Which component of treatment is important for changes of cortical epileptic afterdischarges after status epilepticus in immature rats?

Role of lithium chloride and paraldehyde in acute changes after lithium-pilocarpine status epilepticus (SE) induced at postnatal day 12 was studied in 15-day-old rats. In addition to SE group four other groups were formed: naïve animals without any injection, lithium chloride group, paraldehyde group and lithium-paraldehyde group. Cortical epileptic afterdischarges (CxADs) induced by increasing intensities of stimulation current were used as a measure of excitability. SE animals did not exhibit any change in duration of CxADs with increasing stimulation intensity in contrast to naïve control with a progressive prolongation of CxAD. LiCl group was similar to SE rats whereas paraldehyde and lithium-paraldehyde groups exhibited some progress in duration of ADs. Lithium chloride participates in short-term changes of CxADs after SE. Paraldehyde and combination of lithium and paraldehyde are similar to naïve controls.

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.

Vibrational spectral assignments of paraldehyde by ab initio and density functional methods.

The FTIR and Laser-Raman spectra of paraldehyde have been recorded in the regions 4000-400 cm(-1) and 3500-250 cm(-1) respectively. Molecular electronic energy, geometrical structure, harmonic vibrational spectra, infrared intensities and Raman scattering activities have been computed at the HF/6-31G(d,p) and B3LYP/6-31G(d,p) levels of theory. The results were compared with experimental values with the help of scaling procedures. The observed wave numbers in FTIR and Laser-Raman spectra were analyzed and assigned to different normal modes of the molecule. Most of the modes have wave numbers in the expected range and are in good agreement with computed values.

DNA-protein cross-link formation in Burkitt lymphoma cells cultured with benzaldehyde and the sedative paraldehyde.

Exposure to aldehydes represents potential risks to human and animal health. Cyclic aldehydes such as benzaldehyde, 2-furaldehyde, and paraldehyde were found to induce formation of stable DNA-protein cross-links (DPXs) in cultured human lymphoma cells. A relationship between increased cytotoxicity and DPX formation was observed with each aldehyde. Paraldehyde is a sedative drug used predominately in treatment of ethanol withdrawal. Paraldehyde was the most potent cross-linking aldehyde studied, yet least cytotoxic. Although DPX formation by aliphatic aldehydes is well-known, this study confirms the potential for cyclic aldehydes to cause formation of DPXs in cultured cells at therapeutically relevant doses.

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.

Determination of paraldehyde by gas chromatography in whole blood from children.

A rapid, sensitive and selective gas chromatographic method with flame ionization detection was developed for the determination of paraldehyde in small blood samples taken from children. Whole blood samples (300 microl) collected in a 3 ml Wheaton glass sample vial were spiked with acetone (internal standard: 15 ng) followed by addition of concentrated hydrochloric acid. The mixture was heated in the sealed airtight sample vial in a water bath (96 Celsius; 5 min) to depolymerize paraldehyde to acetaldehyde. A 2 ml aliquot of the headspace was analyzed by gas chromatography with flame ionization detector using a stainless steel column (3 m x 4 mm i.d.) packed with 10% Carbowax 20 M/ 2% KOH on 80/100 Chromosorb WAW. Calibration curves were linear from 1.0-20 microg (r2>0.99). The limit of detection was 1.5 microg/ml, while relative mean recoveries at 2 and 18 microg were 105.6 +/- 8.4 and 101.2 +/- 5.9%, respectively (n = 10 for each level). Intra- and inter-assay relative standard deviations at 2, 10 and 18 microg were <15%. There was no interference from other drugs concurrently used in children with severe malaria, such as anticonvulsants (diazepam, phenytoin, phenobarbitone), antipyretics/analgesics (paracetamol and salicylate), antibiotics (gentamicin, chloramphenicol, benzyl penicillin) and antimalarials (chloroquine, quinine, proguanil, cycloguanil, pyrimethamine and sulfadoxine). The method was successfully applied for pharmacokinetic studies of paraldehyde in children with convulsions associated with severe malaria.

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Phenytoin or paraldehyde as the second drug for convulsions in children.

A short cut review was carried out to establish whether phenytoin or paraldehyde should be given as the second drug for resistant fits in children. Altogether 41 papers were found using the reported search, of which none answered the question posed. Further research is needed in this area.

Brain-derived neurotrophic factor superinduction parallels anti-epileptic--neuroprotective treatment in the pilocarpine epilepsy model.

