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.

Fosphenytoin in infants of extremely low birth weight.

Fosphenytoin, a phosphorylated prodrug of phenytoin, is useful for acute seizures, is given by parenteral administration, and has few cardiac and local irritation adverse effects. There is limited experience in the administration of this new agent to newborns, and concern has been raised regarding the conversion of the prodrug to phenytoin. In two low--birth-weight infants, it was observed that fosphenytoin was converted adequately with varying effects on seizure control.

Relative bioavailability of lamotrigine chewable dispersible tablets administered rectally.

STUDY OBJECTIVE: To determine the relative bioavailability of lamotrigine (LTG) chewable dispersible tablets after rectal administration. DESIGN: Two-period, crossover study with a 2-week washout between dosing periods. SETTING: Clinical research center. PATIENTS: Twelve healthy adult volunteers. INTERVENTION: One hundred milligrams of a LTG chewable dispersible tablet was administered by oral and rectal routes. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected before and up to 120 hours after drug administration. The samples were analyzed for LTG by high-performance liquid chromatography, and the relative bioavailability was determined. Drug concentrations were lower after rectal than after oral administration. The relative bioavailability (F = AUC(rectal)/AUC(oral)) was 0.52 +/- 0.23 (SD). CONCLUSION: Drug prepared from LTG chewable dispersible tablets is absorbed rectally, although not to the same extent as when given orally. Rectal administration of suspension of these tablets can be an acceptable route of administration.

Rectal absorption of lamotrigine compressed tablets.

PURPOSE: Interruption of oral drug administration poses a significant clinical problem for antiepileptic drugs that have no parenteral formulation. If a drug is absorbed rectally, rectal administration can be a useful alternative when the oral route of administration is not possible. The purpose of this study was to compare the single-dose pharmacokinetics of lamotrigine (LTG) compressed tablets after rectal and oral administration in healthy volunteers. METHODS: A single LTG compressed tablet (100 mg) was administered orally and rectally to 12 volunteers in this single-dose, two-period, crossover study with a 2-week washout between doses. For rectal administration, tablets were crushed and suspended in 10 mL of water. Plasma samples were collected from 0 to 120 hr after each dose and analyzed for LTG by an HPLC method developed for this investigation. RESULTS: LTG plasma concentrations were lower after rectal administration versus oral administration. The average area under the curve was 28.90 +/- 9.5 microg/mL/hr after rectal administration and 51.71 +/- 19.2 microg/mL/hr after oral administration. The average maximum LTG concentration was 0.53 +/- 0.14 microg/mL after rectal administration and 1.45 +/- 0.35 microg/mL after oral administration. The relative bioavailability for LTG compressed tablets was 0.63 +/- 0.33 for rectal administration. There were no drug-related rashes or serious side effects. CONCLUSIONS: LTG suspension prepared from LTG compressed tablets is absorbed rectally, although not to the same extent or rate as when given orally.

An open-label study of repeated use of diazepam rectal gel (Diastat) for episodes of acute breakthrough seizures and clusters: safety, efficacy, and tolerance. North American Diastat Group.

PURPOSE: To assess safety of diazepam rectal gel (DZPRG) for control of acute seizures in epilepsy patients and to evaluate tolerance with repeated use of DZPRG at intervals of > or =5 days. METHODS: Subjects were persons with epilepsy, age 2 years or older, with seizure clusters or prolonged seizures. Onset of a treatable episode was defined; caregivers were trained to administer DZPRG and to monitor respiration, seizures, and adverse effects (AEs). DZPRG was dispensed in a single-use, prefilled syringe; dosage was determined by age and weight. Maximal use was > or =5-day intervals, < or =5 times/month. After use, caregivers returned data booklets and syringe. Caregivers and physicians completed global ratings yearly. RESULTS: In 149 subjects treated, 77% of 1,578 administrations resulted in seizure freedom for the next 12 h. One hundred twenty-five received two or more treatments (two to 78; median, 8), 0.03-4.3/month (median, 0.4). To evaluate tolerance, subjects with two or more episodes were divided into low (two to seven episodes) and high use (eight to 78 episodes treated). There was no difference in proportion seizure free 12 h after the first administration versus last administration, for either infrequent or frequent administration. Sedation occurred in 17%, attributed to DZPRG in 9%. No respiratory depression was attributable to DZPRG. Three subjects withdrew because of AEs attributable to (agitation) or possibly attributable to DZPRG (chest pain, rash). Five subjects withdrew because of AEs unrelated to DZPRG. Caregiver and physician global ratings were highly positive at both 12 and 24 months. CONCLUSIONS: DZPRG is safe and effective in children and adults with epilepsy with breakthrough seizures. Neither tolerance nor significant medication-related AEs were seen with repeated DZPRG administration at intervals > or =5 days.

