Review of the efficacy of rectal paraldehyde in the management of acute and prolonged tonic-clonic convulsions.

INTRODUCTION: The aim of this prospective audit was to assess the effectiveness and safety of rectal paraldehyde in the management of acute, including prolonged, tonic-clonic convulsions. There are very limited published data on its effectiveness and safety, and previous data have focused on its intramuscular route of administration. METHODS: Four hospitals participated in the study. Information was collected on each dose of paraldehyde used for the treatment of a tonic-clonic convulsion over 1 year. Data were not included on patients treated with rectal paraldehyde for other seizure types or non-convulsive status epilepticus. RESULTS: Data analysis was undertaken regarding 53 episodes in 30 patients. Patient's ages ranged from 5 months to 16 years (mean 6.12 years, median 5.91 years). A pre-existing diagnosis of epilepsy was recorded in 35 episodes (66%). The mean dose of paraldehyde was 0.65 ml/kg (SD 0.22, 95% CI 0.59 to 0.71) and median dose 0.79 ml/kg. Rectal paraldehyde terminated the convulsion in 33 (62.3%) of the 53 episodes. In the 35 episodes where a pre-existing diagnosis of epilepsy was recorded, paraldehyde stopped the convulsion on 26 (74.3%) occasions. There was no difference in the dose of paraldehyde between the episodes where the convulsion was or was not terminated. There was no recorded respiratory depression in any episode. CONCLUSIONS: This study provides unique evidence that rectal paraldehyde is effective and safe in treating acute prolonged tonic-clonic convulsions. This would appear to confirm that paraldehyde should remain a treatment for the management of prolonged tonic-clonic convulsions, including convulsive status epilepticus.

Response to diazepam in children with malaria-induced seizures.

Malaria infection reduces the binding capacity of benzodiazepine receptors in mice. We studied the efficacy of diazepam terminating seizures in children with falciparum malaria. Diazepam stopped seizures in fewer patients with malaria parasitaemia (chi(2)=3.93, P=0.047) and those with clinical diagnosis of malaria (chi(2)=9.84, P=0.002) compared to those without. However malaria was not identified as an independent risk factor for diazepam's failure to stop seizures in children.

Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial.

BACKGROUND: In sub-Saharan Africa, rectal diazepam or intramuscular paraldehyde are commonly used as first-line anticonvulsant agents in the emergency treatment of seizures in children. These treatments can be expensive and sometimes toxic. We aimed to assess a drug and delivery system that is potentially more effective, safer, and easier to administer than those presently in use. METHODS: We did an open randomised trial in a paediatric emergency department of a tertiary hospital in Malawi. 160 children aged over 2 months with seizures persisting for more than 5 min were randomly assigned to receive either intranasal lorazepam (100 microg/kg, n=80) or intramuscular paraldehyde (0.2 mL/kg, n=80). The primary outcome measure was whether the presenting seizure stopped with one dose of assigned anticonvulsant agent within 10 min of administration. The primary analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00116064. FINDINGS: Intranasal lorazepam stopped convulsions within 10 min in 60 (75%) episodes treated (absolute risk 0.75, 95% CI 0.64-0.84), and intramuscular paraldehyde in 49 (61.3%; absolute risk 0.61, 95% CI 0.49-0.72). No clinically important cardiorespiratory events were seen in either group (95% binomial exact CI 0-4.5%), and all children finished the trial. INTERPRETATION: Intranasal lorazepam is effective, safe, and provides a less invasive alternative to intramuscular paraldehyde in children with protracted convulsions. The ease of use of this drug makes it an attractive and preferable prehospital treatment option.

Outcome of status epilepticus in immature rats varies according to the paraldehyde treatment.

