Lidocaine anestehsia and liposuction

La lidocaina come anestetico locale nella chirurgia del

contorno corporeo

Il punto di vista dell’anestesistaClaudio Mellonilibero professionista

Consulente di anestesia: Villa Torri,Bologna;Villa Chiara,Bologna,Poliambulatorio Gynepro,Bologna

Dosaggi di lidocaina nella tecnica tumescente

Klein JA.Tumescent technique for regional anesthesia

permits lidocaine doses of 35 mg/kg for liposuction. J. Dermatol. Surg. Oncol. 16: 248, 1990.

Lillis PJ. Liposuction surgery under local anesthesia: Limited blood loss and minimal lidocaine absorption. J. Dermatol. Surg. Oncol. 14: 1145, 1988. cita 88 mg/kg come sicuro

Coleman WP. Tumescent anesthesia with a lidocaine dose

of 55 mg/kg is safe for liposuction. Dermatol. Surg. 22: 919, 1996

Lillis, P. J. Liposuction surgery under local anesthesia: Limited blood loss and minimal lidocaine absorption. J.

Dermatol. Surg. Oncol. 14: 1145, 1988

measured serum lidocaine concentrations in 20 patients after suction lipectomy with the tumescent technique.

Total lidocaine dose ranged between 2000 mg and 5600 mg.

Blood samples drawn 15, 30, and 60 minutes after infiltration revealed lidocaine concentrations <1.7 µg/ml in all cases.

No signs of toxicity were reported.

Come mai tali dosaggi di lidocaina sono stati tollerati?

NON si sa Ipotesi l’assorbimento dal tessuto sotto cutaneo e adiposo è

molto lento vascolarizzazione scarsa adrenalina lo riduce ulteriormente,impedendo così il raggiungimento di livelli plasmatici

tossici la successiva suzione asporta una discreta quota del farmaco

infiltrato contribuendo alla sicurezza.I dati disponibili indicano una quota di rimossione della lido infiltrata variabile dal 10% al 31% » Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich

R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524.

» Hagerty T,Klein, P. Fat partitioning of lidocaine in tumescent liposuction. Ann. Plast. Surg. 42: 372,1999.

Dosaggio massimo di lidocaina

Il dosaggio massimo raccomandato in letteratura è di 7 mg/kg U.S. Food and Drug

Administration and manufacturers. » Lidocaine hydrochloride package insert. Astra Pharmaceutical Products, 1995.

Per infiltrazione:4,5 mg/kg and 6 mg/kg +adr(Goodman Gillman,the Pharmacological basis of Therapeutics)

200 mg o 500 mg se associata a adrenalina:Guida all’Uso dei farmaci

300 mg o 500 mg + adr:Cousins, Neural Blockade.,Lippincott Ed.

Pressione di infiltrazione s.c.

la pressione alla quale si effettua la iniezione (Alta Max press tissutale durante iniezione 339 +/- 63

mmHg vs bassa pressione 27 +/- 9 mmHg) non ha effetti sulla curva di assorbimento………» Rubin JP, Bierman C, Rosow CE, Arthur GR, Chang Y, Courtiss EH

, May JW Jr.The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of lidocainePlast Reconstr Surg. 1999 Mar;103(3):990-6;.

» Termpo di infiltrazione :16 min con alta pressione vs 20 con bassa

Velocità di infiltrazione

27 mg/min o 200 mg/min di lidocaina diluita e con epinefrina non determinano differenti livelli plasmatici di lidocaina( nelle prime 2 h)

Butterwick KJ, Goldman MP, Sriprachya-Anunt S. Lidocaine levels during the first two hours of infiltration of dilute anesthetic solution for tumescent liposuction: rapid versus slow delivery .Dermatol Surg. 1999 Sep;25(9):681-5.

Aghi spinali e cannule sottili multiorifizi

Sicurezza

Potete sempre garantire che durante l’infiltrazione non avvenga una accidentale iniezione ev.?

Livelli plasmatici in arteria dopo iniezione ev rapida o lenta di lidocaina

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Concentrazioni plasmatiche di lidocaina dopo iniezione in 4 sedi differenti


Concentrazioni plasmatiche di lidocaina e prilocaina dopo 400 mg inietttati per via

peridurale


Livelli plasmatici di lidocaina in un paziente dopo sgonfiaggio della cuffia ( anestesia endovenosa

con 3 mg/kg di lidocaina 0.5% e 45 min di

applicazione del tourniquet).Tucker GT,Boas RA. Pharmacokinetic

aspects of intravenous regional anesthetics.Anesthesiology 1971;34:578.


Accumulo locale e sistemico di lidocaina dopo bolo peridurale per anestesia e infusione

continua per analgesia postop.da Holmdahl MH et al.Clinical

aspects of continuous epidural blockade for postoperative pain relief.Ups.J.Med.Sci.77,47:1972.


