Intoxication of the Fetus by a Local Anesthetic

Sinclair, John C.; Fox, H.; Lentz, Joseph F.; Fuld, Gilbert L.; Murphy, Jerome

doi:10.1056/nejm196511252732201

Cited by 80 publications

(5 citation statements)

References 12 publications

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“…The procedures used in this study to synthesize the prilocaine isomers were described in Vardanyan et al 17 Prilocaine's four isomers were Figure 1. The same behavior was also observed for articaine (5). The structure of articaine along with its ESI-MS/MS spectra is depicted in Figure S1.…”

Section: Synthesis Of Prilocaine Positional Isomerssupporting

confidence: 73%

“…2 Lidocaine is predominantly metabolized to monoethylglycinexylidide (MEGX), which presents toxicological actions similar to those of lidocaine. Several accidental fatalities, suicides, and intoxication cases following intravenous injection of these local anesthetic drugs have been reported, [3][4][5] while fatal cases of oral lidocaine ingestion are rare. 6 Cases of fatal intoxication caused by these medicines are also commonly due to the combination of several drugs such as cocaine, with local anesthetic drugs, such as lidocaine, prilocaine, and procaine.…”

Section: Introductionmentioning

confidence: 99%

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Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

et al. 2020

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The demand for clinical toxicology analytical methods for identifying drugs of abuse and medicinal drugs is steadily increasing. Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites by GC‐EI‐MS and LC‐ESI‐MS/MS is of great analytical challenge. These compounds exhibit only/mostly fragments/product ions representing the amine‐containing residue, while the aromatic amide moiety remains unidentified. This task becomes even more complicated when discrimination between positional isomers of such compounds is required. Here, we report the development of a derivatization procedure for the differentiation and structural elucidation of a mixture of local anesthetic drugs and their metabolites that possess tertiary and secondary amines in water and urine. A method based on two sequential “in‐vial” instantaneous derivatization processes at ambient temperature followed by LC‐ESI‐MS/MS analysis was developed. 2,2,2‐Trichloro‐1,1‐dimethylethyl chloroformate (TCDMECF) was utilized to selectively convert the secondary amines into their carbamate derivatives, followed by hydrogen peroxide addition to produce the corresponding tertiary amine oxides. The resulting derivatives exhibited rich fragmentation patterns, enabling improved structural elucidation of the original compounds. The developed method was successfully applied to the differentiation and structural elucidation of prilocaine and its four positional isomers, which all possess similar GC and LC retention times and four of them exhibit almost identical EI‐MS and ESI‐MS/MS spectra, enabling their structural elucidation in a single LC‐ESI‐MS/MS analysis. The developed technique is fast and simple and enables discrimination between isomers based on different diagnostic ions/fragmentation patterns.

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Section: Synthesis Of Prilocaine Positional Isomerssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

et al. 2020

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“…In 1965 Sinclair et al 5 reported on four infants intoxicated by mepivacaine inadvertently injected into the foetal scalp during caudal anaesthesia. The consequences of the unusually .high concentrations of local anaesthetic were described.…”

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confidence: 99%

Transmission of lidocaine hydrochloride across the placenta during caesarian section

Fox¹,

Houle

1969

Can. Anaes. Soc. J.

