Acute Phenobarbital Poisoning for the Management of Seizures in Newborns and Children; A Systematic Literature Review.

OBJECTIVES: While phenobarbital (PB) is commonly used for the management of seizures in newborns and pediatrics, its administration may accompany acute poisoning. We aimed to review the literature to find out the frequency of PB poisonings in newborns and children with seizures. METHOD: A literature search was performed by two independent reviewers to find relevant articles about PB toxicity in neonates and pediatrics that were treated for the seizure. RESULTS: 18 articles met the inclusion criteria and were included in this systematic review. The main reasons for PB poisoning in studied patients were therapeutic intoxication. Reported signs of PB poisoning were lethargy, sedation, lack of sucking, fever, skin rash, hepatic inflammation and alopecia. Moreover, respiratory depression, encephalopathy, myocardial failure, syndrome of inappropriate antidiuretic hormone, and coma were among the complications of acute PB toxicity in children and infants. CONCLUSION: PB therapy for the management of seizures in newborns and children might be associated with poisoning. Although supportive and symptomatic treatments are available for PB overdose, it should be administered with caution, using drug monitoring to avoid toxicity.

Renal replacement therapy in severe phenobarbital poisoning: Another brick in the wall / Diálisis extracorpórea en el caso de grave fenobarbital envenenamiento: otro ladrillo en la pared

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Successful use of the two-tube approach for the treatment of phenobarbital poisoning without hemodialysis.

Half-life of the antipsychotic vegetamin is very long, partially due to the presence of phenobarbital, and mortality due to phenobarbital poisoning is high. Here, we present the case of a 22-year-old female admitted to the emergency department with disturbed consciousness due to vegetamin overdose. Her blood phenobarbital level was elevated to 123 µg/ml. Phenobarbital undergoes enterohepatic circulation, and its retention in the intestine causes its blood levels to remain sustained. The utility of hemodialysis for drug poisoning has been previously reported; however, its efficiency is not yet established and its efficacy is low for drugs with long half-lives such as phenobarbital. Therefore, we performed a two-tube approach to adsorb phenobarbital in the intestines with activated charcoal delivered via a gastric tube and to remove the phenobarbital-adsorbed activated charcoal using whole bowel irrigation via an ileus tube 2 h later. The patient successfully eliminated the charcoal via stool, the blood phenobarbital level decreased drastically without hemodialysis, and the clinical course improved. We propose that this two-tube approach is suitable for treatment of poisoning with drugs that undergo enterohepatic circulation and have long half-lives.

An analytical strategy for the identification of carbamates, toxic alkaloids, phenobarbital and warfarin in stomach contents from suspected poisoned animals by thin-layer chromatography/ultraviolet detection.

In this study, an analytical strategy to identify brucine, strychnine, methomyl, carbofuran (alkaline compounds), phenobarbital, and warfarin (acid compounds) using thin-layer chromatography (TLC) screening with ultraviolet (UV) detection at 254 nm in stomach content is shown. The optimum mobile phase was found to be a chloroform: ethyl acetate: diethylamine (0.5:8.5:1) mixture for alkaline substances while a mixture of chloroform: acetone (9:1) has given better results for acidic substances. As for extraction, an equal proportion between distillated water and crude material (1:1) is required. For alkaline compounds, a filtration system was created in order to avoid any interferences from the biological matrix while for acidic compounds only centrifugation (4000 rpm/10 minutes) was required to obtain an appropriate sample. After the respective pretreatments, a one-step liquid-liquid extraction (LLE) has been employed for alkaline substances using a 3 mL of chloroform: ethyl ether (2:1) mixture for 2 min while acidic analytes used 3 mL of chloroform only during 5 min. For both methodologies described, the respective organic layers were dried down and re-suspended with 50 µL of methanol for further TLC plate application. The methodologies have been developed, successfully validated and applied to gastric contents from real case samples of suspected animal poisoning. Positive results from TLC/UV screening were confronted with HPLC-UV and confirmed by GC-MS.

