thiopental and Drug-Overdose

Thiopentone elimination has been described using Michaelis-Menten pharmacokinetics in adults after prolonged infusion or overdose, but there are few reports of elimination in neonates.. Time-concentration profiles for neonates (n=37) given single-dose thiopentone were examined using both first-order (constant clearance) and mixed-order (Michaelis-Menten) elimination processes using nonlinear mixed effects models. These profiles included a 33-week post-menstrual age (PMA) neonate given an overdose. A two-compartment mamillary model was used to fit data. Parameter estimates were standardized to a 70 kg person using allometric models.. There were 197 observations available for analysis from neonates with a mean post-menstrual age of 35 (SD 4.5) weeks and a mean weight of 2.5 (SD 0.9) kg. They were given a mean thiopentone dose of 3 (SD 0.4) mg/kg as a rapid bolus. Clearance at 26 weeks PMA was 0.015 l/min/70 kg and increased to 0.119 l/min/70 kg by 42 weeks PMA. The maximum rate of elimination (V(max)) at 26 weeks PMA was 0.22 mg/min/70 kg and increased to 4.13 mg/min/70 kg by 42 weeks PMA. These parameter estimates are approximately 40% adult values at term gestation. The Michaelis constant (K(m)) was 28.3 [between subject variability (BSV) 46.4%, 95% confidence interval (CI) 4.49-99.2] mg/l; intercompartment clearance was 0.44 (BSV 97.5%, 95% CI 0.27-0.63) l/min/70 kg; central volume of distribution was 46.4 (BSV 29.2%, 95% CI 41.7-59.8) l/70 kg; peripheral volume of distribution was 95.7 (BSV 70.3%, 95% CI 61.3-128) l/70 kg.. Both first-order and mixed-order processes satisfactorily described elimination. First-order elimination adequately described the time-concentration profile in the premature neonate given an overdose. Clearance is immature in the pre-term neonate although there is rapid maturation around 40 weeks PMA, irrespective of post-natal age.

Topics: Adult; Algorithms; Bayes Theorem; Body Weight; Chromatography, High Pressure Liquid; Data Interpretation, Statistical; Drug Overdose; Gestational Age; Humans; Hypnotics and Sedatives; Infant, Newborn; Infant, Premature; Nonlinear Dynamics; Population; Thiopental

The suicide of a 43-year-old male by intravenous injection of cisatracurium, a non-depolarizing neuromuscular blocking agent, and thiopental, an ultra-short-acting barbiturate, is presented. Systematic toxicological screening by gas chromatography-mass spectrometry (GC-MS), liquid chromatography (LC)-diode-array detection, and LC-MS-MS confirmed the presence of thiopental. A large peak in the GC-MS chromatogram was matched by the Pfleger-Maurer library as corlumine, but neither atracurium neither its metabolite, laudanosine, were detected. To confirm the absence or the presence of laudanosine in the blood sample, an ultra-performance liquid chromatography-MS-MS method for cisatracurium and laudanosine quantification was developed. The calibration range was 2.5-500 ng/mL for laudanosine and 10-500 ng/mL for cisatracurium. The biases were lower than 12.3%. Intraday and interday precisions, expressed as coefficient of variation, were lower than 13.3%. This method allowed to confirm the presence of laudanosine and measurement of laudanosine in all samples. The femoral blood concentration was therapeutic (0.46 μg/mL). This case report documents a possible analytical pitfall and describes a simple and fast method for cisatracurium determination. Moreover, the purpose of this case report was to document the postmortem redistribution of cisatracurium and laudanosine, which could help make it possible to interpret tissue or cardiac blood concentrations in forensic cases where femoral blood is not available.

Topics: Adult; Atracurium; Drug Overdose; Fatal Outcome; Humans; Hypnotics and Sedatives; Injections, Intravenous; Male; Neuromuscular Blocking Agents; Suicide; Thiopental

Thiopental may be used for sedation before intubation in newborn infants. A boy, born at 33 weeks of gestation (gw); birth weight 2435 g, was prescribed thiopental 3 mg/kg before intubation. He developed temporary hypotension and oxygen desaturation, and remained unconscious for longer than expected with a suppressed electroencephalography for 48 h. Serum thiopental concentration was 82, 59, 42 and 32 micromol/L after 20 min and 6, 24 and 68 h respectively. Serum concentrations from five newborn infants at the same time points after intubation with the same thiopental dose were used as reference values, and indicated a 10-fold overdose in the index case. The cause of the overdose could not be identified. The infant recovered; cerebral magnetic resonance imaging at the age of 42 gw and psychomotor development at 2 years were normal. These results show that thiopental concentrations are variable in neonates and there is a high risk of dosage error as no specific paediatric formulation is available.. Well-designed procedures and continuous education are required to prevent errors and adverse events during drug delivery to newborn infants. To develop a safe method of administration for thiopental, an extended pharmacokinetic and pharmacodynamic study in neonates is warranted.

Topics: Dose-Response Relationship, Drug; Drug Overdose; Erythrocyte Transfusion; Humans; Infant, Newborn; Infant, Premature; Male; Oxygen Inhalation Therapy; Reference Values; Thiopental; Unconsciousness

Topics: Adrenergic beta-Antagonists; Coronary Disease; Drug Overdose; Heart Arrest; Humans; Thiopental

Topics: Drug Overdose; Electroencephalography; Female; Humans; Injections, Spinal; Middle Aged; Morphine; Pentobarbital; Postoperative Complications; Seizures; Thiopental

Topics: Acetaminophen; Adult; Anesthesia, General; Anesthesia, Obstetrical; Cesarean Section; Drug Overdose; Female; Fetal Distress; Humans; Isoflurane; Liver Failure; Nitrous Oxide; Succinylcholine; Thiopental

Topics: Adolescent; Akathisia, Drug-Induced; Diazepam; Drug Overdose; Flumazenil; Humans; Injections, Intravenous; Intubation, Gastrointestinal; Lorazepam; Male; Psychomotor Agitation; Substance Withdrawal Syndrome; Therapeutic Irrigation; Thiopental

Topics: Barbital; Barbiturates; Drug Overdose; Pentylenetetrazole; Sodium; Thiopental