Fatalities Following Intravenous Use of Sodium Diphenylhydantoin for Cardiac Arrhythmias

Unger, Allen H.

doi:10.1001/jama.1967.03120170107029

Cited by 56 publications

(8 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The magnitude of the response depends on the condition of the patient or experimental animal (i.e., conscious or anesthetized) and both the total dose and the infu- (Delgado-Escueta et al, 1982). In seriously ill or hypotensive patients or in anesthetized animals, the cardiovascular effects of phenytoin sodium are prominent (Unger and Sklaroff, 1976;Zoneraich et al, 1976).…”

Section: ) In Humans and In Dogsmentioning

confidence: 99%

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

et al. 1989

View full text Add to dashboard Cite

ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Section: ) In Humans and In Dogsmentioning

confidence: 99%

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

et al. 1989

View full text Add to dashboard Cite

show abstract

“…push carries the risk of serious adverse effects on the cardiorespiratory system. [5][6][7] Second, although the continuous infusion is currently in great demand, diluting the phenytoin sodium injection with i.v. infusion fluid should be avoided.…”

mentioning

confidence: 99%

Contribution of Glucose to Crystallization of Phenytoin in Injectable Dosage Form by Dilution with Infusion Fluids

Onuki

Hasegawa

Ikegami-Kawai

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

The crystallization of phenytoin occurring after its dilution with infusion fluid is a major concern in the clinical use of injectable phenytoin. To gain further understanding of the crystallization, this study assessed details of the involvement of glucose in this action. For sample preparation, phenytoin crystals were created by diluting the injectable phenytoin with infusion fluids with different glucose concentrations at different temperature, and then the characteristics of the crystallization (e.g., crystal size in the long direction, accumulated amount over 24 h, and crystallization rate constant) were measured. Results of the analysis of variance indicated that the glucose concentration and temperature had significant impacts on the crystallization. The mode of action of the glucose concentration was suggested to be different from that of the incubation temperature. This study also examined the molecular mobility of components (i.e., glucose, propylene glycol, phenytoin) in the admixtures using diffusion NMR techniques. The findings will provide valuable information for the clinical use of injectable phenytoin.

show abstract

“…push has a risk of serious adverse effects on the cardiorespiratory system. [5][6][7] In contrast, the addition of phenytoin sodium injection to an i.v. infusion is not recommended because of its low solubility and resultant precipitation; this means that continuous infusion should be avoided.…”

mentioning

confidence: 99%

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

Onuki

Ikegami-Kawai

Ishitsuka

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

The precipitation of phenytoin sodium injection provoked by mixing with infusion fluids renders its use in clinical practice difficult, as rapid intravenous (i.v.) push and i.v. infusion are supposed to be avoided. As some of its aspects remain unclear, this study tried to elucidate this precipitation mechanism. In particular, this study focused on the significant precipitation induced by glucose infusion fluid. The precipitation provoked by 5% glucose infusion fluid was obviously different from the precipitation that accompanied simple pH reduction, in terms of the growth mode and morphology of crystals. In addition, the effect of glucose was partially unrelated to pH reduction. NMR measurements including a two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) spectrum indicated the specific interaction between glucose and propylene glycol, which is incorporated into phenytoin sodium injection as a solubilizing agent. These results led to the conclusion that this interaction was crucial for the precipitation of phenytoin, as it diminished the solubilizing effect of propylene glycol, resulting in the enhancement of the crystallization of phenytoin. The determination of phenytoin solubility in aqueous solutions at different pH values revealed that phenytoin incorporated in the admixture could be dissolved completely, as long as the injection was diluted with saline or water. These findings offer a profound insight into the formulation design of phenytoin sodium injection and its use in clinical practice.Key words phenytoin; precipitation; glucose infusion fluid; propylene glycol; 2-dimensional nuclear Overhauser effect spectroscopy Phenytoin sodium injection is indicated for the control of status epilepticus of the grand mal type and for the prevention and treatment of seizures that occur during neurosurgery. As phenytoin is a weak-acid drug (pK a =8.3) 1) with low solubility at biological pH values, 2,3) phenytoin sodium injection is prepared using an organic cosolvent consisting of 40% (v/v) propylene glycol and 10% (v/v) ethanol, with the pH adjusted to 12.The intravenous (i.v.) administration of phenytoin sodium has long represented a dilemma. The rate of administration is strictly limited; the delivery of the injection is recommended at a rate not exceeding 50 mg/min, 4) as a rapid i.v. push has a risk of serious adverse effects on the cardiorespiratory system.5-7) In contrast, the addition of phenytoin sodium injection to an i.v. infusion is not recommended because of its low solubility and resultant precipitation; this means that continuous infusion should be avoided.Many reports in the literature describe precipitation occurring by mixing phenytoin sodium injection with various infusion fluids. [8][9][10][11][12][13][14][15] The reduction in pH that accompanies the dilution with the infusion fluids is widely recognized as the principal cause of the precipitation; 16,17) the pH of the admixture is reduced once the phenytoin sodium injection is diluted in an excessive amount of infusion fluids. ...

show abstract

Fatalities Following Intravenous Use of Sodium Diphenylhydantoin for Cardiac Arrhythmias

Cited by 56 publications

References 8 publications

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

Contribution of Glucose to Crystallization of Phenytoin in Injectable Dosage Form by Dilution with Infusion Fluids

A 5% Glucose Infusion Fluid Provokes Significant Precipitation of Phenytoin Sodium Injection via Interruption of the Cosolvent Effect of Propylene Glycol.

Contact Info

Product

Resources

About