized tomography scan to exclude intracranial hemorrhage/infarction should be considered according to the case. A video-electroencephalographic (EEG) diagnostic criterion was not used to confirmed clinical seizures because bedside EEG was not available.

Treatment protocol

The neonates were randomly assigned (single-blinded) to treatment with either PB or LZP or PHT according to a block design to ensure balanced treatment assignment. PB (20 mg/kg), LZP (0.05 mg/kg) or PHT (20 mg/kg) was administered intravenously (IV) over a 5 min period. The primary end point was complete control of seizures, within 2.5 min of starting a single dose anti-epileptic drug (AED) therapy, as determined by a physician. Treatment was considered to have failed if the neonate had an episode of seizures lasting longer than 5 min or a total of 2.5 min of seizure activity within 5-min period after a single dose. 5 min was chosen, as the most significant biochemical effects of neonatal seizures, are the changes in energy metabolism, which occur within 5 min after the onset of a seizure.[4],[5] Hence, rapidly acting drugs with the aim of quick response time in terms of seizure control was chosen rather than waiting for a period of 20–30 min by which time most of irreparable damage would have occurred. If clinical seizures resumed after therapy had been discontinued, the attending physician decided whether to use another anticonvulsant. The heart rate and rhythm, mean blood pressure, and respiratory status were monitored continuously during treatment.


  Results Top


Total number of NICU admissions during 1-year period was 1359 (full-term 1107 and preterm 252). Out of them, 121 (8.9%) neonates presented with seizures. Of them 95 (8.5%) were full-term and 26 (10.3%) were preterm of the 121 neonates with seizures who were screened for treatment enrolment: 15 were excluded (ventilator support 10, hypoglycaemia 2, hypocalcaemia 2, hyponatremia 1). Total 106 neonates were enrolled in the study. 35 were assigned to receive PB, 35 to receive PHT and 36 to receive LZP [Table 1]. Treatment assignment and outcomes of 106 neonates with seizures after giving PB, LZP, and PHT [Table 2] and [Flow Chart 1 [Additional file 1] ],[Flow Chart 2 [Additional file 2] ], [Flow Chart 3 [Additional file 3] ] and adverse events found on neonates after anti-epileptic treatment [Table 3]. Subtle seizures were found in 82 (67.8%) neonates, clonic in 20 (16.5%), tonic in 16 (13.2%), and myoclonic seizures in 3 (2.5%) as compared with subtle seizures were most common in neonates, followed by clonic, tonic, and myoclonic seizures (Volpe [3]). Of the various etiology for neonatal seizures birth asphyxia (60.8%) was the leading cause found in this study.
Table† 1: Characteristics of neonates

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Table† 2: Outcomes of neonates with seizures

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Table† 3: Adverse events found on neonates after AED treatment in present study

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{Inline 1}{Inline 2}{Inline 3}


  Discussion Top


Among the 35 neonates assigned to receive PB (20 mg/kg), the seizures were completely controlled within 2.5 min with a single dose in 22 (63%), as compared with 24 (69%) of the 35 neonates in the PHT group (20 mg/kg), and 32 (89%) of the 36 neonates in the LZP group (0.05 mg/kg). The complete control of neonatal seizures was similar in the two groups (PB and PHT), but there was significantly better control seen in (89%) in the LZP group (P < 0.05). There were 13 (37%) neonates in the PB group in whom the seizures were not completely controlled after a single dose of 20 mg/kg, as compared with 11 (32%) of the 35 neonates in the PHT group (20 mg/kg), and 4 (11%) of the 36 neonates in the LZP group (0.05 mg/kg). Treatment failure for neonatal seizures was similar in the two groups (PB and PHT), but it was significantly less (11%) in the LZP group (P < 0.05). In the PB group 8 (23%) needed other AED to achieve seizure control and among them 5 (14%) required both drugs (PB and PHT) to control seizures during a hospital stay. In the PHT group 12 (34%) needed other AED to achieve seizure control, among them 8 (23%) required both drugs (PB and PHT) to control seizures during the hospital stay. In the LZP group 10 (28%) needed other AED to achieve seizure control; among them 6 (16%) required only one drug PB to control seizures during a hospital stay. This indicated that none of the three drugs is better than the other, when it comes to controlling persistent seizures.