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SEVERAL BEPOIRTS have been published on the effects of epidural analgesia upon pregnant women at delivery, and on the passage of local analgesics across the placenta. TM Morishima 1 and her group measured mepivacaine concentrations in the blood of mothers delivered vaginally, and in neonates after single and multiple dose epidural blockade using 1.5 per cent mepivaeaine.In 1965 Sinclair et al. 5 reported on four infants intoxicated by mepivacaine inadvertently injected into the foetal scalp during caudal anaesthesia. The consequences of the unusually .high concentrations of local anaesthetic were described. Recently Rosefsky and Petersiel 6 examined two cases of foetal death following paracervical block. In both instances, toxic levels of the local anaesthetic were implicated as the cause of foetal death. A high rate of foetal bradyeardia and depression have been noted following lidocaine paracervical blocks. 7We present observations on the use of 2 per cent lidocaine hydrochloride with 1:200,000 epinephrine for lumbar epidural anaesthesia during emergency and elective caesarian sections. The maternal and foetal concentrations of lidoeaine were relatively low, maternal complications were within acceptable limits, and the infants were vigorous at delivery. METHODNineteen women who received epidural analgesia for caesm'ian section were studied. Twelve patients had elective repeat caesarian sections and seven had emergency operations as a result of cephalopelvie disproportion. There were no other complicating features, except in case 3, a 31-year-old patient who had been treated for diabetes mellitus since the age of ten.Premeditation consisted of atropine sulphate 0.4 mg intramuscularly one hour prior to surgery. With the patient in the sitting position, a #16 Tuohy needle was inserted into the epidural space between the third and fourth lumbar vertebrae, using the loss of resistance technique, s Three millflitres of sterile saline were injected through the needle to open the epidural space, and a polyvinyl catheter was inserted one needle-length eephalad. The patient was then placed in the supine position. Blood pressure was recorded using a sphygmomanometer cuff. A #19 guage scalp vein needle was placed in a radial artery after local infiltration of the overlying skin with 0.2 cc of 1 per cent procaine.Samples of 5 ml each of heparinized maternal arterial blood were taken before the injection of 2 per cent lidocaine with 1:200,000 epinephrine into the epidural space and again as the baby was delivered. The first maternal specimen was *Royal Victoria Hospital, Montreal. 135

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“…Murphy et al (119) recorded fetal bradycardia and two fetal deaths associated with bupivacaine paracervical block. Similar deleterious effects of mepivacaine on the neonate were noted after direct injection of this drug into the fetus (120). Vasopressors have been used to correct adverse effects of maternal anesthetic agents, and the question of fetal risk from these cor rective measures has arisen.…”

Section: Drug Effects On the Developing Hostmentioning

confidence: 91%

Developmental Pharmacology: A Review of its Application to Clinical and Basic Science

Wilson¹

1972

Annu. Rev. Pharmacol.

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Drugs administered to the maturing host may (a) be used to alleviate diseases peculiar to his age group, (b) undergo alterations in metabolic fate and distribution to influence therapeutic effectiveness as compared with adults, or (c) show unexpected adverse effects as a result of systems placed at risk during development. Pharmacologic treatment of neonatal "physio logic " hyperbilirubinemia has been studied, and drugs undoubtedly will be designed for a specific effect on other diseases characterized by a slow rate of enzyme (or transport mechanism) maturation. Many developmental phar macology studies have considered the effect of host physiology on actions of a drug or, conversely, the effect of a drug on the host. For example, failure in drug efficacy may be secondary to a low conversion of the parent drug to active metabolite (host effect on drug) or structural malformations may be the result of drug action on a developing tissue (drug effect on host). Dif ferences in clinical response or potential toxicity for a drug are demon strated by comparative studies in the adult versus the young. Of more im portance, however, is an explanation for the observed age-related differ ences in drug action. Such explanations are often broadly applicable to in vestigations with adults and enhance rational therapeutics in children. Un fortunately, more age-related drug actions have been described than ex plained. Developmental pharmacologists must now accept the challenge to build programs that encourage observation and explanation of drug-host in teractions on an age continuum (1).This review will cite studies to illustrate the three areas of developmen tal pharmacology outlined above. The effect of enzyme inducing agents on hyperbilirubinemia will be considered as an example of drug use for an ill ness commonly found in children. The development of liver mixed function oxidase activity as influenced by hormones will illustrate modification of drug fate by age of the host. Brief reference to tetracycline effects on teeth 1 This monograph was prepared with support from the Clinical Pharmacology

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Intoxication of the Fetus by a Local Anesthetic

Cited by 80 publications

References 12 publications

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

Structural elucidation of amino amide‐type local anesthetic drugs and their main metabolites in urine by LC‐MS after derivatization and its application for differentiation between positional isomers of prilocaine

Transmission of lidocaine hydrochloride across the placenta during caesarian section

Developmental Pharmacology: A Review of its Application to Clinical and Basic Science

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