Comparing the effect of intermittent diazepam and continuous phenobarbital in preventing recurrent febrile seizures among children under 6 years old: A systematic review and meta-analysis
Leili Faraji Gavgani1, Delara Laghousi2, Parvin Sarbakhsh3, Leila Jahangiri4, Nafiseh Vahed5, Sakineh Hajebrahimi6
1 Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences; Research Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
2 Social Determinants of Health Research Centre, Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Statistics and Epidemiology, Faculty of Health, Tabriz University of Medical Sciences, Tabriz, Iran
4 Department of Health Education and Health Promotion, School of Health, Tabriz University of Medical Sciences, Tabriz, Iran
5 Research Center for Evidence Based Medicine, Iranian EBM Center: A Joanna Briggs Institute Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
6 Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
|Date of Submission||25-Dec-2021|
|Date of Decision||19-Nov-2022|
|Date of Acceptance||16-Jan-2023|
|Date of Web Publication||21-Apr-2023|
Dr. Delara Laghousi
Social Determinants of Health Research Centre, Health Management and Safety Promotion Research Institute, Tabriz University of Medical Sciences, Tabriz
Source of Support: None, Conflict of Interest: None
Background: Febrile convulsion (FC) is the most common and preventable seizure in children. This study aimed to assess the effectiveness of the diazepam and phenobarbital for preventing recurrent FC. Materials and Methods: In this systematic review study, literature published in English language were carefully searched in biological databases (Cochrane Library, Medline, Scopus, CINHAL, Psycoinfo, and Proquest) by February 2020.Randomized clinical trials (RCTs) and Quasi randomized trial were included in the review. Two researchers checked the literature independently. The quality of studies was assessed using the JADAD score. The potential risk for publication bias was assessed by Funnel plot and Egger's test. Meta regression test and sensitivity analysis were used to identify the reasons for heterogeneity. Given the results of assessing heterogeneity, the random effect model in RevMan5.1 software was used for meta analysis. Results: Four out of 17 studies had compared the effect of diazepam and phenobarbital in preventing recurrent FC. The result of the meta analysis showed that the use of diazepam in comparison with phenobarbital reduces the risk of recurrence FC by 34% (risk ratio = 0.66, 95% confidence interval [CI] = [0.36–1.21]), but the relationship was not statistically significant. In assessing the effect of diazepam or phenobarbital versus placebo, the results showed that the use of diazepam and phenobarbital has reduced the risk of recurrent FC by 49% (risk ratio = 0.51, 95% CI = [0.32–0.79]) and 37% (risk ratio = 0.63, 95% CI = [0.42–0.96)]), respectively, and these relationships were statistically significant (P < 0.05). Results of the meta regression test showed that the follow up time can be a reason for the heterogeneity between trials with the comparison of diazepam versus phenobarbital (r = 0.047, P = 0.049) and Phenobarbital versus placebo (r = 0.022, P = 0.016). According to the results of Funnel plot and Egger's test, there was evidence of publication bias (P = 0.0584 for comparison of diazepam vs. phenobarbital; P = 0.0421 for comparison of diazepam vs. placebo; P = 0.0402 for comparison of phenobarbital vs. placebo). Conclusion: The results of this meta analysis indicated that preventive anticonvulsants can be useful in preventing recurrent convulsions in cases of febrile seizures.