Rectal diazepam gel for treatment of acute repetitive seizures. The North American Diastat Study Group.

The purpose of these investigations was to determine from combined data the response to rectal diazepam (DZP) gel (Diastat [Athena Neurosciences, South San Francisco, CA]) in home treatment of children with episodes of acute repetitive seizures (ARS). A subset of patients aged 2-17 years were selected from two prospective placebo-controlled studies of children and adults. In both studies a prospective, double-blind, placebo-controlled design was used. The treatment groups (68 DZP; 65 placebo) did not differ significantly in age, race, seizure type or etiology, or in the median number of ARS episodes per month before study entry. DZP-treated children demonstrated a significant reduction in median seizure frequency compared with the placebo group (0.00 vs 0.25 seizures per hour, P = 0.001). Significantly more DZP-treated children remained seizure free during the observation period (40 vs 20, P = 0.001). Somnolence was the only adverse effect present significantly more often in the DZP-treated children (25.0% vs 7.7%, P = 0.0095). There were no instances of serious respiratory depression. Rectal DZP was demonstrated to be an effective and safe treatment to abort an episode of ARS in a child and, additionally, lessened the likelihood of seizure recurrence within the next 12 hours.

Treating repetitive seizures with a rectal diazepam formulation: a randomized study. The North American Diastat Study Group.

OBJECTIVE: To evaluate the effectiveness and safety of a single-dose treatment for acute repetitive seizure (ARS) episodes (e.g., clusters) administered in a nonmedical setting by caregivers. BACKGROUND: Patients with epilepsy may experience ARS episodes despite optimal anticonvulsant treatment. Such episodes require rapid treatment as medical emergencies. Typically, the patient is treated in an emergency medical setting with i.v. medication by trained medical personnel. METHODS: The authors undertook a multicenter, randomized, parallel, double-blind study of a single administration of Diastat (diazepam rectal gel) for treating episodes of ARS. ARS episodes and treatment criteria were defined for each patient at the start of the study. Caregivers were taught to determine ARS episode onset, administer a predetermined dose of study medication, monitor outcome, count respirations, and record seizures and adverse events. RESULTS: A total of 29 centers enrolled 158 patients, of whom 114 patients had a treated ARS episode (Diastat, n = 56; placebo, n = 58). Diastat treatment reduced median seizure frequency (p = 0.029). More Diastat patients were seizure free post-treatment (Diastat, 55%; placebo, 34%; p = 0.031). Kaplan-Meier analysis of the time to the next seizure favored Diastat treatment (p < 0.007). The most common adverse event was somnolence. CONCLUSION: Administration of a single rectal dose of Diastat was significantly more effective than placebo in reducing the number of seizures following an episode of ARS. Caregivers could administer treatment safely and effectively in a nonmedical setting.

Late improvements in mobility after acquired brain injuries in children.

The purpose of this investigation was to describe the late improvements in functional mobility in children who have sustained severe acquired anoxic or traumatic brain injuries. Ninety-eight children from a consecutive series of 199 with acquired brain injuries met inclusion criteria. As expected, children with traumatic injuries had better mobility at time of discharge from rehabilitation than did children with anoxic injury. In addition, children with traumatic injuries improved more in mobility status during the first 2 years after injury than did children with anoxic injury. The children who continued to improve in mobility after discharge were unconscious for a shorter time. Children who became community ambulators during the first year after discharge had higher mobility ratings at discharge. Although children who eventually achieved more functional mobility were admitted to rehabilitation service sooner after injury, discriminant analysis revealed that the duration of unconsciousness, and therefore severity of injury, was more closely correlated with the final mobility status.

Failure of absorption of baclofen after rectal administration.