The Use of Peritoneal Dialysis in Phenobarbitone Toxicity in a Critically Unwell Neonate.

BACKGROUND: Phenobarbitone (PB) is the first-line anti-convulsant for neonatal seizures. The use of peritoneal dialysis (PD) to enhance drug elimination in cases of neonatal PB overdose has not been reported. OBJECTIVE: To report a case of neonatal severe PB toxicity and review the elimination of PB by PD. METHODS: Assessment of PD drug clearance. RESULTS: A neonate with prolonged seizures was administered PB. Encephalopathy and myocardial failure developed, which were initially suspected to be secondary to hypoxia. At 42 h of age, the serum PB concentration was in the toxic range at 131 mg/L. Despite supportive care, the infant's condition deteriorated with escalating inotropes and the need for CPR. Enhanced PB elimination via multiple-dose activated charcoal and exchange transfusion were considered too risky. Hourly PD cycles via Tenckhoff catheter were commenced, based on reports suggesting that PD enhances PB clearance. The clinical state of the infant then improved. PD administration was continued for 60 h, recovering 20% of the estimated total PB body load. The infant survived and there were no PD complications. CONCLUSIONS: PD increased PB clearance in this neonate, correlating with clinical recovery. Where other techniques are not possible, PD may have a role to play in enhancing PB elimination.

Determination of phenobarbital in hair matrix by liquid phase microextraction (LPME) and gas chromatography-mass spectrometry (GC-MS).

A method for identification and quantification of phenobarbital in hair samples by liquid phase microextraction (LPME) and gas chromatography-mass spectrometry (GC-MS) has been presented. Drug-free hair specimens were collected and separated in 50mg aliquots. Each aliquot was washed with 2.0mL of dichloromethane for 15min at 37°C. Standards and deuterated internal standards for calibration and quality control samples were added to the washed hair aliquot and the sample was submitted to complete digestion with sodium hydroxide (NaOH) 1.0mol/L for 15min at 70°C. The dissolved sample was submitted to LPME. After extraction, the residue was derivatized with tetramethylammonium hydroxide (TMAH) and analyzed by GC-MS. The limit of detection (LOD) was 0.1ng/mg and the limit of quantification (LOQ) was 0.25ng/mg. The calibration curve was linear over a concentration range of 0.25ng/mg to 10ng/mg (r(2)>0.99). The intra- and inter-assay precisions, given by RSD, were less than 6% for phenobarbital. Fortified samples of secobarbital and pentobarbital were also submitted to the validated method. The method was successfully applied to hair samples collected from three volunteers who reported regular use of phenobarbital (clinical treatment). The concentrations found were 9.5, 15.1 and 16.3ng/mg of phenobarbital. To contemplate the concentrations found, dilution integrity tests were also validated. The LPME and GC-MS method showed to be suitable for the detection of phenobarbital in hair samples and can be promptly used for different purposes whenever required.

[Suicide attempt by means of phenobarbital overdose. Effective treatment with continuous veno-venous hemodialysis]. / Phenobarbitalintoxikation in suizidaler Absicht. Kontinuierliche venovenöse Hämodialyse als effektive Therapie.

A 68-year-old woman tried to commit suicide using phenobarbital, which was initially prescribed for her dog that suffered from seizures. At admission she was unconscious and ventilated. Five days of intensive care therapy did not improve her state of consciousness. Subsequent continuous veno-venous hemodialysis accelerated the elimination of phenobarbital compared to endogenous elimination by a factor of five. The patient survived without sequelae. Detailed history taking and well-timed indication for dialysis were crucial.

A case of pseudoseizures precipitated by anticonvulsant toxicity.

We report a case of induction of pseudoseizures by anticonvulsant toxicity in a patient with underlying seizure disorder, hence supporting the argument of an organic subtype of pseudoseizure.