Infusione cont.

bolo

Lidocaine plasma concentration over time for each experimental group (±SEM). In the two groups with epinephrine, the time to maximal lidocaine concentration (Tmax) was 11 hours after injection, whereas Tmax was

reached in 3.4 hours in the groups without epinephrine (p < 0.001). Rubin JP, Bierman C, Rosow CE, Arthur GR, Chang Y, Courtiss EH, May JW Jr.The tumescent technique: the effect of

high tissue pressure and dilute epinephrine on absorption of lidocainePlast Reconstr Surg. 1999 Mar;103(3):990-6


Lido 0.1 con epinefr 1:1.000.000 s.c.

faccia lat della coscia;no lipectomia

Senza adr.

Con adr.

Rubin JP, Xie Z, Davidson C, Rosow CE, Chang Y, May JW Jr.Rapid absorption of tumescent lidocaine above the clavicles: a prospective clinical study. Plast Reconstr Surg. 2005;115:1744-51.

Concentrazioni plasmatiche di lidocaina dopo tumescenza a livello del collo o della coscia.. Time to reach

maximal lidocaineconcentration was 5.8 hours after neck injection and 12.0 hours after thigh

injection (p 0.00Rubin JP, Xie Z, Davidson C, Rosow CE, Chang Y, May JW Jr.Rapid absorption of tumescent lidocaine above the clavicles: a prospective clinical study. Plast Reconstr Surg.

2005;115:1744-51.


neck

thigh

Curve di assorbimento della tumescenza con lidocaina con simulazione in caso di

infiltrazione simultaneaRubin JP, Xie Z, Davidson C, Rosow CE, Chang Y, May JW Jr.Rapid absorption of tumescent lidocaine above the clavicles: a prospective clinical

study. Plast Reconstr Surg. 2005;115:1744-51.


additiva

collo

coscia

Ma non si tratta solo di lidocaina............

La MEGX è un metabolita attivo

Plasma Concentrations of Monoethylglycinexylidide during and after Breast Augmentation Rygnestad, T, Samdal

F.Plast reconstruct Surg 2000

106:728-31. The plasma concentration of monoethylglycinexylidide (MEGX; microgams per

milliliter) versus the time after the end of the injection..


A total dose of 825 to 1280 mg of 0.2% and 0.5% lidocaine with epinephrine corresponding to 16.3 to 21.8 mg/kg (mean

18.2 mg/kg)

The plasma concentration of MEGX +lidocaine (micrograms per milliliter) versus the time after the

end of the injectionPlasma Concentrations of Monoethylglycinexylidide during and after Breast Augmentation

Rygnestad, T, Samdal F.Plast reconstruct Surg 2000 106:728-31


Tempo di raggiungimento dei livelli massimi di lido e megx dopo infiltrazione per tumescenza :Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich

R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide

in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524 dose media di lido 22 mg/kg

Livelli plasmatci massimi di lidocaina e megx dopo infiltrazione per tumescenza:dose media di lido 22

mg/kgKenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and

Monoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524

Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich R,Brown

SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis

Study.J Plast Surg . 114,2004, 516-524

absorbed lidocaine was estimated to be 1197.7 mg (range, 911.0 to 1596.0 mg).: 64 percent (range, 45 to 93 percent) of the infiltrated dose was ultimately absorbed.

Lipoaspirate analysis showed that 178.1 mg of lidocaine (range, 154 to 204 mg), 9.8 percent (range, 9.1 to 10.8 percent) of the infiltrated dose was removed during the procedure.

Mean plasma concentration of lidocaine (lido),monoethylglycinexylidide (MEGX), and lidocaine plus monoethylglycinexylidide vs time (mean, SEM). Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich

R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg .

114,2004, 516-524


Dove va a finire la lidocaina che non è nel plasma?

10% (range, 9.1 to 10.8)rimossa durante intervento » Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M,

Rohrich R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524:

31% aspirato nel grasso rimosso o rimasto: rapporto grasso / liquido 1.3- 2.95

Hagerty, T., and Klein, P. Fat partitioning of lidocaine in tumescent liposuction. Ann. Plast. Surg. 42: 372,1999.

Hardy, S. P., Ortiz-Colberg, R., and Poquette, M. A. Re: Fat partitioning of lidocaine in tumescent liposuction. Ann. Plast. Surg. 43: 574, 1999.

Importanza del legame alle proteine plasmatiche

Lidocaina + lipofilica del MEGX e + legata alla 1-acid glycoprotein,:60 to 70 %v s 15% for MEGX

La parte attiva di un farmaco è quella libera Sebbene i livelli di MEGX siano sostanzialmente +

bassi di quelli della lido,la concentrazione della MEGX libera è relativamente + alta e potrebbe determinare un ruolo maggiore nella tox.......