Keywords: Anticonvulsant drugs, febrile convulsion, prevention, prophylaxis, seizure
|How to cite this article:|
Faraji Gavgani L, Laghousi D, Sarbakhsh P, Jahangiri L, Vahed N, Hajebrahimi S. Comparing the effect of intermittent diazepam and continuous phenobarbital in preventing recurrent febrile seizures among children under 6 years old: A systematic review and meta-analysis. J Res Med Sci 2023;28:38
|How to cite this URL:|
Faraji Gavgani L, Laghousi D, Sarbakhsh P, Jahangiri L, Vahed N, Hajebrahimi S. Comparing the effect of intermittent diazepam and continuous phenobarbital in preventing recurrent febrile seizures among children under 6 years old: A systematic review and meta-analysis. J Res Med Sci [serial online] 2023 [cited 2023 Jun 5];28:38. Available from: https://www.jmsjournal.net/text.asp?2023/28/1/38/374339
| Introduction|| |
Febrile seizures (FS) are the most common seizures in children and occur in children with a temperature of 38° C or higher between the age of 6 and 60 months, and are not the result of central nervous system infection or any metabolic imbalance. Despite its predominantly benign nature, a febrile seizure is a terrifying experience for most parents. Approximately 2% and 5% of neurologically healthy infants and children experience at least one febrile seizure. Without taking any preventive measure, a second febrile seizure is likely to occur in about 29%–35% of patients., A third febrile seizure is reported in about 50% of the patients who had a second febrile seizure. In other words, only 15% of the children with a history of FS may have three FS. Despite the benign nature of FS, seeing any fever in the child makes parents feel worried. Parents should be counseled about the risk of recurrence of FS and how to deal with a seizure. There are two types of prevention measures, intermittent with oral diazepam or other anticonvulsant drugs during febrile illnesses and continuous treatments with phenobarbital. The use of continuous therapy, due to side effects and lack of demonstrated long-term benefits, is no longer accepted. According to the Cochrane systematic review, side effects were observed in 30%–40% of children on the continuous use of phenobarbital or benzodiazepines. According to the general consensus, the use of intermittent diazepam or other anticonvulsants in preventing FS is also not routinely indicated and in some situations at the onset of a febrile illness may be considered. Considering the low quality and various designs of the conducted studies in this concept, the present systematic review and meta-analysis were performed to estimate the risk of recurrent febrile seizure following the use of phenobarbital or diazepam among children ≤6 years old with a history of febrile convulsions (FCs).
| Methods|| |
The preferred reporting items for systematic reviews and meta-analyses checklist were used to report the selected clinical trial articles for present systematic review and meta-analysis. The clinical trial articles related to the topic of FC and its prophylactic measures (diazepam or phenobarbital) among children which were published in English by February 2020 as well as papers presented at the conferences were reviewed. The comprehensive electronic database of Medline, Cochrane Library, PubMed, Scopus, CINHAL, Psycoinfo, Google Scholar, and Proquest databases was searched. In addition to the mentioned databases, the reference lists of the retrieved articles were also searched manually. Included keywords were: “Febrile Convulsion,” “ Febrile Seizure,” “Anticonvulsants,” “Diazepam,” “Phenobarbital,” Preventive measures in Febrile Convulsion,” and in children “Febrile Convulsion.” Other Mesh keywords related to these keywords and the combination of these keywords were also used. Two authors performed the searches independently.
Inclusion and exclusion criteria
Studies with the design of randomized controlled trials (RCTs) or Quasi-Experimental Research were included in the analysis. Our eligible criteria were as follows: (1) Experimental studies about the prevention of FC among children with the age of ≥6 years; (2) experimental group receiving intermittent diazepam or continuous phenobarbital; (3) comparison group receiving of diazepam or phenobarbital or other anticonvulsant agents or placebo; and (4) outcome: Recurrence rate of FC. After extracting articles from databases, the duplicated articles were excluded. At the next step, articles were screened based on relevant titles and abstracts by two authors independently. In cases where it was not possible to select an article based on mentioned information in the abstract, the full text of the article was screened. The disagreements about the eligibility of the articles were resolved through discussion between the two authors. The outcome assessed was seizure recurrence at the following time in children aged ≤6 years in the intervention and nonintervention groups.
