Comparison of intranasal midazolam with intravenous diazepam for treating acute seizures in children

Midazolam, a water-soluble benzodiazepine, is usually given intravenously in status epilepticus. The aim of this study was to determine whether intranasal midazolam is as safe and effective as intravenous diazepam in the treatment of acute childhood seizures. Seventy children aged 2 months to 15 years with acute seizures (febrile or afebrile) admitted to the pediatric emergency department of a general hospital during a 14-month period were eligible for inclusion. Intranasal midazolam 0.2 mg/kg and intravenous diazepam 0.2 mg/kg were administered after intravenous lines were established. Intranasal midazolam and intravenous diazepam were equally effective. The mean time to control of seizures was 3.58 (SD 1.68) minutes in the midazolam group and 2.94 (SD 2.62) in the diazepam group, not counting the time required to insert the intravenous line. No significant side effects were observed in either group. Although intranasal midazolam was as safe and effective as diazepam, seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Intranasal midazolam can possibly be used not only in medical centers, but also in general practice and at home after appropriate instructions are given to families of children with recurrent seizures.     

Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: A randomized controlled trial

A study was done to examine the efficacy of buccal midazolam in controlling convulsion in children by comparing it with intravenous diazepam, a standard mode of treating convulsions. One hundred and twenty cases presenting with convulsions to emergency were treated randomly with either buccal midazolam (in a dose of 0.2 mg/kg) or intravenous diazepam (in a dose of 0.3 mg/kg). Partial seizures, generalized tonic, clonic and tonic–clonic convulsions were included irrespective of duration or cause. One episode per child only was included. The frequency of overall control of convulsive episodes within 5 min were 85% and 93.3% in buccal midazolam and intravenous diazepam groups, respectively; the difference was, however, not statistically significant (p = 0.142). The mean time needed for controlling the convulsive episodes after administration of the drugs was significantly less with intravenous diazepam (p = <0.001). The mean time for initiation of treatment was significantly less with buccal midazolam (p = <0.001). The mean time for controlling the convulsive episodes after noticing these first were significantly less with buccal midazolam than with intravenous diazepam (p = 0.004) that is likely to be due to longer time needed for initiating treatment with intravenous diazepam in preparing the injection and establishing an IV line. There was no significant side effect in both the groups. The findings suggest that buccal midazolam can be used as an alternative to intravenous diazepam especially when getting an IV line becomes difficult. In situations where establishing an IV line is a problem, buccal midazolam may be the first choice.     

Intranasal midazolam vs rectal diazepam in acute childhood seizures

One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.     

Respiratory depression in children receiving diazepam for acute seizures: a prospective study

The aim of this study was to determine the incidence of respiratory depression following the use of diazepam in children presenting with seizures. All children presenting with seizures to a children's A & E department over a period of 9 months were studied prospectively. Respiratory depression was defined as a fall in respiratory rate or oxygen saturation, or apnoea resulting in ventilation or resuscitation with bag-and-mask oxygen. There were 130 patient episodes involving 97 children who received treatment for their seizures before admission and/or in the A & E department. Administration of diazepam resulted in 122 patient episodes. The route of administration was rectal in 91 episodes, intravenous in 12 episodes, and both rectal and intravenous in 19 episodes. Eleven children had respiratory depression in relation to diazepam administration. Eight of these children required ventilation. The overall incidence of respiratory depression following the use of diazepam was 9%. The incidence of respiratory depression following diazepam given intravenously or rectally is high. The use of diazepam as first-line therapy for children with acute seizures needs to be reviewed.     

Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteers

Objective – The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies. Methods – Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four‐way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration. Results – The C_max and T_max values for i.n. DZP and MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively. Conclusion – Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half‐life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted.     

