The Gasping Syndrome and Benzyl Alcohol Poisoning

Gershanik, Juan J.; Boecler, Betty; Ensley, Harry E.; McCloskey, Sharon E.; George, William J.

doi:10.1056/nejm198211253072206

Cited by 241 publications

(111 citation statements)

References 6 publications

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“…23 In 1997, the report of the Working Party for Medicines in Children of the Australian Drug Evaluation Committee was issued. 3 This report made a number of suggestions as to how the use of such drugs in children could be improved. Nearly 5 years later, few, if any, of these recommendations have been implemented.…”

Section: Discussionmentioning

confidence: 99%

Unlicensed and Off-Label Drug Use in an Australian Neonatal Intensive Care Unit

2002

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ABSTRACT. Objectives. To determine the extent of unlicensed and off-label drugs prescribed in the level 3 neonatal intensive care unit (NICU) at the Royal Women's Hospital, Melbourne, Australia.Methods. A prospective cohort study was conducted of all infants who were admitted to the NICU during a 10-week period. Each drug prescribed was evaluated in relation to the licensed approved uses to determine whether the drug was administered in a licensed manner or was unlicensed or used in an off-label manner.Results. There were a total of 101 admissions involving 97 infants. A total of 1442 prescriptions were administered; 42% were licensed, 11% were unlicensed, and 47% were off-label. Twenty-one percent were off-label for 2 or more reasons. Eighty percent of infants received either an unlicensed or an off-label prescription or both; this proportion rose to 93% of extremely low birth weight infants.Conclusions. This is the largest study performed of unlicensed and off-label drug use in the NICU. This practice remains widespread despite clear recommendations to improve this undesirable situation. The attendant risks to infants and prescribers remain. It is time for legislation to be introduced to govern this area.

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Section: Discussionmentioning

confidence: 99%

Unlicensed and Off-Label Drug Use in an Australian Neonatal Intensive Care Unit

2002

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“…vents such as benzyl alcohol 1) and propylene glycol 2−4) , which are often hazardous to premature and neonatal infants. Therefore, there is a strong demand for the development of a phenobarbital preparation for intravenous injection that is free of these additives.…”

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confidence: 99%

A Clinical Trial Assessing the Efficacy and Safety of a New Injectable Formula of Sodium Phenobarbital Containing No Additives for the Treatment of Neonatal Seizures

Kawada

Itoh

Itani

et al. 2011

Jpn. J. Clin. Pharmacol. Ther.

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Aims：A new phenobarbital preparation for injection containing no additives（NOBELBAR® ）was developed in Japan for safer use in neonates with seizures. This study was conducted to evaluate the clinical efficacy and safety of NOBELBAR®for the treatment of neonatal seizures. Methods：This investigator-initiated clinical trial was an open-label, uncontrolled, multicenter study, conducted in compliance with the good clinical practice. Phenobarbital was initially administered intravenously at a loading ／／ dose of 20 mg／kg. An additional dose of 20 mg／kg was given if the seizures did not resolve. The primary efficacy was evaluated 30 minutes after the administration of the loading dose. Infants who responded to the loading ／ administration received maintenance therapy with 2.5 to 5 mg／kg intravenous phenobarbital once daily for 6 days. Results：NOBELBAR®was administered to 10 neonates with seizures. The primary efficacy was evaluated as complete response in all patients. Adverse events were reported in 9 of the 10 patients（90％), most of which ／ were mild. Plasma phenobarbital concentrations ranged from 18.7 to 45.3 mg／mL. Conclusion：The study demonstrated that NOBELBAR®was effective for the control of neonatal seizures, and plasma drug concentrations were maintained within the therapeutic range. Approved for manufacturing and marketing was obtained based on the results of this study and other relevant data. （Clinical Trials. number, UMIN-C000000410, JMA-ⅡA00002.)

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“…A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al 1974;Gershanik et al 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.…”

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confidence: 99%

“…As recently as the early 1980's ignorance of the general principles of neonatal hepatic drug metabolism still resulted in significant morbidity and mortality (Gershanik et al 1982). For example, impaired neonatal glucuronidation resulted in the 'gray toddler' syndrome with the use of the antibiotic chloramphenicol (Craft et al 1974) and the ''gasping baby'' syndrome with the use of benzyl alcohol (Gershanik et al 1982).…”

mentioning

confidence: 99%

“…For example, impaired neonatal glucuronidation resulted in the 'gray toddler' syndrome with the use of the antibiotic chloramphenicol (Craft et al 1974) and the ''gasping baby'' syndrome with the use of benzyl alcohol (Gershanik et al 1982). Even today, the paediatric patient often remains a ''therapeutic orphan'', with the majority of currently available drugs marketed with a disclaimer concerning the lack of information regarding safety and efficacy in children, and submitted data on new drugs often providing no information of the same.…”

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Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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The Gasping Syndrome and Benzyl Alcohol Poisoning

Cited by 241 publications

References 6 publications

Unlicensed and Off-Label Drug Use in an Australian Neonatal Intensive Care Unit

Unlicensed and Off-Label Drug Use in an Australian Neonatal Intensive Care Unit

A Clinical Trial Assessing the Efficacy and Safety of a New Injectable Formula of Sodium Phenobarbital Containing No Additives for the Treatment of Neonatal Seizures

Neonatal Hepatic Drug Elimination

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