Data extraction and quality assessment
Two researchers checked the literature according to the inclusion and exclusion criteria, independently. The main characteristics of the included studies in this systematic review were as follows: First author's last name, year, country of the study population; type of study design; type of interventions and dose of drugs; the number of intervention and comparison groups; the age of study population; follow-up duration; outcome measure; and frequency of outcome. In case of disagreement between the two researchers, the decision was made by discussion or by the third researcher. The quality of trials was independently assessed by two researchers using the JADAD rating scale [Table 1]. Articles with a score of 0–2 were of low quality and those with a score of 3–5 points were of high quality.
To compare the effect of diazepam and phenobarbital with each other and to compare the effect of diazepam and phenobarbital with placebo in preventing FC using odd's ratio, a Forest plot diagram was drawn separately. Cochran's Q and I2 tests were used to evaluate the heterogeneity of the studies. Due to the different designs between studies, the random effect model was used for meta-analysis. Meta-regression test and sensitivity analysis were used to identify the reasons for heterogeneity. The Funnel plot and Egger's test were used to examine the possibility of the publication bias.,, The RevMan version 5.1 software and Stata (Release 17. College Station, TX: StataCorp LLC) were applied for analysis.
| Results|| |
A total of 450 articles with the research questions of PICO (P: Children under 6 years old with a FC; I: Diazepam or phenobarbital; C: Control groups; and O: Recurrence of febrile seizure) were identified. After removing duplicated and irrelevant articles (n = 47) by screening the titles and abstracts of retrieved articles, 335 articles were excluded. By screening the full text of retrieved articles based on the inclusion and exclusion criteria, 51 articles were excluded [Appendix 1]. Finally, 17 articles were identified for review and meta-analysis [Table 1] and [Figure 1]. All of the included articles had an interventional design (22 RCT and 1 Quasi-experimental research) and were in English. The characteristics of the selected articles are displayed in [Table 2]. The majority of included articles had different intervention design. The quality of trials mostly was moderate to high [Table 1].
Among included studies, only 4 studies had reported the recurrence rates of FC after treatment with diazepam in comparison to the phenobarbital (I-squared = 40%), 6 studies had compared diazepam and placebo (I-squared = 47%), and 9 studies phenobarbital and placebo (I-squared = 54%). The results of meta-analysis using the random effect model showed that the use of diazepam in comparison with phenobarbital reduces the risk of recurrence FC by 34%, but the relationship was not statistically significant (risk ratio = 0.66, 95% confidence interval [CI]: 0.36–1.21, P = 0.18) [Figure 2]. The meta-analysis of studies reporting the effect of diazepam or phenobarbital in comparison with placebo showed that the use of diazepam in comparison with placebo significantly reduces the risk of recurrence FC by 49% (risk ratio = 0.51, 95% CI = 0.32–0.79, P = 0.002) [Figure 3] and the use of phenobarbital in comparison with placebo significantly reduces the risk of recurrence FC by 37% (risk ratio = 0.63, 95% CI = 0.42–0.96, P = 0.03) [Figure 4]. In assessing the presence of publication bias, the results revealed that the funnel plots of three meta-analysis are asymmetrical and there are no trials in the lower right corner, suggesting that small trials not favoring the intervention were not published. Egger's test results (P = 0.0584 for comparison of diazepam vs. phenobarbital; P = 0.0421 for comparison of diazepam vs. placebo; P = 0.0402 for comparison of phenobarbital vs. placebo) showed evidence of publication bias. Therefore, it could be concluded that there is a source for publication bias [Figure 5]. According to the results of the meta-regression test, the follow-up time can be a reason for heterogeneity of trials with the comparison of diazepam vs. phenobarbital (r = 0.047, P = 0.049) and phenobarbital versus placebo (r = 0.022, P = 0.016) [Table 3].