Pharmacokinetics of rectal diazepam in the prevention of recurrent febrile convulsions

To determine the optimum dosage schedule for intermittent rectal diazepam in suppository form for the prevention of recurrent febrile convulsions, we studied the pharmacokinetics of diazepam administered in repeated rectal doses. The plasma concentration-time data for diazepam on twice repeated rectal dosing with 0.5 mg/kg at 8-hour intervals in six infants showed that therapeutic plasma levels could be attained within 30 minutes and maintained for the first 24 hours. Most of the observed plasma diazepam levels were found to be within +/- one standard deviation of the values calculated from the pharmacokinetic parameters in six other infants with single rectal dosing. Computer-simulated plasma level profile suggested that plasma diazepam levels may reach the toxic range after administration of five or more doses. Twice repeated rectal dosing with 0.5 mg/kg of diazepam in suppository form at 8-hour intervals during the febrile period may be a rational approach for the prevention of recurrent febrile convulsions.     

Prognosis and risk factors in febrile convulsions: a prospective study of 150 children in Kuwait

One hundred and fifty children with febrile convulsions (FC) were followed up for 3-10 years. They were divided into two groups: group A consisted of 120 children whose disorder was under control, and group B 30 patients in whom the disorder was not under control. Risk factors for uncontrolled FC and later development of epilepsy were looked into. In group A, 8 patients (6.6%) developed epilepsy, while another 3 (2.5%) had a single afebrile seizure. In group B, 10 (33.3%) children developed epilepsy, while 1 (3.3%) had a single afebrile seizure. The difference in the later occurrence of epilepsy between the two groups was statistically significant.     

A prospective study of acute movement disorders in children

Aim The purpose of this study was to report a prospective cohort of children with acute‐onset movement disorders. Method We report on 52 individuals (31 females, 21 males; mean age 6y 5mo, range 2mo–15y) with acute‐onset movement disorders managed at a busy tertiary paediatric referral hospital over a 40‐month period. Results In descending order of frequency, the movement disorders reported were chorea, dystonia, tremor, myoclonus, and parkinsonism. It was possible to divide the participants into three groups: (1) those with inflammatory or autoimmune disorders (n=22), (2) those with non‐inflammatory disorders (n=18), and (3) those with psychogenic disorders (n=12). The inflammatory or autoimmune aetiologies included N‐methyl‐d ‐aspartate receptor encephalitis (n=5), opsoclonus–myoclonus syndrome (n=4), Sydenham chorea (n=3), systemic lupus erythematosus (n=3), acute necrotizing encephalopathy (n=3), and other types of encephalitis (n=4). Other important non‐inflammatory movement disorder aetiologies included drug‐induced movement disorder (n=6), post‐pump chorea (n=5), metabolic (n=3) and vascular (n=2) disease. The participants with psychogenic movement disorders (n=12) were all over 10 years of age and were more likely to be female. Tremor and myoclonus were significantly over‐represented in the psychogenic movement disorder subgroup. The outcomes of the total cohort were variable, and included full recovery, severe morbidity, and death. Interpretation Acute‐onset movement disorders in children are important and may be treatable. Management should focus upon identifying the cause and treating the underlying disease process, as symptomatic treatment of the abnormal movements is variably effective.     

Effectiveness of intranasal zolmitriptan in acute cluster headache: a randomized, placebo-controlled, double-blind crossover study

BACKGROUND: Cluster headache is a form of primary headache in which attacks are rapid in onset with very severe pain. The mainstays of acute therapy are inhaled oxygen and sumatriptan succinate injection. OBJECTIVE: To evaluate zolmitriptan nasal spray in the acute treatment of cluster headache. METHODS: Ninety-two patients, aged 40 +/- 10 years (mean +/- SD) (80 men and 12 women), with International Headache Society-defined cluster headache were randomized into a placebo-controlled, double-blind crossover study. Patients treated 3 headache attacks using placebo for 1 attack, 5 mg of zolmitriptan nasal spray (ZNS5) for 1 attack, and 10 mg of zolmitriptan nasal spray for 1 attack. The primary end point was headache relief at 30 minutes, defined as reduction from moderate, severe, or very severe pain to no or mild pain. The study was approved by the appropriate ethics committees. RESULTS: Sixty-nine patients were available for an intention-to-treat analysis. The 30-minute headache relief rates were placebo, 21%; ZNS5, 40%; and ZNS10, 62%. Modeling the response as a binary outcome, the Wald test was significant for the overall regression (chi(2)(1) = 29.4; P<.001), with both ZNS5 and ZNS10 giving significant effects against placebo. Headache relief rates for patients with episodic cluster headache were 30% for placebo, 47% for ZNS5, and 80% for ZNS10, while corresponding rates for patients with chronic cluster headache were 14%, 28%, and 36%, respectively. Zolmitriptan was also well tolerated. CONCLUSION: Five-milligram and 10-mg doses of zolmitriptan intranasal spray are effective within 30 minutes and well tolerated in the treatment of acute cluster headache. Trial Registration controlled-trials.com Identifier ISCRTN27362692.     