Anaesthesist. 2007 Aug;56(8):785-9. Links [Tumescent anaesthesia for dermatological surgery. Plasma concentrations of lidocaine and prilocaine] [Article in German] Rudlof K, Rüffert H, Wehner M, Wetzig T, Eichhorn K, Olthoff D. Klinik und Poliklinik für Anästhesiologie und Intensivtherapie, Universitätsklinikum Leipzig AöR, Liebigstr. 20,

04103 Leipzig. [email protected] BACKGROUND: Tumescent anaesthesia is currently used for several dermatological procedures. The objective

of this study was to determine the plasma concentrations of local anaesthetics under real operating conditions with this anaesthetic technique. METHODS: A total of 31 patients received 3 different anaesthetic solutions with prilocaine and lidocaine for several surgical procedures. The concentrations of local anaesthetics, methemoglobin, epinephrine as well as the occurrence of adverse reactions were determined 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after administration RESULTS: Maximum plasma concentrations of prilocaine were measured predominantly after 3 and 6 h, for lidocaine after 6 h. In two patients maximum plasma levels occurred 24 h after infiltration. Although toxic concentrations were not exceeded, side-effects could be observed in four patients. CONCLUSIONS: Even if the measured concentrations of local anaesthetics appeared to be safe, slight and moderate side-effects could be observed in 12.9% of cases. Maximum plasma levels of local anaesthetics may still occur 24 h after administration.


Nordström H, Stånge K. Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia. Acta Anaesthesiol Scand. 2005

Nov;49(10):1487-90.

35 mg per kg bodyweight of lidocaine for abdominal liposuction.

3 lt of buffered solution of 0.08% lidocaine with epinephrine was infiltrated subcutaneously over the abdomen in 8 female patients at a rate of 116 ml/min

monitored intravenous (i.v.) light sedation. Plasma levels of lidocaine and signs of subjective and

objective symptoms were recorded every 3 h for 20 h after liposuction.


RESULTS of Plasma lidocaine levels and risks after liposuction

with tumescent anaesthesia. Acta Anaesthesiol Scand. 2005 Nov;49(10):1487-90. :

Peak plasma levels (2.3 +/- 0.63 microg/ml) of lidocaine occurred after 5-17 h.

No correlation was found between peak levels and dose per kg bodyweight or total amount of lidocaine infiltrated.

One patient experienced tinnitus after 14 h when a plasma level of 3.3 microg/ml was recorded.

CONCLUSION: Doses of lidocaine up to 35 mg/kg were sufficient for abdominal liposuction using the tumescent technique and gave no fluid overload or toxic symptoms in eight patients, but with this dose there is still a risk of subjective symptoms in association with the peak level of lidocaine that may appear after discharge.


Conclusioni dalla letteratura citata

Ci sono significative differenze interindividuali nei livelli plasmatici di lidocaina

Il picco del livello plasmatico di lidocaina si raggiunge assai tardivamente

Anche la MEGX picca tardivamente I 2 farmaci sommano la tox................... Ci sono altri problemi che complicano il quadro.........

Pazienti a rischio di tox della lidocaina

Riduzione di flusso epatico :insuff epatica .....

CHF: MEGX / lido » Halkin, H., Meffin, P., Melmon, K. L., et al. Influence of congestive heart

failure on blood vessels of lidocaine and its active monodeethylated metabolite. Clin. Pharmacol. Ther. 17: 669, 1975.

Fin qui


Lo stress altera i livelli plasmatici di lidocaina

Eur J Drug Metab Pharmacokinet. 2002 Oct-Dec;27(4):229-32. Links Stress-induced lidocaine modification in serum and tissues. Saranteas T, Tesseromatis C, Potamianou A, Mourouzis C, Varonos D.

influence of acute (trauma) and chronic (cold swimming and adjuvant rheumatoid arthritis) stress on lidocaine concentrations in plasma.

Forty male Wistar rats were used. The animals were divided into four groups. Group A served as control. Group B underwent mandible osteotomy. Group C was submitted to swimming stress in cold water 4 degrees C for ten minutes daily for 15 minutes, while group D underwent experimental arthritis with Freud's adjuvant. All groups received lidocaine i.m (2.5 mg/kg). Blood samples were collected and FFA (free fatty acid), unbound-lidocaine, albumin and a1-acid glycoprotein concentrations were estimated. Furthermore, the adrenals, heart and liver were isolated. The adrenals' relative weight (adrenal weight/body weight) was assessed, while lidocaine concentrations in the heart and the liver incubation medium were measured by intertechnic a-counter. Lidocaine and FFA levels in serum as well as the adrenal weights demonstrated a significant elevation in stress-groups as compared to the control group. Furthermore, in the stress-groups, lidocaine concentrations in heart tissue were significantly increased, whereas in the liver they were significantly reduced as compared to the control group. Our results indicate that stress can alter lidocaine levels in plasma and tissues, suggesting that stress should be considered an important factor when determining the dosage of lidocaine in clinical application.


Ma La lidocaina tissutale residua contribuisce alla analgesia postoperatoria?


Livelli tissutali di lidocainaKenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M,

Rohrich R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg .

114,2004, 516-524

Area mammaria

Peak local tissue concentrations of lidocaine were in the 0- to 4-hour collection, immediately

postoperatively in both left and right femurs [18.5 (7.89) microg/ml mean (SEM) and27.7 (13.18)microg/ml, respectively]. Lidocaine levels decreased exponentially from

the initialpeak, 4 to 8 hours postoperatively at the infiltrated sites in both left and right femurs

[4.4 (1.83) and 4.3 (4.83) , as the drug was absorbed and redistributed totissue distal from the infiltrated sites. In contrast,peak levels in the control probe

occurredin the 8- to 12-hour collection [3.94 (2.4)mirog/ml].