On comparing the results obtained from the present study with those done earlier we found that – while; Volpe [3] estimates that the expected response to anticonvulsants is 40% to the initial 20 mg/kg loading dose (LD) of PB, 70% to a total of 40 mg/kg of PB, 85% to a 20 mg/kg LD of PHT, and 95–100% and 0.05–0.10 mg/kg LZP thus indicating a better control with LZP which our study concurs with. Painter et al.[6] noted the control of electrical seizures was similar in the two groups (PB and PHT). Among the 30 neonates assigned to receive PB, the seizures were completely controlled in 13 (43%), as compared with 13 of the 29 neonates in the PHT group (45%), this also was similar to the results obtained in the present study. Maytal et al.[7] administered IV LZP at 0.05 mg/kg after seizures did not respond to 40 mg/kg of PB in seven patients and repeated it up to a total dose of 0.15 mg/kg. LZP controlled seizures completely in six patients and decreased them in one child. Two patients needed only one dose, three patients received two doses, and two patients received three doses. If seizures recurred, either PB or PHT was used. There were no adverse effects. Boylan et al.[8] had studied 14 neonates with seizures. Four responded to PB; these had normal or moderately abnormal EEG background abnormalities and the outcome was good. In the other 10 neonates, electrographic seizures increased after treatment, whereas electro-clinical seizures reduced. Three neonates were treated with second line anticonvulsants, of whom two responded. One of these had a normal neurodevelopmental score at 1-year, but the outcome for the remainder of the whole group was poor. Painteret al.[6] noted there were no changes in heart rate, heart rhythm, mean arterial pressure, or respiratory status that could be related to the plasma concentrations of free PB or PHT. In our study as well, there were no significant changes in temperature, pulse, and respiratory rate that could be related to PB, LZP, and PHT therapy (P > 0.05). Deshmukh et al.[9] reported cessation of seizure in seven infants to whom they administered LZP at 0.05 mg/kg over 2–5 min with no adverse events.

Five (14%) of the neonates had adverse events with LZP: Drowsy (n = 2), and hypotonia (n = 3) in present study [Table 3] which co-relates with Reiter and Stiles [10] study. Since LZP is eliminated by glucuronidation, which is decreased in the preterm infant, its accumulation may occur, leading to sedation and hypotonia, but this does not correlate with a study by Deshmukh et al.[9] and Maytal et al.[7] as they reported no adverse events.

In a set up where mechanical ventilation facility is not there or inadequate, the results indicate that PB had the worst outcome as far as the deaths were concerned, followed by LZP and PHT. However, LZP had faster seizure control forfirst episode of neonatal seizure. For recurrent or persistent seizures, all drugs were similar in efficacy.


  Conclusion Top


  • Subtle seizures (67.8%) were most common in neonates, followed by clonic, tonic, and myoclonic seizures. Birth asphyxia was the predominant cause of seizures (63%), followed by idiopathic, sepsis, and intracranial hemorrhage
  • Complete control of neonatal seizures within 2.5 min. was similar in the two groups (PB (63%) and PHT (67%), but there was significantly better seizure control (89%) in the LZP group (P < 0.05)
  • Deaths were highest, 12 in PB group, followed by LZP, 7 and PHT, 3
  • Adverse events were: PB 11 (drowsiness); PHT 4 (thrombophlebitis 3, nystagmus 1); LZP 5 (drowsiness 2, hypotonia 3)
  • For control of 1st seizures.


Lorazepam:

  • It was better than PB and PHT as efficacy was more
  • Less response time to control seizures
  • Less treatment failure
  • No AED therapy needed beyond discharge


  • For control of recurrence and persistent seizure; none of the three drugs is better than the other
  • Mortality in LZP group was more than PHT group though it was half of PB group, and it was statistically significant (P = 0.02).


Source of funding

Nil.

Conflicts of interest

There are no conflicts of interest.





 
  References Top

1.
Volpe JJ. Neonatal seizures. In: Neurology of the Newborns. 4th ed. Philadelphia, PA: WB Saunders; 2001. p. 178-214.  Back to cited text no. 1
    
2.
Bassan H, Bental Y, Shany E, Berger I, Froom P, Levi L, et al. Neonatal seizures: Dilemmas in workup and management. Pediatr Neurol 2008;38:415-21.  Back to cited text no. 2
    
3.
Volpe JJ. Neonatal seizures: Current concepts and revised classification. Pediatrics 1989;84:422-8.  Back to cited text no. 3
    
4.
Wasterlain CG, Shirasaka Y. Seizures, brain damage and brain development. Brain Dev 1994;16:279-95.  Back to cited text no. 4
    
5.
Fujikawa DG, Dwyer BE, Lake RR, Wasterlain CG. Local cerebral glucose utilization during status epilepticus in newborn primates. Am J Physiol 1989;256:C1160-7.  Back to cited text no. 5
    
6.
Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 1999;341:485-9.  Back to cited text no. 6
    
7.
Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol 1991;6:319-23.  Back to cited text no. 7
    
8.
Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed 2002;86:F165-70.  Back to cited text no. 8
    
9.
Deshmukh A, Wittert W, Schnitzler E, Mangurten HH. Lorazepam in the treatment of refractory neonatal seizures. A pilot study. Am J Dis Child 1986;140:1042-4.  Back to cited text no. 9
[PUBMED]    
10.
Reiter PD, Stiles AD. Lorazepam toxicity in a premature infant. Ann Pharmacother 1993;27:727-9.  Back to cited text no. 10
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Abstract
Introduction
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Results
Discussion
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Introduction
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