We wished to determine the degree to which baclofen was absorbed from an aqueous vehicle after rectal administration. A comparison was made to absorption after oral administration. After oral administration, the baclofen half-life was 2.3 to 3.4 hours and peak serum concentrations were achieved from 1 to 2.1 hours after administration. No measurable absorption was observed after rectal administration of the drug in any subject. Rectal administration of baclofen is not a clinically sound treatment option when oral administration of the drug is not possible. For patients receiving chronic baclofen therapy, other medications such as a benzodiazepine should be considered at times when oral administration of medication is not possible.

Failure of absorption of gabapentin after rectal administration.

PURPOSE: We wished to determine the extent of absorption of gabapentin (GBP) after rectal administration to children on maintenance therapy. METHODS: Two children scheduled for extensive surgery received GBP rectally and orally. A pharmacokinetic profile was derived after each route of administration. RESULTS: Serum GBP levels after rectal administration decreased at a rate similar to their rate of decrease after oral administration. However, GBP concentrations were much lower after rectal administration; therefore, we concluded that the aqueous solution was poorly absorbed rectally. The GBP half-life (t1/2) for the 2 children after oral doses were 4.2 and 4.8 h. CONCLUSIONS: Rectal administration of GBP is not satisfactory when oral administration is interrupted. When oral GBP therapy is temporarily discontinued, clinicians should consider administration of alternative antiepileptic drugs (AEDs) that can be administered parenterally or rectally.

Automatic garage door openers: hazard for children.

OBJECTIVES: Despite significant advances in automatic garage door opener design, automatic garage door openers continue to severely injure or kill children. In this investigation, we sought to determine the frequency and circumstances of accidents that have caused severe injury or death to children. We also tried to develop a means by which homeowners can evaluate their door openers. METHODS: We present the histories of three children severely injured or killed by automatic garage door openers. We reviewed national data of similar accidents primarily published by the US Product Safety Commission and Underwriters Laboratories. Also, we evaluated 50 automatic door openers for safety of operation. The reversing mechanisms of door openers were tested using a cardiopulmonary resuscitation mannequin, a roll of paper towels, and a block of wood. RESULTS: In the United States, at least 85 children have had permanent brain injury or have died since 1974 as a result of accidents involving automatic door openers. A review of circumstances of the accidents illustrates that accidents are caused both by use of the openers by children and by faults in design. Most accidents have occurred when children have found access to the activation devices and have been entrapped under closing doors that failed to reverse. However, in one case, an adult activated the opener and left the premises before the door completely closed. Our evaluation of 50 garage door openers showed that although 88% percent reversed when encountering a block of wood, 40% failed to reverse when coming down on a supine, child-sized cardiopulmonary resuscitation mannequin. CONCLUSIONS: Automatic garage door openers pose a serious risk of severe injury or death to children. It is probable that many doors would not reverse if they came down on a young child. Therefore, we have devised a way for homeowners to test their door openers that closely mimics our evaluations using the mannequin by using a large roll of paper towels. If the door fails to reverse using this test, we suggest that homeowners disconnect their openers and operate the doors manually until the openers are serviced or replace their automatic openers with one that meets the latest Underwriters Laboratory standards. We also have other recommendations regarding the safe operation of the doors, including improving the safety standards for openers in apartment complexes. Compliance with these recommendations should reduce the number of injuries to children caused by garage door openers.

Perioperative blood loss: the effect of valproate.

The purpose of this investigation was to determine the effect of the use of valproate (VPA) on bleeding and requirement for replacement blood products in patients undergoing major surgical procedures. One hundred thirty-nine patients had posterior spinal fusion performed by 1 of 3 surgeons at our institution from 1987 to 1993. The clinical status of the patient, pre- and postoperative laboratory values, type and extent of instrumentation, surgeon performing the procedure, and medications (including VPA) were variables considered. The outcome measures were intra- and postoperative blood loss and number of blood products used. Intraoperative blood loss was correlated with the method of instrumentation, platelet count, and the surgeon performing the procedure. Postoperative blood loss was correlated with the diagnosis of cerebral palsy. By hierachical stepwise regression analysis, the only outcome measure correlated with VPA was the number of blood products used.

Baclofen for chronic hiccups.

Chronic hiccups is a rare occurrence but can be debilitating for the patient. Successful intervention is seldom reported. The present case is a young adult who had severe almost continuous hiccups for 3 years after placement of a feeding gastrostomy and Nissen fundoplication. Within weeks of initiation of baclofen treatment, the hiccups ceased. Recurrences of hiccups have responded to increases in baclofen dosage.