|Figure 2: Forest plot for prophylaxis of recurrence febrile convulsion with Diazepam compared to the Phenobarbital|
Click here to view
|Figure 3: Forest plot for prophylaxis of recurrence febrile convulsion with Diazepam compared to the placebo|
Click here to view
|Figure 4: Forest plot for prophylaxis of recurrence febrile convulsion with phenobarbital compared to the placebo|
Click here to view
|Figure 5: Assessment of publication bias by funnel plots for articles comparing Diazepam versus Phenobarbital (a), Diazepam versus Placebo (b), and Phenobarbital versus Placebo (c) in prevention of febrile convulsion|
Click here to view
|Table 3: Accessing the reason for heterogeneity of trials with meta-regression test|
Click here to view
Results of sensitivity analysis to omit the Thilothammal et al. study due to statistical reason (outlier result in the funnel plot) showed that there is still a protective effect for phenobarbital against the recurrence of febrile convulsive compared to placebo, but this protective effect was not statistically significant (risk ratio = 0.74, P = 0.08).
| Discussion|| |
Although due to the benign and self-limiting nature of febrile seizure as well as the potential toxicity associated with anticonvulsant drugs, prophylactic treatment with these drugs is not routinely recommended, in some cases, especially when the anxiety and stress of parents are high or when the child is at high risk of recurrence of seizures due to several risk factors, prophylactic treatment can be considered.,, Among anticonvulsant drugs, the most commonly used drugs for the prophylaxis of recurrent FS are phenobarbital and diazepam. This study aimed to compare the use of oral or rectal diazepam during febrile illness and continuous use of phenobarbital with each other or with placebo to prevent recurrence of FS among children under 6 years of age. Out of 17 articles related to the purpose of the study, 6 studies examined the effect of diazepam versus placebo, 9 studies phenobarbital versus placebo, and 4 studies phenobarbital and diazepam. The study design of all these studies was a randomized clinical trial (RCT). However, there was a relatively high heterogeneity between studies. For example, in the four studies of Salehiomran in 2016, Beyraghi in 2008,Ramakrishnan in 1986, and Knudsen in 1978, with comparison, the effectiveness of phenobarbital versus diazepam, the study population and follow-up periods were relatively different. For example, in the two studies of Iran, Salehiomran, and Beyraghi et al. studies, the follow-up times were 12–18 months. Moreover, in the Salehiomran et al.'s study, children with a history of three simple or complex FC were included. However, in the Ramakrishnan study, children with a history of one FC were included and followed up for 6 years. The result of the meta-regression test in assessing the role of different follow-up periods in diversity between studies was also significant. Research has indicated that an important source of heterogeneity is variations in study quality. A large survey has also shown that <20% of the studies satisfied five of the seven examined methodological standards. Our meta-analysis showed that the risk of recurrent FC was lower in children taking diazepam than in those taking phenobarbital, but this relationship was not statistically significant. Moreover, our results demonstrated that diazepam or phenobarbital reduced the risk of FC recurrence by about 50% more than placebo and the relationship was also statistically significant. Of nine studies comparing the effect of phenobarbital vs. placebo, seven studies reported that phenobarbital is more effective than placebo in preventing FC recurrence. Only in two studies by Ramakrishnan and McKinlay et al., phenobarbital had increased the risk of FC recurrence by 50% and 25%, respectively, compared to placebo or no intervention. In the Ramakrishnan study, children with a history of FC were randomly divided into four groups of 30 individuals as follows: Group 1: Continuous phenobarbital; Group 2: Intermittent phenobarbital; Group 3: Intermittent diazepam, and Group 4: No intervention. Among the continuous use of phenobarbital's group, 3 out of 30 children had a history of epilepsy in one of their parents, 4 children had a history of FC in one of the siblings, and 3 children had a seizure without fever. However, in the no-intervention group, none of the children had a positive family history of FC. However, the