Bupivacaine toxicity

The earliest signs of CNS toxicity are circumoral and tongue numbness, tinnitus, tremor, and dizziness. These appear at plasma lidocaine (lignocaine) concentrations of about 5 pg-mL-1. The value for prilocaine is similar to lidocaine but bupivacaine toxicity appears at about half those of lidocaine. Further progression is evidenced by drowsiness, visual disturbances, or muscle twitching (plasma lidocaine of 5-10 pg-mL-1). Over 10 p-mL-1 grand mal convulsions, coma and respiratory arrest are likely. Serious CNS toxicity is indicative of imminent and potentially fatal cardiac toxicity since lidocaine is associated with direct cardiac depression at plasma concentrations in excess of 20 pg-mL-1. 

Etidocaine is a long-acting amide LA with a physicochemical and clinical profile similar to bupivacaine. Toxic side-effects occur at total doses of 300 to 400 mg. It is clinically available in combination with the vasoconstrictor adrenaline. 

JJ McCloskey. Bupivacaine toxicity secondary to continuous caudal epidural infusion in pediatric patients. Anesth Analg 75 287, 1992. 

BETA-BLOCKERS BUPIVACAINE Risk of bupivacaine toxicity Beta-blockers, particularly propranolol, inhibit hepatic microsomal metabolism of bupivacaine Watch for bupivacaine toxicity -monitor ECG and BP... 

Pickering AE, Waki H, Headley PM, Paton JF. Investigation of systemic bupivacaine toxicity using the in situ perfused working heart-brainstem preparation of the rat. Anesthesiology 2002 97(6) 1550-6. 

Pretreatment with oral ranitidine 150 mg 1.5 to 2 hours before bupivacaine for extradural anaesthesia for caesarean section, increased the maximum plasma levels of bupivacaine in 10 patients by about 36%, when compared with 10 patients given no pretreatment. Another study found that two oral doses of ranitidine 150 mg caused a 25% increase in the mean AUC of bupivacaine, but this was not statistically significant. No increased bupivacaine toxicity was described in any of these reports. However, two other studies in 36 and 28 women undergoing caesarean section found no measurable effect on the bupivacaine disposition when given ranitidine 150 mg the night before and on the morning of anaesthesia, or ranitidine 50 mg intramuscularly 2 hours before anaesthesia, respectively. ... 

A confusing situation. No clinically important interaction has been established, but be alert for any evidence of increased bupivacaine toxicity resulting from raised total plasma levels and rises in unbound bupivacaine levels during the concurrent use of cimetidine and possibly ranitidine. Cimetidine (but not ranitidine) has been shown to raise plasma lidocaine levels when lidocaine is used as an antiarrhythmic (see Lidocaine + H2-receptor antagonists , p.264), but some of the studies cited above found cimetidine did not affect lidocaine levels when lidocaine is used as an anaesthetic. However, in the studies comparing the effects of cimetidine and famotidine, cimetidine was found to increase lidocaine levels and it was suggested that famotidine may be preferable to cimetidine as pretreatment before epidural lidocaine. ... 

Cave G, Harvey M, Prince G, Lahner D, Desmet J. Effect of hypertonic saline on electrocardiography QRS duration in rabbit model of bupivacaine toxicity resuscitated by intravenous lipid. Anaesthesia 2010 65 792-8. 

Piper SL, Kim HT. Comparison of ropivacaine and bupivacaine toxicity in human articular chondrocytes. J Bone Joint Surg Am 2008 90(5) 986-91. 

A 21-day-old male weighing 2715 g received a dorsal penile block for elective circumcision. He received two 1-mL doses of 0.5% bupivacaine spaced apart by 2-3 min. Within minutes of the injections, the infant became lethargic and showed disconjugate gaze, intermittent exotropia and altered consciousness with hypotonia upon arrival to the emergency department. A serum sample revealed a bupivacaine concentration of 0.76gg/mL, which is consistent with bupivacaine toxicity. At 22 h after the event the infant fully recovered in the paediatric intensive care unit without any sequelae. 

French LK, Cedar A, Hendrickson RG. Case report bupivacaine toxicity with dorsal penile block for drcumcisioit. Am Fam Physician 2012 86(3) 222. 

Chloroprocaine hydrochloride [3858-89-7] is characterized by low potency, rapid onset, short duration of action, and low systemic toxicity. It is indicated for infiltration anesthesia at 1—2% and for extradural anesthesia at 2—3% when short surgical procedures are performed under regional anesthesia. Chloroprocaine may be mixed with long duration agents such as bupivacaine (22, R = n-Q [) to afford a more rapid onset and shorter duration of action than bupivacaine alone. 