A comparison of midazolam nasal spray and diazepam rectal solution for the residential treatment of seizure exacerbations

Rectal diazepam is established as a standard rescue or emergency treatment for seizure or status epilepticus; however, the rectal route of administration has not been universally accepted. To determine if an alternative route of administration of a benzodiazepine was equally effective, we compared a novel midazolam HCl concentrated nasal spray (MDZ‐n) with diazepam rectal solution (DZP‐r) in the treatment of prolonged seizures in a residential epilepsy center. In 21 adult patients with medically refractory epilepsy, 124 seizure‐exacerbations were treated by their caregivers, alternatively with 10 mg DZP‐r and 10 mg concentrated MDZ‐n, two or three treatments with each medication for each patient. No difference was demonstrated in efficacy or time to effect between the two drugs. Common treatment emerging adverse effects were drowsiness for both drugs in more than 50% of the administrations, and short‐lasting local irritation after 29% of MDZ‐n. No severe adverse events occurred. The nasal spray was preferred to the rectal solution by 16 of 21 caregivers and patients conjointly. MDZ‐n was equal to DZP‐r with respect to efficacy and side effects in the suppression of seizure exacerbations. The majority of patients and caregivers preferred the nasal spray over the rectal formulation.     

Late-onset epilepsy in children with acute febrile encephalopathy with prolonged convulsions: A clinical and encephalographic study

The aim of this study is to analyze the characteristics of epilepsies as the sequelae of acute febrile encephalopathy with prolonged convulsions during childhood. Sixteen patients (M:F = 9:7) aged 2–13 years (mean 6.1 years) with history of febrile acute encephalopathy were retrospectively reviewed. These patients experienced febrile encephalopathy at the age of 11 months to 4 years, with 11 individuals presenting with findings of a biphasic clinical course (n = 5), frontal predominant (n = 8) lesions, and/or reduced diffusivity in the cerebral white matter on magnetic resonance imaging (MRI; n = 3). The remaining 5 patients had unilateral lesions that manifested the phenotype of hemiconvulsion–hemiplegia–epilepsy syndrome (HHES). Epilepsy emerged with a latent period of 2 months to 2 years after the acute phase of febrile encephalopathy. Head nodding or spasm with subsequent motion arrest and brief tonic seizures were the main seizure phenotypes. Ictal records of epileptic seizures were available in 9 patients. Epileptiform discharges with a focal or uneven distribution appeared at the seizure onset and lasted less than 1 s in all patients; these were followed by either generalized attenuation or fast activity in 8 patients with head nodding, spasm, or brief tonic seizures, and by localized fast activity in 1 patient with versive tonic seizures. Notably, the seizure onset area was often located outside the severe lesions on MRI, i.e., in the parietal areas in patients with frontal predominant lesions, and in the spared hemisphere of HHES. Although phenobarbital, zonisamide, carbamazepine, clobazam, clonazepam, and clorazepate were partially effective in some patients, daily seizures persisted in 11 patients. Callosotomy was performed in 2 patients, and beneficial effects were observed in both. These characteristics suggested a broad distribution of augmented excitability in these patients, resulting in the rapid propagation of epileptic activity in the initial phase of ictal phenomena. Thus, this study investigates the most severe subgroup of epilepsy following febrile acute encephalopathy and provides the basis for further exploration of the pathogenesis and treatment of characteristic seizures in this population.     

Intermittent prophylaxis in febrile convulsions: diazepam or valproic acid?