PURPOSE: To test effects of paraldehyde on behavioral outcome of status epilepticus (SE) in developing rats. METHODS: Motor SE was induced by LiCl-pilocarpine in rats on postnatal (P) day 12 or 25. Two hours after SE onset, animals were injected with a single dose of paraldehyde (0.07 and 0.3 ml/kg in the P12 group and 0.3 and 0.6 ml/kg in the P25 group). Effects on seizure severity and mortality were evaluated. Growth of animals and their motor abilities were monitored until the adulthood. Three months after SE, cognitive abilities were tested by using the Morris water maze. RESULTS: Both tested doses of paraldehyde equally affected motor seizures. Convulsions continued until the paraldehyde administration, but then they quickly subsided in all groups. During the subsequent 24 h, occasional clonic seizures occurred in P25 animals treated with the lower dose of paraldehyde. Only hyperactivity and/or automatisms were observed in the other experimental groups. Mortality was not affected by the dosage of paraldehyde. The higher dosage of paraldehyde improved recovery after SE in both age groups. No difference was found in motor abilities between controls and SE animals, except shortening of time spent on the rod in the rotarod test in the P12 group. In P25 rats, treatment with a higher dosage of paraldehyde improved learning abilities compared with the lower dosage. In the P12 group, animals treated with the lower dosage exhibited slightly impaired learning compared with controls and animals receiving the higher dosage. CONCLUSIONS: Paraldehyde injected 2 h after SE onset modulates long-term outcome in immature rats in a dose-related manner.

Pervasive seizures caused by hypoxic-ischemic encephalopathy: treatment with intravenous paraldehyde.

Seizures are commonly associated with hypoxic-ischemic encephalopathy. Although the majority of cases are controlled with first- or second-line therapy, others develop pervasive seizures, requiring multiple anticonvulsants. To provide data on the incidence of seizures and response to anticonvulsant therapies, a cohort of 90 term infants with hypoxic-ischemic encephalopathy treated at our institution between January 1, 1995, and July 1, 1999, was reviewed. Of the 60 infants who developed seizures, 59 received phenobarbital initially; in 29 cases, the seizures resolved. The remaining 30 infants received phenytoin as a second-line anticonvulsant, and seizures stopped in 10 cases. The 20 infants with ongoing pervasive seizures were treated with intravenous paraldehyde.

Septicaemia among neonates with tetanus.

In a study of 149 cases of neonatal tetanus (NNT) admitted into the University of Calabar Teaching Hospital, 49 (33 per cent) were also found to have septicaemia. The dominant organisms were coliforms and Staphylococcus aureus. A comparison of the clinical features of the septicaemic and non-septicaemic neonates showed umbilical cord infection to be an indicator of septicaemia. There was no significant difference in the case fatality rates of the two groups of patients and the overall case fatality was low (37 per cent). This is attributable to early diagnosis and treatment of the septicaemia cases. It is suggested that paediatricians should have a high index of suspicion of septicaemia among cases of NNT as a means of reducing case fatality.

Pharmacokinetics and clinical use of parenteral phenytoin, phenobarbital, and paraldehyde.

Intravenous phenytoin, phenobarbital, and paraldehyde are effective and safe for the treatment of acute seizures such as status epilepticus. All of these drugs should be infused in a diluted solution and at a slow rate to minimize the occurrence of adverse effects.

Rectal anticonvulsants in pediatric practice.

Children with seizure disorders frequently are treated with anticonvulsant medications such as clonazepam, valproic acid, carbamazepine, and ethosuximide, which cannot be given parenterally. When the child is unable to take these anticonvulsants orally, he or she may be given parenteral doses of phenobarbital or phenytoin. In many cases, these two medications have failed previously to control seizures, leading to the use of the more recently developed drugs. The use of rectal preparations of some anticonvulsant medications is highly useful and effective when the child is unable to take oral medications because of repeated vomiting, gastrointestinal surgery, and status epilepticus associated with lack of venous access. Rectal use of anticonvulsants has a role in the management of hospitalized seizure patients and can be learned by parents needing to treat their children's seizures at home while awaiting other medical care.

Delivery of paraldehyde in 5% dextrose and 0.9% sodium chloride injections through polyvinyl chloride i.v. sets and burettes.