Levobupivacaine hydrochloride (Chirocaine) is the S-enantiomer of bupivacaine. It too has long action. Animal studies show that it has less CNS and cardiac toxicity than does bupivacaine. It also is slightly more motor sparing than is bupivacaine. 

Bupivacaine is an amide compound with a duration of nerve blocking effect of around 3 hours. It is about four times more potent than lidocaine (lignocaine) and has an intermediate-to-slow onset of action. Bupivacaine is prepared as the hydrochloride salt in aqueous solutions in concentrations of 0.25%, 0.50%, and 0.75%. The incidence of motor block increases with increasing concentration. High doses of bupivacaine are associated with cardiac toxicity. Particular care must be exercised to avoid inadvertent overdosage or when the drug is administered to patients taking concurrent cardioactive medication. 

This is an amide local anaesthetic and is widely used on account of its rapid onset, medium duration of effect, and low toxicity. It is less highly protein-bound than the longer-acting amides (Table 5.1) but it has a useful duration of effect and is the most versatile of all local anaesthetics. It is of intermediate potency and has less toxic potential than bupivacaine. It is available in aqueous solution as the hydrochloride salt in concentrations of 0.5-2.0% with and without adrenaline (epinephrine). Topical preparations are also available as gels or aerosols in 2-4% concentrations. 

When used for spinal anaesthesia, 0.75% ropivacaine produces less intense sensory and motor block than 0.5% bupivacaine. It is suitable for regional, spinal and epidural block but not for regional intravenous anaesthesia. The addition of adrenaline (epinephrine) does not prolong the duration of anaesthesia in brachial plexus or epidural block. Ropivacaine is indistinguishable from bupivacaine when used in obstetric anaesthesia. Its direct myocardial toxicity is somewhat less than that of bupivacaine. 

Resuscitation from bupivacaine cardiovascular toxicity is extremely difficult even for experienced clinicians. Recent studies suggest that propofol can be useful in resuscitating patients acutely exposed to toxic levels of bupivacaine. The (S)-isomer, levobupivacaine, appears to have a lower propensity for cardiovascular toxicity than the racemic mixture or the (7 >isomer and has been approved for clinical use. The clinical effects of ropivacaine are similar to those of bupivacaine, but ropivacaine is allegedly associated with a lower potential for cardiovascular toxicity. Ropivacaine is available only as the ( SJ-stereoisomer, which has inherently less affinity for the cardiac sodium channel. However, both cardiac toxicity and CNS toxicity have been reported when large doses of ropivacaine were used for peripheral nerve blocks. 

Bupivacaine Same as lidocaine Same as lidocaine Longer-duration procedures Parenteral duration 2-4 h Toxicity CNS excitation cardiovascular collapse... 

The racemic compound bupivacaine, which was first synthesized by Ekenstam et al. in 1957, is an amide-type LA with a high lipophilicity, protein binding and pKa giving rise to an intermediate onset and a long duration of action. At the same time, bupivacaine has a high toxicity potential relatively often associated with convulsions and life-threatening cardivascular collapse (Moore et al., 1978). Levobupivacaine, the (S)-enantiomer of bupivacaine, has recently been developed for clinical use addressing the enantioselectivity of side-effects of bupivacaine (see below). 

With local infiltration, toxic side-effects like convulsions and cardiovascular collaps occur in the dose range of 2.5 to 3 mg/kg body weight. Because of its systemic toxicity, bupivacaine is contraindicated for intravenous regional anesthesia. 

A need was seen for a synthetic and less toxic anesthetic. In 1905, Procaine was synthesized and became the prototype for synthesized anesthetics for the next 50 years. In 1948, Lidocaine was developed and is now the most commonly used local anesthetic. Other synthesized local anesthetics include bupivacaine and tetracaine. 

Luduena FP, Hoppe JO (1952) Local anaesthetic activity, toxicity and irritancy of 2-alkoxy analogs of procaine and tetracaine. J Pharm Exp Ther 104 40-53 Luduena FP, Hoppe JO, Coulston F, Drobeck HP (1960) The pharmacology and toxicology of mepivacaine, a new local anesthetic. Toxicol Appl Pharmacol 2 295-315 Luduena FP, Bogado EF, Tullar BF (1972) Optical isomers of mepivacaine and bupivacaine. Arch Int Pharmacodyn 200 359-369... 

A healthy 17-year-old man received an interscalene brachial plexus block using mepivacaine 600 mg and bupivacaine 150 mg. He became disorientated and showed signs of local anesthetic toxicity, for which he was given midazolam 5 mg. Flumazenil 0.5 mg was given 23 minutes after the end of the procedure, causing opisthotonos. 

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