Kluver-Bucy syndrome following heat stroke in a 12-year-old girl.

A 12-year-old girl developed Kluver-Bucy syndrome (KBS) following heat stroke. She demonstrated the features typical of human KBS, including visual agnosia, hypermetamorphosis, hypersexuality, language disorder with aphasia, hyperorality, placidity, flat affect, and memory dysfunction. Magnetic resonance imaging 11 1/2 months after onset disclosed mild, diffuse atrophy. Fourteen months after onset, she did not consistently respond to language or communicate verbally, and was dependent on others. A comparison is made with previously reported KBS cases in children.

Outcome of severe anoxic/ischemic brain injury in children.

The outcome of 25 children who had anoxic or ischemic brain injuries at 2 months to 14 years of age is reported. Follow-up was from 1 to 14 years after injury; causes were near-drowning, 11; suffocation, 7; cardiac arrest, 3; electrocution with cardiac arrest, 2; strangulation, 1; aborted sudden infant death syndrome, 1. All patients were unconscious for at least 24 hours. Of 11 remaining in vegetative states, 5 died. Seven children regained some language skills and are in special education or self-contained classrooms. Seven are profoundly impaired and show only a social smile. Cognitive and motor outcomes were correlated with the severity of injury as indicated by the duration of unconsciousness. All children who regained language skills or the ability to walk were unconscious less than 60 days. Dystonic rigidity was observed in all children who were nonambulatory. Outcome was also correlated with the cause of injury; mortality, cognitive outcome, feeding outcome, and duration of unconsciousness were all worse in children with near-drowning.

Outcome of children with prolonged unconsciousness and vegetative states.

The outcomes of 60 children unconscious for 90 days or longer following acquired brain injury are reported. Eight children who died had remained in persistent vegetative states. As expected, most neurologic improvement occurred within the first year after injury, although some delayed improvements were observed. Outcomes were strongly correlated with causes of brain injury. Better cognitive and motor function was observed with nonanoxic injuries. No child in this report with anoxic brain injury regained functional cognitive or motor skills, although 3 became socially responsive. The remarkable contrast with adults following acquired brain injury is the significantly longer survival of children. The only children who died had remained in persistent vegetative states.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance.

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple stepwise linear regression. Children who were receiving enzyme-inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme-inducing antiepileptic drugs.

Movement disorders after status epilepticus and other brain injuries.

A retrospective medical record review was conducted of 173 consecutive children hospitalized for acquired brain injuries on a specialized pediatric rehabilitation service. The chart review identified children who developed movement disorders with acquired brain injuries: 8 with status epilepticus, 2 with trauma, and 1 with anoxia. Movement disorders were observed more frequently following status epilepticus (8 of 12) than following other causes of acquired brain injury (3 of 161; P = .0001). Four additional children had severe neurologic deficits following status epilepticus but did not develop movement disorders. The 11 patients who developed movement disorders had choreiform movements predominantly. Even though status epilepticus is a clinical phenomenon resulting from a variety of etiologies, the features of movement disorders in these children were strikingly similar. The pathophysiology of this complication is unknown.

External leakage from feeding gastrostomies in patients receiving valproate sprinkle.

We reviewed the incidence of external leakage from feeding gastrostomies in 8 patients who received valproate sprinkle (VPA-S). We also identified a control group of 31 children with feeding gastrostomies who were also cared for in our clinic, but who did not receive VPA-S. All patients in both groups have had their feeding gastrostomy greater than or equal to 6 months. Four of 8 children who received VPA-S through feeding gastrostomies developed problems with recurrent external leakage. The incidence of external leakage in our control group of children who had not received VPA-S was 2 in 31 (6.4%). We hypothesize that the external leakage is caused by adherence of the undissolved VPA-S particles to the exterior of the tube, preventing close approximation of the tube to the gastrostomy stoma. In most cases, VPA-S could continue to be administered and the problem of leakage reduced if the tubes were more frequently changed and/or a larger size were used. Complications with either leakage or occlusion were noted in all patients with the button feeding tube who had received VPA-S. Because of the especially high complication rate associated with administration of VPA-S in children with the "button" feeding tubes, we discourage VPA-S administration to children with that device.