Regione mammaria

Livelli tissutali di lidocaina e analgesia

Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine andMonoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524

4-5 microg/lt di tessuto Kopacz and BernardsKopacz, D. J., and Bernards, C. M. Effect of clonidine on

lidocaine clearance in vivo: A microdialysis study in humans. Anesthesiology 95: 1371, 2001.

Bernards, C. M., and Kopacz, D. J. Effect of epinephrine on lidocaine clearance in vivo: A microdialysis study in humans. Anesthesiology 91: 962, 1999.

25 microg/lt per il pizzicotto 42microg/lt per il tatto 20 microg/lt per il freddo. .

Livelli tessutali di lidocaina Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M,

Luby M, Rohrich R,Brown SA.D.Pharmacokinetics and Safety of Lidocaine andMonoethylglycinexylidide in Liposuction: A Microdialysis Study.J Plast Surg . 114,2004, 516-524

I livelli plasmatici di lidocaina vanno a picco da 8 a 16 h dopo l’intervento e persistono per 36 h

Ma……….i livelli tissutali di lido sono subterapeutici già dopo 4 o 8 h

Tsai PS, Buerkle ,H, Huang LT, Lee TC,. Yang C, Lee JHLidocaine Concentrations in Plasma and Cerebrospinal

FluidAfter Systemic Bolus Administration in Humans .Anesth Analg 1998;87:6014

Preclinical studies suggest that systemic lidocaine acts at the level of the spinal dorsal horn to inhibit hyperalgesia resulting from nerve injury, yet no clinical data are available to support this view. Therefore, we sought to characterize the time course of lidocaine in the plasma and cerebrospinal fluid (CSF) after an IV bolus injection of lidocaine 2 mg/kg in patients scheduled for surgery involving spinal anesthesia. Sixty-five patients were randomly allocated to one of five study groups (n = 13 per group) receiving IV lidocaine before CSF/ plasma sampling at 5, 10, 15, 30, or 60 min. Gas chromatographic analysis of these samples revealed a fast but transient peak (5-15 min) in lidocaine plasma levels (1.7 ? 0.16 pg/mL), which declined rapidly thereafter.

Only small concentrations of IV lidocaine were found in the CSF (6%-8% of plasma concentration), but this fraction remained stable from 15 min until termination of

the experiment. No statistical correlation was observed between plasma and CSF lidocaine levels. These data suggest that because of the prolonged availability of lidocaine at the spinal dorsal horn level, systemic administration of lidocaine suppresses central sensitization within the spinal cord after nerve injury in humans.

Implications: Cerebrospinal fluid concentrations of lidocaine after its systemic bolus delivery in humans indicate that the spinal cord may be the major site of antinociceptive action by this route of drug

administration.


Perché la lidocaina è efficace nel dolore (acuto ma + spesso cronico) iperalgesico

neuropatico da lesione nervosa? Il declino plasmatico dopo un bolo ev della

lidocaina è rapido Invece Il livello csf è basso ma persistente nel tempo La prolungata esposizione del corno post del

midollo spinale alla lido porta alla soppressione della sensibilizzazione centrale

Azione antinocicettivaServizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Time course of plasma lidocaine concentrations (A) and

cerebrospinal fluid (CSF) concentrations (B) after the IV administration of lidocaine 2 mg/kg. The x axis

shows the time points at whichsamples were taken after lidocaine administration (5-60 min after IV lidocaine). The y axis presents the lidocaine concentrations as assessed by gas chromatography for plasma (A) and cerebrospinalfluid (B). All data are presented as measurements of individual samples (open symbols) and their

correlating median values (filled symbols).


Quindi l’effetto antinocicettivo della

lidocaina

Se effetto analgesico da lidocaina c’è ,esso dipende dalla concentrazione spinale attiva sul midollo, corno posteriore ,non a livello tessutale………

meno si sa degli effetti a livello centrale………


Livelli di lido in cardiologia………..


general anesthesiacan alter the pharmacokinetics of disparatedrugs through direct effects on drug elimination mechanismsand/or indirect effects on hemodynamics.


Livelli plasmatici di lidocainae

anestesia generale


E’ noto che la AG modifica la distribuzione del flusso ematico ,la emodinamica generale e distrettuale

Mather LE, Runciman WB, Ilsley AH. Anesthesia-induced changes in regional blood flow. Implications for drug disposition.Reg Anesth 1982;7(suppl):S23–S33

Runciman WB, Myburgh J, Upton RN, Mather LE. Effects of anaesthesia on drug disposition. In: Feldman SA, Scurr CF, Paton W, eds. Mechanisms of action of drugs in anaesthetic practice. 2nd ed. London: Edward Arnold, 1993:83–128


Mather LE, Runciman WB, Ilsley AH. Anesthesia-induced changes in regional blood flow. Implications for drug disposition.Reg Anesth 1982;7(suppl):S23–S33

Runciman WB, Myburgh J, Upton RN, Mather LE. Effects of anaesthesia on drug disposition. In: Feldman SA, Scurr CF, Paton W, eds. Mechanisms of action of drugs in anaesthetic practice. 2nd ed. London: Edward Arnold, 1993:83–128


Copeland , SE , Ladd LA, Gu, XO, Mather LE.The Effects of General Anesthesia on Whole

Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg 2008;106:1440 –9

Study of influence of GA on the pharmacokinetics of six local anesthetics administered IV at approximately the highest recommended doses.

