Bupivacaine Toxicity in Pregnant and Nonpregnant Ewes

Morishima, Hisayo O.; Pedersen, H.; Finster, Mieczyslaw; Hiraoka, Hitoshi; Tsuji, Akiko; Feldman, Hal S.; Arthur, G. R.; Covino, Benjamín G.

doi:10.1097/00000542-198508000-00003

Cited by 118 publications

(21 citation statements)

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“…However, reversible maternal as well as fatal reactions secondary to convulsions and cardiac arrest have been reported for bupivacaine in human labour due to excessive doses, low individual toxic thresholds or unrecognized intravascular injections (Editorial 1986;Moore et al 1971;Ryan 1973;Hodgkinson 1978;Albright 1979;Thornburn & Moir 1984). Animal studies suggest an increase in systemic toxicity (both cardioand neurotoxicity) following administration of bupivacaine in a late state of pregnancy (Morishima et al 1985; Crandell & Kotelko 1985;Ravindran et al 1982;Datta et al 1983). Serious foetalheonatal reactions seem to be very rare, but have been reported after paracervical block, most likely as a result of the direct entry of bupivacaine into the placental circulation (Beazley 1972).…”

Section: Introductionmentioning

confidence: 99%

Toxicity of Bupivacaine and Ropivacaine in Relation to Free Plasma Concentrations in Pregnant Rats: A Comparative Study

Danielsson¹,

Danielson²,

Böö³

et al. 1997

Pharmacology & Toxicology

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Abstract:The relationship between free drug concentration and toxicity of bupivacaine and ropivacaine, a new local anaesthetic agent, was studied in a pregnant rat model. The compounds were given subcutaneously to rats in late pregnancy. Dose levels (bupivacaine 5.5 to 24 mgikg and ropivacaine 5.3 to 26 mg/kg) were selected based upon the proposed human dosage and the known pharmacological activity of the compounds. Chewing, spasm, dyspnoea, drowsiness, salivation and convulsions were observed in a dose-dependent manner in the animals given 14 to 24 mg/kg of bupivacaine, while only a few animals receiving 26 mg/kg of ropivacaine showed less severe symptoms. Deaths from clonic convulsions were occasionally seen in animals receiving 14 mg/kg or more of bupivacaine. No animals receiving ropivacaine died. No effects on litter size, offspring loss or weight of the offspring at birth were observed with one exception. After 24 mgikg of bupivacaine an increased postnatal loss of the offsprings were noticed, most likely due to impaired maternal care. Protein binding, at expected C, , , , were significantly lower for ropivacaine (around 49%) compared with bupivacaine (around 69%) at dose levels. The results suggest an increased safety margin before onset of toxic side effects after treatment with ropivacaine, compared to bupivacaine, in pregnant rase.Clinical data confirm that bupivacaine is a useful drug in obstetric anaesthesia if proper precautions are taken (Editorial 1986;Moore et al. 1971). However, reversible maternal as well as fatal reactions secondary to convulsions and cardiac arrest have been reported for bupivacaine in human labour due to excessive doses, low individual toxic thresholds or unrecognized intravascular injections (Editorial 1986;Moore et al. 1971;Ryan 1973;Hodgkinson 1978;Albright 1979;Thornburn & Moir 1984). Animal studies suggest an increase in systemic toxicity (both cardioand neurotoxicity) following administration of bupivacaine in a late state of pregnancy (Morishima et al. 1985; Crandell & Kotelko 1985;Ravindran et al. 1982;Datta et al. 1983). Serious foetalheonatal reactions seem to be very rare, but have been reported after paracervical block, most likely as a result of the direct entry of bupivacaine into the placental circulation (Beazley 1972).Ropivacaine is a new long-acting local anaesthetic agent with pharmacodynamic properties similar to those of bupivacaine (Akerman et al. 1988). Unlike bupivacaine, which is a racemic mixture, ropivacaine is exclusively the S(-)-enantiomer. Ropivacaine is less cardio-and neurotoxic in non-pregnant animals than bupivacaine (Rutten et al. 1989; Arthur et al. 1986) and has been less prone to produce central nervous and cardiovascular symptoms after intravenous injection in human volunteers (Scott et al. 1989). Comparative data regarding its toxicity in humans are for obvious reasons very difficult to obtain. The main objective of this investigation was to compare the threshold for the induction of toxic effects in pregnant rats in relation to the p...

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Section: Introductionmentioning

confidence: 99%

Toxicity of Bupivacaine and Ropivacaine in Relation to Free Plasma Concentrations in Pregnant Rats: A Comparative Study

Danielsson¹,

Danielson²,

Böö³

et al. 1997

Pharmacology & Toxicology

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“…Durch eine zusätzliche Blockade mitochondrialer Vorgänge [95] ist die kardiale Toxizität von (Levo-)Bupivacain sehr hoch. Letzteres bedingt auch ein sehr frühes Einsetzen der kardialen Toxizität: Während andere Lokalanästhetika einen größeren Dosisunterschied zwischen dem Auftreten von zerebralen und kardialen Intoxikationsphänomenen aufweisen ("cc-index"), liegen die kritischen Dosierungen bei Bupivacain sehr eng beieinander [71,107] -im Einzelfall kann sogar die kardiale Toxizität vor der zerebralen auftreten. Eine sehr gute Übersicht zur Pharmakologie der Lokalanästhetika findet sich bei Graf u. Niesel [38].…”