Removal of toxic substances by a selective membrane plasma separator.

We devised a method of plasma exchange with dialysis (PED), in which selective plasma exchange (sPE) is performed using a selective membrane plasma separator (EC-2A) with an albumin-sieving coefficient of 0.3 while the dialysate flows outside the hollow fibers, and reported the usefulness of the system for treating acute liver failure. Thereafter, EC-4A with an albumin-sieving coefficient of 0.6 was developed, which was expected to be even more effective for removing protein-bound substances. In order to examine whether or not EC-4A might be applicable to blood purification therapy against drug poisoning, we compared the efficacies of sPE, PED, and direct hemoperfusion (DHP) using an activated carbon column for the removal of phenobarbital and lithium. Subjects undergoing the extracorporeal circulation study were assigned to the sPE group, PED group, or DHP group, and the changes in the blood concentrations of phenobarbital and lithium were measured over 180 min. A significant decrease of the phenobarbital concentration over time was seen in the PED group, as compared to that in the sPE group (P < 0.0001), while no significant difference in the concentration was observed between the PED and DHP groups. The PED group showed a significant decrease of the lithium concentration over time, as compared to the DHP group (P < 0.0001), while no significant difference in the concentration was observed between the PED and sPE groups. Thus, PED was as effective as DHP for removing phenobarbital and was as effective as sPE for removing lithium. These results suggest that PED therapy using EC-4A may be a feasible modality for the treatment of drug poisoning.

Molecular pathology of brain matrix metalloproteases, claudin5, and aquaporins in forensic autopsy cases with special regard to methamphetamine intoxication.

Methamphetamine (METH) is a highly addictive drug of abuse and toxic to the brain. Recent studies indicated that besides direct damage to dopamine and 5-HT terminals, neurotoxicity of METH may also result from its ability to modify the structure of blood-brain barrier (BBB). The present study investigated the postmortem brain mRNA and immunohistochemical expressions of matrix metalloproteases (MMPs), claudin5 (CLDN5), and aquaporins (AQPs) in forensic autopsy cases of carbon monoxide (n = 14), METH (n = 21), and phenobarbital (n = 17) intoxication, compared with mechanical asphyxia (n = 15), brain injury (n = 11), non-brain injury (n = 21), and sharp instrument injury (n = 15) cases. Relative mRNA quantification using Taqman real-time PCR assay demonstrated higher expression of AQP4 and MMP9, lower expression of CLDN5 in METH intoxication cases and lower expression of MMP2 in phenobarbital intoxication cases. Immunostaining results showed substantial interindividual variations in each group, showing no evident differences in distribution or intensity among all the causes of death. These findings suggest that METH may increase BBB permeability by altering CLDN5 and MMP9, and the self-protective system maybe activated to eliminate accumulating water from the extracellular space of the brain by up-regulating AQP4. Systematic analysis of gene expressions using real-time PCR may be a useful procedure in forensic death investigation.

[BIS values were useful on the evaluation of consciousness recovery in acute Vegetamin-A poisoning: report of a case].

A 37-year-old man was admitted to our hospital with acute phenobarbital poisoning. On arrival, he was in deep coma with respiro-circulatory depressions. The serum concentration of the agent was elevated to 149.04 µg/mL which was consistent with a lethal concentration level. He underwent a gastric lavage, administration of activated charcoal, urinary alkalinazation and bowel irrigation. Respiro-circulatory status was recovered rapidly, while the serum concentration of phenobarbital did not decrease smoothly. Although the concentration of the agent decreased to 77.07 µg/mL that should be a comatose level, BIS values were gradually elevated, and then eventually the patient regained his consciousness. Because he was a chronic user of Vegetamin-A containing phenobarbital, the serum level might not have been correlated with symptoms. BIS values were highly reflective of the consciousness level, so it could be a useful indicator for predicting the consciousness levels of patients in deep coma with acute poisoning from hypnotic agents.