Chronically instrumented ewes (approximately 45–50 kg, n 18) infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg),

levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg)

on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by

achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart

and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by

equilibrium dialysis in vitro.


Copeland , SE , Ladd LA, Gu, XO, Mather LE.The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –9 RESULTS: Blood local anesthetic concentrations were doubled with

anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine S-bupivacaine and R-prilocaine S-prilocaine, but, mepivacaine clearance was not

enantioselective. Halothane did not influence blood binding of the local anesthetics.CONCLUSIONS: General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.


Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg 2008;106:1440

–9

Doses (as base) of : 100 mg bupivacaine, 125 mg levobupivacaine, 150 mg ropivacaine, 350 mg lidocaine, 350 mg mepivacaine, 350 mg prilocaine as HCl salts) were diluted to 30 mL with 0.9% saline, and

infused into a central venous catheter over 3 min


Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –9

produced CNS excitotoxicity accompanied by acute CVS stimulation in all conscious sheep; no overt effects were observed in anesthetized sheep, but general anesthesia caused CVS depression, which was exacerbated by all local anesthetics.

Fatalities occurred with bupivacaine (n 3), levobupivacaine (n 2),ropivacaine (n 2), and prilocaine (n 1), all in conscious sheep.

Arterial blood levels of LA always greater under anesthesia Copeland , SE , Ladd LA, Gu, XO,

Mather LE.The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –9


Pharmacokinetics of LA in adult sheep ,consious or under GA Copeland , SE , Ladd LA, Gu, XO,

Mather LE.The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –


Pharmacokinetics of LA in adult sheep ,consious or

under GA Copeland , SE , Ladd LA, Gu, XO, Mather LE.The Effects of General Anesthesia on Whole Body and Regional

Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg 2008;106:1440


Cmax

TmaxCL

Vss

T1/2

MRT

Copeland , SE , Ladd LA, Gu, XO, Mather LE.The Effects of General Anesthesia on

Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –

Anesthesia approximately doubled the blood concentrations of all local anesthetics compared with the respective values while conscious (Figs. 1 and 2).

Anesthesia affected the pharmacokinetic variables of all six drugs by decreasing their distribution and clearance, but with relatively minor differences between drugs (Tables 1 and 2).



Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg

2008;106:1440 –

In this study, we found that general anesthesia doubled the drug blood concentrations of all six local

anesthetics, when compared with the conscious state, by increasing Cmax/unit dose (an indirect measure of distributional clearance), decreasing Vss (a direct measure of peripheral uptake), and decreasing CL (a direct measure of hepatic elimination). Anesthesia also decreased MRT and T[1/2] (by decreasing Vss more than CL), and Tmax was a little earlier in conscious animals (an indirect consequence of the CNS excitotoxicity). At the same time, the toxic response was altered: despite undergoing much greater CVS depression, all anesthetized animals survived doses that were lethal in someconscious sheep.5 Thus, drug blood concentration– response relationships were distorted by inclusion of general anesthesia in the model.


Buona biblio sugli AL e loro tox Copeland , SE , Ladd LA, Gu, XO,

Mather LE.The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg 2008;106:1440 –


Copeland SE, Ladd LA, Gu X-Q, Mather LE. Effects of general

anesthesia on the central nervous system and cardiovascular

system toxicity of local anesthetics. Anesth Analg 2008;106:1429–39

*Behavioral, cardiovascular, and pharmacokinetic responses

previously instrumented ewes (approximately 45–50 kg, n 18),

on separate occasions when conscious and anesthetized8halothane /O2)

bupivacaine (100 mg),levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), prilocaine (350 mg), and saline (control) infused IV over 3 min.


Results of toxic doses of LA in sheep,conscious and

anesthetized LA caused convulsions in conscious sheep, but no overt CNS effects in

anesthetized sheep. Negative inotropy and slight bradycardia without changes in arterial blood pressure

occurred initially in conscious sheep,followed by positive inotropy, tachycardia, and hypertension at the abrupt onset of CNS excitotoxicity, along with widening of QRS complexes.

Fatal cardiac arrhythmias occurred in, respectively, 3 of 11, 2 of 12, and 2 of 13 conscious sheep infused with bupivacaine, levobupivacaine, and ropivacaine; in 1 of 9 with prilocaine, electromechanical dissociation (followed by polymorphic ventricular tachycardia) caused death.