relationship between seizures and family history of seizures was not statistically significant. In this study, diazepam was recommended as a preferred FC prophylactic drug. In the McKinlay study, in the phenobarbital group, 12 out of 41 children (29%) and in the control group, 14 out of 60 patients (23%) had a recurrent FC during follow-up period. In other words, the risk of recurrent FC among phenobarbital group was 25% higher than the no treatment group. However, the relationship was not statistically significant. In this study, there was no significant difference in age and sex between groups, but when children were divided into two age groups of ≤2 years and over 2 years, the risk of recurrent FC in the phenobarbital group was 38% lower than control group (risk ratio = 0.62). However, in children >2 years old, the risk of recurrent FC was two times more than the control group (risk ratio = 2.16). In the McKinlay study, although the number of children with a previous complicated FC was higher in the control group than the phenobarbital group (43% vs. 27%), but the recurrent rate of FC in the phenobarbital group was higher than the control group. Therefore, they did not recommend the use of phenobarbital as a prophylactic drug, especially in children at high risk of recurrent FC. According to the Cochrane Review 2013, there was no clinical benefit for children with a history of FC using diazepam or phenobarbital. Due to the benign nature of FC and the high rate (30%) of side effects of anticonvulsant drugs, it was recommended that only patients' parents or families should be supported to receive medical counseling services, information about primary services, recurrent rate of febrile seizure, and nature of the febrile seizure. However, in the Cochrane review 2017, it was reported that the intermittent use of diazepam or continuous use of phenobarbital could be effective in the recurrence rate of FS. The results of this systematic review and meta-analysis were also consistent with the results of Cochrane Review 2017.
| Conclusion|| |
Our results indicated that intermittent diazepam and continuous phenobarbital reduce the risk of recurrent FCs among children with a history of FC. Moreover, due to the benign but frightening nature of FC, patients' parents or caregivers should be consulted.
Limitations of the study
There are some limitations in the review. There were not enough new trials with high qualities. Most studies were done 1–2 decades ago and mostly had heterogeneous designs in terms of follow-up, randomization, and blindness.
This review was supported by the Evidence-Based Medicine (EBM) center and received approval from the Ethical Committee of Tabriz University of Medical Sciences (IR.TBZMED.VCR.REC.1399.015).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Fetveit A. Assessment of febrile seizures in children. Eur J Pediatr 2008;167:17-27.
Leung AK, Hon KL, Leung TN. Febrile seizures: An overview. Drugs Context 2018;7:212536.
Patterson JL, Carapetian SA, Hageman JR, Kelley KR. Febrile seizures. Pediatr Ann 2013;42:249-54.
Patel N, Ram D, Swiderska N, Mewasingh LD, Newton RW, Offringa M. Febrile seizures. BMJ 2015;351:h4240.
Gupta A. Febrile seizures. Continuum (Minneap Minn) 2016;22:51-9.
Barzegar M, Valizadeh S, Gojazadeh M, Asghari Jafarabadi M, Zamanzadeh V, Shahbazi S. The effects of two educational strategies on knowledge, attitude, concerns, and practices of mothers with febrile convulsive children. Thrita 2016;5:e33411.
Offringa M, Newton R, Cozijnsen MA, Nevitt SJ. Prophylactic drug management for febrile seizures in children. Cochrane Database Syst Rev 2017;2:CD003031.
Jadad AR, Cook DJ, Browman GP. A guide to interpreting discordant systematic reviews. CMAJ 1997;156:1411-6.
Ioannidis JP. Interpretation of tests of heterogeneity and bias in meta-analysis. J Eval Clin Pract 2008;14:951-7.
Lin L, Chu H. Quantifying publication bias in meta-analysis. Biometrics 2018;74:785-94.
van Enst WA, Ochodo E, Scholten RJ, Hooft L, Leeflang MM. Investigation of publication bias in meta-analyses of diagnostic test accuracy: A meta-epidemiological study. BMC Med Res Methodol 2014;14:70.
Walker E, Hernandez AV, Kattan MW. Meta-analysis: Its strengths and limitations. Cleve Clin J Med 2008;75:431-9.
Salehiomran M, Hoseini SM, Ghabeli Juibary A. Intermittent diazepam versus continuous phenobarbital to prevent recurrence of febrile seizures: A randomized controlled trial. Iran J Child Neurol 2016;10:21-4.