The delivery of paraldehyde in 5% dextrose injection and 0.9% sodium chloride injection was studied, and the potential interaction between paraldehyde and plastic i.v. containers and sets was evaluated. Paraldehyde was mixed with either 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags to form a 4% solution. The bags were fitted with standard i.v. administration sets or burettes with administration sets. The solutions were allowed to drip through the i.v. sets for six hours at room temperature. Samples were taken from the i.v. bag or burette and from the distal end of the i.v. sets at zero, two, four, and six hours. Paraldehyde concentrations were measured using a stability-indicating gas chromatographic method, and the presence of plasticizers was detected by a scanning ultraviolet spectrophotometer. The cumulative amount of paraldehyde delivered at the end of the administration set at six hours was 84% for 5% dextrose solutions in burettes, and 89% or 90% for all other solutions and i.v. sets. An ultraviolet-light-absorbing substance appeared in some of the samples, although a relationship between the presence of this substance and type of solution, time of sampling, or site of sample did not emerge. Particulate matter appeared after two hours in all burettes. Approximately 10%-16% of paraldehyde in 5% dextrose or 0.9% sodium chloride injection is lost when delivered from PVC i.v. bags through standard i.v. administration sets and burettes over a six-hour period.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous paraldehyde for seizure control in newborn infants.

We studied 14 newborn infants with seizures after birth asphyxia or other causes. Paraldehyde was given as a 200 mg/kg IV bolus followed by an infusion of 16 mg/kg/h (10 cases), or as a 400 mg/kg bolus (4 cases). Serum concentrations of paraldehyde were higher in periods of adequate seizure control than in periods of little or no response. Paraldehyde serum concentrations above 10 mg/dl were associated with anticonvulsant effects and were achieved in most neonates with a 2-hour infusion of 200 mg/kg/h. If there is no effect, serum concentrations are probably below 10 mg/dl and an additional 200 mg/kg can be given safely over 1 hour.

Compatibility of paraldehyde with plastic syringes and needle hubs.

The compatibility of paraldehyde with plastic syringes and needle hubs was evaluated. Paraldehyde, USP, was stored in three types of 5-ml syringes: Plastipak, Glaspak, and all glass; the latter type served as the control. At specified times up to 24 hours, the contents of the syringes was evaporated to constant weight, and the residue was weighed. To evaluate the effect of paraldehyde on plastic needle hubs, needles with plastic and metal hubs were immersed in paraldehyde for 24 hours, and the paraldehyde was evaporated. No measurable change in residue weight was noted in any syringes for up to three hours. Compared with the control, there was a significant increase in the average weight of residue in the Glaspak and in the Plastipak syringes at 6, 12, and 24 hours. There was no significant difference in the weight of residue between the Glaspak and Plastipak syringes at those times, however. The amount of residue for the plastic and metal needle hubs was not significantly different. The source of the extractive residue appeared to be the rubber plunger tip. Since the nature of the extractive material in the residue is not known, paraldehyde should be administered in all-glass syringes if possible; other syringe types can be used only if the drug is administered immediately. The use of needles with plastic hubs is acceptable.

Pharmacokinetics of paraldehyde disposition in the neonate.

The pharmacokinetic parameters controlling paraldehyde elimination were determined in nine infants infused with paraldehyde at the rate of 150 mg/kg/hr in a 5% solution in 5% dextrose for the treatment of status epilepticus. The mean +/- SEM values for the observed parameters were as follows: rate constant for the disposition of paraldehyde 0.0680 +/- 0.0071 hr,-1 half-life 10.2 +/- 1.0 hr; volume of distribution 1.73 +/- 0.20 L/kg; clearance 0.121 +/- 0.023 L/hr/kg. Phenobarbital administration prior to or within 24 hours of the cessation of paraldehyde infusion decreased both paraldehyde clearance and volume of distribution in a manner linearly related to the logarithm of the phenobarbital dose. The rate constant for paraldehyde elimination was decreased as a linear function of the logarithm of the combined dose of administered phenobarbital and phenytoin. No acetaldehyde was detected in any blood samples. Paraldehyde administration was not correlated with any adverse reactions or toxicities.

Paraldehyde therapy in childhood status epilepticus.

Intravenous (IV) diazepam or phenobarbital is generally accepted as the initial treatment of choice for status epilepticus in children. The risk of severe respiratory depression with either drug is a major problem, particularly in emergency centers that do not have appropriate equipment or personnel for rapid endotracheal intubation of infants. While some pediatric centers are not reluctant to recommend paraldehyde for secondary therapy in status epilepticus, most texts and publications recommend it only as a last resort because of reported complications. We investigated the benefits and complications from varied dosing regimens in 16 trials. The results indicated no significant complications in patients who did not receive an initial IV bolus. Even though treatment with phenobarbital or diazepam and phenytoin sodium had failed, 37% had a good therapeutic response.