In anesthetized sheep, cardiovascular depression, preexisting from the general anesthesia, was exacerbated by all local anesthetics, and increased QRS width was prolonged; concurrent blood local anesthetic concentrations were doubled.

Nevertheless, all anesthetized animals survived.


CONCLUSIONS: General anesthesia produced physiological perturbations, exacerbated local anesthetic-induced cardiovascular depression, and changed the pharmacokineticsof toxic doses of local anesthetics. However, cardiovascular fatalities from local anesthetics occurred only in conscious animals.


The dominant effect of all local anesthetics was overt CNS excitotoxicity in all conscious sheep. There were eight fatalities, all in

conscious animals and this was a significant finding (Table 1) (conscious versus anesthetized: proportion test Zcorr 2.54, P 0.011; Fisher’s exact test P 0.0061).

Postmortem findings in these subjects were unremarkable.


Left ventricular dp/dt in consciuos or anesthetized sheep before and after a toxic

dose of LA


Lidocaine toxic dose in a conscious sheep,non lethal


bupivacaine(100 mg) infusion,

demonstrating predrug, onset of CVS toxicity,

episodes of ventricular tachycardia, recovery

withoutsequelae;


bupivacaine (100 mg) infusion, demonstrating predrug, onset of CVS

toxicity, sustained myocardial

contractility during wide QRS complex tachycardia followed by hemodynamic

impairment, then cardiovascular collapse

associated with polymorphic ventricular

tachycardia


prilocaine (350 mg) infusion, demonstrating

predrug, onsetof CVS toxicity; sinus

rhythm, a supraventricular premature contraction

then tachycardia; decreased contractility;

electromechanicaldissociation resulting in

cardiovascular collapse is not shown occurred later

at 1180 s.


When conscious, initial myocardial depression (decreasing LV-dP/dtmax) was quickly reversed with the onset of CNS excitotoxicity. The longer acting local anesthetics usually produced a transient, irregular bradycardia, premature contractions, then episodes of tachycardia, including polymorphic ventricular tachycardia (VT) which resolved, usually abruptly (Fig. 3A), or resulted in cardiovascular collapse and death (Fig. 3B). The one fatality from prilocaine infusion (Fig. 3C) differed in that the first abnormality was decreased contractility, which progressed to apparent electromechanical dissociation and protracted polymorphic VT.


The maximal effects generally occurred at or near the time of completion of local anesthetic infusion but, in conscious sheep, were influenced by the time at which CNS excitotoxicity began. The preexisting myocardial depression from halothane anesthesia was markedly exacerbated by infusion of all local anesthetics, with further decreases in dP/dtmax, MABP, CO, and SV (Fig. 4) that were usually maximal at 5 min and resolved by 30 min (Fig. 5). QTc was decreased by 15%–20% in anesthetized ewes only. The effects of anesthesia began to regress soon after the halothane was turned off (30 min), and cardiovascular variableshad returned to baseline by 60 min. CVS

stimulation sometimes occurred during recovery from anesthesia before tracheal extubation. Malignant dysrhythmias were not seen in anesthetized animals, and all anesthetized animals survived.


SED10 and SED30 were correlated, and only SED10 is shown for brevity. The effects shown in Figures 5 and 6, except for Emax for QRS width, differed between conscious and anesthetized conditions (all P0.001); in anesthetized sheep, increases in QRS width lasted longer, resulting in greater values of SED10 and SED30 (P0.001). There were no important differences between drugs but, overall, the changes were greater in magnitude and/or duration for the longer-acting local anesthetics than for the shorteracting (and least for prilocaine), and were more prolonged in anesthetized sheep.


Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)Contr Bupi Levo Ropi Lido Mepi Prilo

Contr Bupi Levo Ropi Lido Mepi Prilo

Contr Bupi Levo Ropi Lido Mepi Prilo


Figure 5. The time course of the mean values of

maximum value of the first derivative of left

ventricular pressure(LV-dP/dtmax), estimated total peripheral resistance (TPR) and QRS width for

bupivacaine (Bup), levobupivacaine (Lev),

ropivacaine (Rop), lidocaine (Lid),

mepivacaine (Mep), and prilocaine (Pri) in

comparison to control (Con). Error bars have

been omitted for clarity. Similar time courses were observed for mean arterial

blood pressure (MABP), heart rate (HR), cardiacoutput (CO) and values derived from them. The

drugs were infused from 0 to 3 min. General

anesthesia with halothane was

induced approximately 30 min before drug infusion, and recovery began 30-min after drug infusion.


In conscious sheep, initial CVS depression was followed by CVS stimulation and QRS widening, with similar maximal effects for all local anesthetics, apparently reflecting the causative CNS excitotoxicity. The ameliorating effect of anesthesia on CNS toxicity was consistent with research reports and clinical practice.24–29 In the anesthetized state, profound CVS depression and prolonged increases in TPR occurred; notwithstanding, all animals survived, despite doubled local anesthetic blood

concentrations (Fig. 1).