Taghdiri MM, Heidari A, Mojarrad M, Fallah M. Study of rectal diazepam in prevention of simple febrile convulsions recurrence. Iran Red Crescent Med J 2011;13:438-9.
Beyraghi N, Hatamian B, Vesal A, Tonekaboni SH. Comparison between diazepam and phenobarbital in prevention of febrile seizure: Clinical trial. Iran J Child Neurol 2008;2:37-40.
Pavlidou E, Tzitiridou M, Panteliadis C. Effectiveness of intermittent diazepam prophylaxis in febrile seizures: Long-term prospective controlled study. J Child Neurol 2006;21:1036-40.
Verrotti A, Latini G, di Corcia G, Giannuzzi R, Salladini C, Trotta D, et al.
Intermittent oral diazepam prophylaxis in febrile convulsions: Its effectiveness for febrile seizure recurrence. Eur J Paediatr Neurol 2004;8:131-4.
Rosman NP, Colton T, Labazzo J, Gilbert PL, Gardella NB, Kaye EM, et al.
A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures. N Engl J Med 1993;329:79-84.
Thilothammal N, Kannan, Krishnamurthy PV, Kamala KG, Ahamed S, Banu K. Role of phenobarbitone in preventing recurrence of febrile convulsions. Indian Pediatr 1993;30:637-42.
Autret E, Billard C, Bertrand P, Motte J, Pouplard F, Jonville AP. Double-blind, randomized trial of diazepam versus placebo for prevention of recurrence of febrile seizures. J Pediatr 1990;117:490-4.
Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures – Effects on intelligence and on seizure recurrence. N Engl J Med 1990;322:364-9.
McKinlay I, Newton R. Intention to treat febrile convulsions with rectal diazepam, valproate or phenobarbitone. Dev Med Child Neurol 1989;31:617-25.
Ramakrishnan K, Thomas K. Long term prophylaxis of febrile seizures. Indian J Pediatr 1986;53:397-400.
Camfield PR, Camfield CS, Shapiro SH, Cummings C. The first febrile seizure – Antipyretic instruction plus either phenobarbital or placebo to prevent recurrence. J Pediatr 1980;97:16-21.
Ngwane E, Bower B. Continuous sodium valproate or phenobarbitone in the prevention of 'simple' febrile convulsions. Comparison by a double-blind trial. Arch Dis Child 1980;55:171-4.
Bacon CJ, Hierons AM, Mucklow JC, Webb JK, Rawlins MD, Weightman D. Placebo-controlled study of phenobarbitone and phenytoin in the prophylaxis of febrile convulsions. Lancet 1981;2:600-4.
Knudsen FU, Vestermark S. Prophylactic diazepam or phenobarbitone in febrile convulsions: A prospective, controlled study. Arch Dis Child 1978;53:660-3.
Heckmatt JZ, Houston AB, Clow DJ, Strephenson JB, Dodd KL, Lealman GT, et al.
Failure of phenobarbitone to prevent febrile convulsions. Br Med J 1976;1:559-61.
Mackintosh TF. Studies on prophylactic treatment of febrile convulsions in children. Is it feasible to inhibit attacks by giving drugs at the first sign of fever or infection? Clin Pediatr (Phila) 1970;9:283-6.
Natsume J, Hamano SI, Iyoda K, Kanemura H, Kubota M, Mimaki M, et al.
New guidelines for management of febrile seizures in Japan. Brain Dev 2017;39:2-9.
Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures American Academy of Pediatrics. Febrile seizures: Clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008;121:1281-6.
Lijmer JG, Bossuyt PM, Heisterkamp SH. Exploring sources of heterogeneity in systematic reviews of diagnostic tests. Stat Med 2002;21:1525-37.
Offringa M, Newton R. Prophylactic drug management for febrile seizures in children. Sao Paulo Med J 2013;131:285.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]