In an open, prospective, randomized, and hospital-based study, comprising 219 consecutive children, 169 were given intermittent prophylaxis for one year, receiving either diazepam or valproic acid after their first febrile convulsion. Children admitted on odd dates (n = 89) were given rectal diazepam in solution every 12 h, whenever the temperature was 38.5 degrees C or more. Children admitted on even dates (n = 80) were given valproic acid as suppositories at times of fever. Twenty-three children in the diazepam group had a recurrence within 1 year versus 14 in the valproic acid group. On an intention-to-treat basis the 12-month recurrence rates in the 2 groups were similar, 27% vs 20%. The latter is well below figures for untreated controls from Denmark (32%), suggesting that intermittent valproic acid at times of fever may be effective, but further studies are needed. The number of complex recurrences, however, were significantly higher in the valproic acid group than in the diazepam group. Parental non-compliance was a major problem, and in the 2 study groups only 5 and 12 children, respectively, with recurrences were treated adequately. Sixty-nine children receiving diazepam had side-effects vs 37 receiving valproic acid. None were serious.     

A longitudinal,randomized, and prospective study of nocturnal monitoring in children and adolescents with epilepsy: Effects on quality of life and sleep

ObjectiveMost studies on seizure detection systems focus more on the effectiveness of devices than on their practicability in and impact on everyday life. Our study investigated the impact of a technical monitoring system on subjective quality of sleep and the lives of affected families. Furthermore, we evaluated the impact of anxiety levels on seizure monitoring and vice versa.MethodsForty-three patients with newly diagnosed epilepsy were included. Initially, the families decided whether they did (group 1, n = 27) or did not (group 2, n = 16) want to use a monitoring device. In group 1, patients were randomly assigned to using Epi-Care® (group 1A, n = 14) or an audio baby monitor (group 1B, n = 13). Quality of life was assessed at two points (t1, at the start of the study and t2, at 5–7 months of follow-up) using the SF-12, Kindl-R, and “Familien-Belastungs-Fragebogen” (German version of the “Impact on Family Scale”). In addition, parental anxiety was measured using the State–Trait Anxiety-Inventory, and subjective quality of sleep was measured using the Pittsburgh Sleep Quality Index. Statistical analysis focused on the possible differences between groups 1 and 2 that may influence parents' decisions and the effects of the presence and types of technical monitoring over time.ResultsAnxiety levels were not significantly different between the groups with and without monitoring (group 1 vs. group 2). We also found no statistically significant, substantial baseline differences between the Epi-Care® and audio baby monitor groups, with at least medium effect sizes (group 1A vs. group 1B). Parents' health-related mental quality of life measured via the SF-12 increased significantly over time in all groups. By tendency, the fear of further seizures as well as the frequency of cosleeping arrangements in the monitoring group decreased during the study and approached the stable values of the control group.SignificanceIndividual parental anxiety levels are not crucial in the decision regarding the use of a monitoring device. A monitoring system may help some families in certain aspects of daily life. During the first months following a diagnosis of epilepsy, quality of life increases independently of the use of a monitoring system.     

Effects of anticonvulsant therapy on vitamin D status in children: prospective monitoring study

Reports of hypovitaminosis D associated with anticonvulsant drugs in pediatric patients are conflicting. The effects of carbamazepine or sodium valproate on vitamin D status were evaluated prospectively in 51 ambulatory epileptic children who were followed during the first year of the study and in 25 and 6 children during the second and third year, respectively. Serum 25-hydroxyvitamin D, parathyroid hormone, calcium, and phosphorus levels were determined before and every 3 months during anticonvulsant therapy. Our subjects were grouped into four classes (0, 1, 2, and 3 consisted of the patients before and during the first, second, and third years of the treatment, respectively). The control group consisted of 80 healthy children. Comparisons between controls and patients of class 0 for the means for each season of all variables showed no significant differences. A decreasing trend in serum 25-hydroxyvitamin D (P < .03) and an increasing trend in serum parathyroid hormone (P < .04) levels were noticed in all seasons from class 0 to class 3. Twenty-five patients (49%) acquired hypovitaminosis D during the study period. The effects of seasonality on serum 25-hydroxyvitamin D, parathyroid hormone, and calcium were noticed in our patients grouped in classes 0, 2 and 3, as well as in controls. Evidence is provided that carbamazepine or sodium valproate can cause hypovitaminosis D in children.