However, other experimental models have shown that although general anesthesia suppresses convulsions and arrhythmias, it does not necessarily promote survival, apparently depending upon the drug and the model.24,25 This demonstration of biphasic CVS effects is partly a consequence of the dosage regimen chosen, compared to other models in which continuous or repeated drug administration are used to achieve a particular end-point, e.g., onset of convulsions, QRS widening, arrhythmogenesis, or CVS collapse, thereby producing other patterns according to experimental factors including state of consciousness and resuscitation. 30–34 We believe that our dosing regimen reasonably represents the situation when conscious patients undergoing major neural blockade accidentally receive local anesthetic IV.


The first sign of serious local anesthetic-induced toxicity

in conscious subjects is often generalized CNS excitotoxicity, with or without CVS signs, but

prodromal signs may be apparent5–7,35 depending mainly

on diligent observation and the rate of local anesthetic



might not be detected by usual clinical monitoring; a rapidly acting

anesthetic for treatment of CNS toxicity would exacerbate the

CVS depression. The CNS response to local anesthetics

has been implicated in their CVS toxicity,13–

15,36,37 but its role remains unclear, partly due to the

variations in experimental factors in the various models used for its

description

Halothane causes profound myocardial depression, and may predispose the heart to arrhythmias19–21,38; however, isoflurane and sevoflurane can suppress multiform QRS waves resulting from bupivacaine.24 Thus, it could reasonably be argued that the combination of toxic concentrations of local anesthetic and anesthesia with a volatile anesthetic other than halothane might cause less CVS depression. The last stage of CVS toxicity, especially from bupivacaine, is typically the sudden development of malignant ventricular arrhythmias (VT preceding fibrillation) resulting in cardiovascular collapse as previously described13,39–41; nevertheless, this did not occur in anesthetized subjects.


In this study, the blood gas changes in conscious sheep were consistent with a clear airway and good oxygenation; CABF was also maintained, and thus it is unlikely that cardiac ischemia or hypoxemia contributed significantly to the cardiac

dysrhythmias caused by the longer-acting drugs in conscious sheep, and dysrhythmias were not found in anesthetized sheep.


In summary, we found that local anesthetic toxicity in halothane-anesthetized sheep was very different from that in conscious sheep (Table 2). In the latter, CNS excitotoxicity stimulated the CVS with malignant, sometimes fatal, cardiac arrhythmias. In the former, marked cardiovascular depression predominated and, despite the blood drug concentrations being approximately doubled in sheep under general anesthesia,16 all sheep survived. This study therefore provides evidence that general anesthesia protects against a dangerous toxic effect of local anesthetics, arrhythmias, and possibly against death. As this study did not address mechanisms, it is not possible to tell from the available evidence whether these observations can be extended to larger doses of local anesthetic or to other forms of general anesthesia.


Figure 7. Mean values of arterial blood pH, Po2,

Pco2 and base excess in studies with infusion of

bupivacaine (Bup),levobupivacaine (Lev),

ropivacaine (Rop) (left 2 panels) lidocaine (Lid),

prilocaine (Pri), and mepivacaine (Mep) (right 2

panels) with infusion of 0.9% saline for controls

(Con) with the sheep conscious or anesthetized

(as indicated). In anesthetized

sheep, halothane was administered from before drug/control infusion until

30 min after infusion


Address correspondence to Emeritus Professor Laurence E.

Mather, Department of Anaesthesia and Pain Management, University

of Sydney at Royal North Shore Hospital, Sydney NSW 2065,

Australia. Address e-mail to [email protected].


Letter to Mather

Dear prof Mather,I have read with the greatest interest your two companion articles on toxicity of local anesthetics*(Copeland , SE , Ladd LA, Gu, XO, Mather LE.The Effects of General Anesthesia on Whole Body and Regional Pharmacokinetics of Local Anesthetics at Toxic Doses.Anesth Analg 2008;106:1440 –9Copeland SE, Ladd LA, Gu X-Q, Mather LE. Effects of generalanesthesia on the central nervous system and cardiovascularsystem toxicity of local anesthetics. Anesth Analg 2008;106:1429–39**,especially so because I have been asked to present a lecture in a forthcoming meeting of plastic surgeons,where I am trying to demonstrate that lidocaine dosages infiltrated for tumescent anesthesia during liposuction must not exceed the maximum recommended dosages of 7,may be 8 mg/kg.Your two articles will be cited and summarized especially in relationship with the practice of combining GA with local for these procedures.again, I must congratulate with you and your staff for these two seminal reports .Of course I am not forgetting all your precious praevious work in the field of LA ;I believe I have read a great lot of them since I enrolled in anesthesia in 1973 and I am happy to see that you are still producing science of the higher quality.Thank you again for the precious contribution you are offering to our specialty,I remain yours very truly

Claudio Melloni,Md.PhD.


Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med

2004;29:564–75


Hemodynamic Physiology andThermoregulation in Liposuction

Plast. Reconstr. Surg. 114: 503, 2004

Hemodynamic Physiology andThermoregulation in Liposuction

Plast. Reconstr. Surg. 114: 503, 2004

operatively and associated with diminished sodium, albumin, urea, and total protein concentrations. 44,45 The ultimate effect of hemodilution and lower blood viscosity is increased flow. Decreased peripheral vascular resistance and vasodilatation (increased arterial radius) were demonstrated in our patients. This relationship is described by Poiseuille’s equation.46 Ultimately a greater volume of blood is ejected from the left ventricle per beat.