Section: Intoxikationenunclassified

Komplikationen bei peripherer Regionalanästhesie

Neuburger

Büttner

2011

Anaesthesist

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Peripheral regional anesthesia is a commonly used and safe procedure and eneral complications or side effects are generally rare. Nerve damage has an incidence <0.1% depending on the definition and the prognosis is good. To avoid bleeding complications the national standards of block performance under antithrombotic therapy should be respected. Intoxication is mainly the result of accidental intravenous administration and is difficult to treat but higher doses of intravenous lipid emulsions can improve the outcome. Potential infectious complications can occur mainly as a result of catheter techniques and require a strict aseptic approach. Further rare complications are allergies, dislocation of catheters and knotting or loops in catheters. Besides the general complications, there are some specific complications depending on the puncture site, such as pneumothorax or renal puncture.

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“…Da es im letzten Schwangerschaftsdrittel durch vermehrte Flüssigkeitseinlage-rung physiologischerweise zu einer relativen Hypoproteinämie kommt, sinkt die Bindungskapazität der Plasmaproteine; dies äußert sich in höheren freien Lokalanästhetikakonzentrationen [147]. Diese Beobachtungen implizieren -zumindest theoretisch -eine erhöhte toxische Potenz der Lokalanästhetika im letzten Trimenon.Diesbezügliche (tier-)experimentelle Ergebnisse sind jedoch uneinheitlich und teilweise sogar widersprüchlich, zumal das Auftreten systemischer Effekte ebenfalls durch die alterierte hormonale Situation während der Schwangerschaft beeinflusst wird [147,154,188,204,205,206,207,208,209]. Daher wird bekanntermaßen empfohlen, Lokalanästhetika wäh-rend der Schwangerschaft und zu geburtshilflichen Eingriffen mit besonderer Vorsicht und Aufmerksamkeit einzusetzen.…”

Section: Formen Der Toxizitätunclassified

“…So konnte für Lidocain bei Schafen eine spezifische CC/CNS-Ratio hinsichtlich der Dosierung von 7,1±1,1 festgestellt werden; für Bupivacain und Ropivacain liegt dieser Quotient bei 3,7±0,5 bzw.4,4±0,9 [154].Die CC/CNS-Ratio für die entsprechenden Plasmaspiegel liegen mit Werten von 3,6±0,3 für Lidocain und 1,6-1,7 für Bupivacain bzw. Etidocain deutlich niedriger [154]. Konkret bedeutet dies, dass das "Sicherheitsspektrum" zwischen dem Einsetzen zentralnervöser Symptome und kardiovaskulärem Kollaps bei Lidocain ca.…”

Section: Toxische Wirkungen Auf Das Kardiovaskuläre Systemunclassified

Toxikologie der Lokalan�sthetika

Zink

Graf

2003

Der Anaesthesist

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Regardless of their specific physico-chemical properties and chemical structures, all local anaesthetic agents block neuronal voltage-gated sodium channels, and thus suppress conduction in peripheral nerves. Since these ion channels ubiquitously appear in excitable membranes, systemic accumulation of local anaesthetic agents may affect the functional integrity of these structures. Clinically, local anaesthetic-induced systemic toxicity results in central nervous and cardiovascular malfunction. With regard to CNS toxicity, symptoms which are largely drug-independent appear in a characteristic biphasic sequence. Nevertheless, the plasma levels necessary to provoke these symptoms are to a large extent agent-specific. Initially, these toxic mechanisms are due to a selective blockade of cortical inhibitory neurons, which enables the formation of seizure potentials within subcortical structures. With high cerebral drug levels, however, excitatory neurons are also increasingly blocked, resulting in coma, apnoeic episodes and circulatory failure. Direct cardiac effects of local anaesthetics can be divided into (i) stereospecific inhibition of intracardial conduction and (ii) unspecific inhibition of myocardial energy supply and ion channels. The corresponding spectrum of symptoms is not uniform and may range from extreme bradycardia, (malignant) ventricular arrhythmia to refractory cardiac arrest. Local tissue toxicity has to be strictly delimited from systemic toxicity and allergies, respectively, which are mainly caused by aminoester agents. Local anaesthetics may cause neuronal and striated muscle injury at the site of injection. With regard to (central) neurotoxicity, "transient neurologic symptoms" and "cauda equina syndrome" have been increasingly recognised. However, the clinical relevance of local anaesthetic-induced myotoxicity is still controversly discussed. In order to avoid systemic accumulation of local anaesthetic agents, several safety procedures have to be considered during the application of these drugs. The treatment of systemic toxicity is strictly dependent on the expression of symptoms. However, hypoxia and acidotic episodes must be avoided and must be treated aggressively.

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Bupivacaine Toxicity in Pregnant and Nonpregnant Ewes

Cited by 118 publications

References 0 publications

Toxicity of Bupivacaine and Ropivacaine in Relation to Free Plasma Concentrations in Pregnant Rats: A Comparative Study

Toxicity of Bupivacaine and Ropivacaine in Relation to Free Plasma Concentrations in Pregnant Rats: A Comparative Study

Komplikationen bei peripherer Regionalanästhesie

Toxikologie der Lokalan�sthetika

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