Antiepileptic drugs provide neuroprotection in several animal models of brain damage, including those induced by status epilepticus (SE). The mechanisms involved in this action are unknown, but neurotrophic factors such as brain-derived neurotrophic factor (BDNF) may play a role. In this study we investigated the changes in BDNF levels in rats in which SE had been induced by pilocarpine injection (400 mg/kg i.p.) and continued for several hours (unprotected group). In other animals (protected groups), SE was suppressed after 30 min by intraperitoneal injection of either diazepam (10 mg/kg) + pentobarbital (30 mg/kg) or paraldehyde (0.3 mg/kg). In diazepam + pentobarbital-treated rats the hippocampal damage caused by SE was significantly lower (p < 0.05) than in unprotected animals. In addition, 2 and 24 h after pilocarpine injection, the levels of BDNF mRNA were moderately increased in the unprotected group, but 'superinduced' in protected animals, especially in the neocortex and hippocampus. A time-dependent increase in BDNF immunoreactivity was also found by western blot analysis in rats treated with diazepam + pentobarbital. In contrast, a decrease of BDNF immunoreactivity occurred in the unprotected group. In conclusion, these results show that neuroprotection induced by anti-epileptic drugs in pilocarpine-treated rats is accompanied by strong potentiation of BDNF synthesis in brain regions involved in SE.

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.

Neurons projecting to the retrocerebral complex of the adult blow fly, Protophormia terraenovae.

Anatomical study of neurons projecting to the retrocerebral complex of the adult blow fly, Protophormia terraenovae, was done by NiCl2 filling and immunocytochemistry. Retrograde filling through the cardiac-recurrent nerve labeled three groups of neurons in the brain/subesophageal ganglion: (1) paramedial clusters of the pars intercerebralis, (2) neurons in each pars lateralis, and (3) neurons in the subesophageal ganglion. The pars intercerebralis neurons send prominent axons into the median bundle and exit from the brain via the contralateral nervus corporis cardiaci. Based on the projection pattern, two types of the pars lateralis neurons can be distinguished: the most lateral pairs of neurons contralaterally extend through the posterior lateral tract and the remainder ipsilaterally extend through the posterior lateral tract. The neurons in the subesophageal ganglion run through the contralateral nervus corporis cardiaci. The dendritic arborization of the pars intercerebralis and pars lateralis neurons is restricted to the superior protocerebral neuropil and to the anterior neuropil of the subesophageal ganglion where the neurons in the subesophageal ganglion also project. Retrograde filling from the corpus allatum indicated that the pars lateralis neurons and a few pars intercerebralis neurons project to the corpus allatum, but that the neurons in the subesophageal ganglion do not. Orthograde filling from the pars intercerebralis and staining by paraldehyde-thionin/paraldehyde-fuchsin indicated that the pars intercerebralis neurons project primarily to the corpus cardiacum/hypocerebral ganglion complex. Immunostaining with a polyclonal antiserum against diapause hormone, a member of the FXPRLamide family, suggests that some of the subesophageal ganglion neurons contain FXPRLamide-like peptides.

Children presenting with convulsions (including status epilepticus) to a paediatric accident and emergency department: an audit of a treatment protocol.

All children who presented in a convulsion, including convulsive status epilepticus, to the accident and emergency department over a 12-month period and who required treatment, were reviewed retrospectively to identify the effectiveness and safety of a specific treatment protocol. This protocol recommends the initial use of one, or if necessary, two doses of rectal or intravenous diazepam (0.4 mg/kg) followed by the simultaneous administration of phenytoin (18 mg/kg) and rectal paraldehyde (0.4 mL/kg), with instructions for maximum doses and timings of administration. Eighty-one evaluable children (52 male) were audited. The mean age of the study population was 4.1 (range 0.1 to 14.9) years. Overall, the presenting convulsion was successfully terminated in 76 children (94%) within the accident and emergency department. In 69 children (85% of the entire study population) this was after a single dose of diazepam (rectal in 41 and intravenous in 28). In only an additional two children did the presenting convulsion stop after a second dose of diazepam. In five of the 10 children (50%) who received paraldehyde and phenytoin as a combination, the convulsion stopped. Nine patients (11%) required admission to the intensive-care unit, five because of persisting convulsive activity, and four because of respiratory depression. The results of this retrospective audit suggest that the current treatment protocol appears to be effective and relatively safe in treating acute convulsions, including convulsive status epilepticus. The audit is to be repeated prospectively to either confirm or refute these findings before recommending any changes to the protocol.

Complications following sedation of paediatric oncology patients undergoing radiotherapy.

Sedation is often required to achieve immobilisation of small children during radiotherapy to avoid irradiation of normal tissues during the course of treatment. At the University College Hospital, Ibadan radiotherapists provide sedation for such patients with administration of parenteral and/or oral promethazine, diazepam, chlorpromazine and paraldehyde. This retrospective review of 84 children aged 1 month to 6 years who received sedation for radiotherapy over a period of twenty-one to twenty-eight days showed that 48% had complications. These included injection cellulitis (85.3%), injection abscess (4.87%), paresis of the lower limb (7.3%), aspiration pneumonia (2.4%). Anaesthetists in developing countries should be encouraged to extend their expertise in caring and resuscitation of sedated or unconscious patients to the radiotherapy unit. This will allow for the use of a wider variety of sedative agents and better monitoring as well as minimise or eradicate complications.