Propofol Sedation Produces Dose-Dependent Suppression ofLidocaine-Induced Seizures in Rats

Victor C. Lee, MD, Jeffrey C. Moscicki, MS, and Cosmo A. DiFazio, MD, PhD

The association of propofol with excitatory motor activity, such as myoclonic jerking and opisthotonus, in humansand in animals suggests that it may aggravate clinical seizure activity in some circumstances, although evidence suggests that under other circumstances,propofol inhibits seizure activity. In the currentstudy, we assessed the effect of sedating doses of propofol on lidocaine-induced seizure activity in spontaneously breathing rats receiving no other anesthetics.Adult Sprague-awley male rats, 300-400 g, were divided into a control group and three experimental groups representing three graded levels of propofol sedation.The control rats then received a lidocaine infusion

at the rate of 150 mg * kg-’ . h-i, resulting in a slow, progressive increase in systemic lidocaine concentrations. At the onset of electroencephalographic (EEG) seizure activity, arterial lidocaine concentrations were obtained. The treated rats received propofol according to three different dose schedules: Dose 1 = 10 mg * kg-’ * h-’ after a 2.5-mg/kg bolus; Dose 2 = 20 mg * kg-r * h-’ afte r a 5-mg/kg bolus; Dose 3 = 40 mg * kg-’ * h-l after a lo-mg/kg bolus. After 30 min, a steady level of sedation, dependent on the dose of propofol, was achieved. The lidocaine infusion was then started, and systemic lidocaine levels were obtained at the onset of EEG seizure activity. The lidocaine was continued until the onset of death by cardiac arrest. Plasma lidocaine was measured by gas chromatography. Analysis of variance and Dunnett’s t-test were used for comparisons with the control values. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 ? 3.5 mg/kg (mean 5 SEM) to 52.5 2 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 2 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3. The lethal dose of lidocaine, 89.4 ? 10.5 mg/kgcontrolversus 108.7 ? 10.3 mg/kg (Dose l), 98.3 5 10.1 mg/kg (Dose 2), and 93.5 ? 10.4 mg/kg (Dose 3) did not differ among groups. The lidocaine levels at seizure threshold were increased in the propofoltreated rats: 16.9 -C 0.5 pg/mL control versus 19.2 5 0.7 pg/mL (Dose 1, P = not significant) and 23.7 ? 1.8 pg/mL (Dose 2, P < 0.05). Continuous propofol sedation in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dosedependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions. Implications: The IV anesthetic drug propofol, given to rats to produce sedation, was found to suppress seizure activity caused by overdosage of the local anesthetic lidocaine.

(Anesth Analg 1998;86:652-7)


Effetto protettivo della sedazione propofolica

Aumenta la dose ev di lidocaina necessaria per ottenere le convulsioni

Parallelamente aumenta il livello plasmatico al quale avvengono le convulsioni: da 16 a 20,25 microgr/ml

Al dosaggio più elevato evita la comparsa delle convulsioni


Continuous propofol sedationin spontaneously breathing rats receiving no

other anesthetics exerts a protective effect againstlidocaine-induced seizures

. Continuous propofol sedation increased the seizure dose of lidocaine from 37.7 ? 3.5 mg/kg (mean 5 SEM) to 52.5 2 2.6 mg/kg (Dose 1, P < 0.05) and 67.9 2 8.6 mg/kg (Dose 2, P < 0.05), and completely abolished lidocaine seizures at Dose 3.

The lethal dose of lidocaine, 89.4 10.5 mg/kgcontrol versus 108.7 ? 10.3 mg/kg (Dose l), 98.3 5 10.1 mg/kg (Dose 2), and 93.5 ? 10.4 mg/kg (Dose 3) did not differ among groups.

The lidocaine levels at seizure threshold were increased in the propofoltreated rats: 16.9 -C 0.5 pg/mL control versus 19.2 5 0.7 pg/mL (Dose 1, P = not significant) and 23.7 ? 1.8 pg/mL (Dose 2, P < 0.05). Continuous propofol sedation

in spontaneously breathing rats receiving no other anesthetics exerts a protective effect against lidocaine-induced seizures in a monotonic, dosedependent fashion. The cardiac arrest dose of lidocaine is unaffected by propofol under these conditions.


FINE


Concentrazioni plasmatiche osservate e predette dopo somministrazione peridurale ripetute di lidocaina da Tucker

GT et al.Observed and predicted accumulation of local anesthetic agents dsuring continuous extradural analgesia.Br.J.Anaesth. 1977;49:237.


Plast Reconstr Surg. 1999 Mar;103(3):990-6; discussion 997-1002. Links

The tumescent technique: the effect of high tissue pressure and dilute epinephrine on absorption of

lidocaine.Rubin JP, Bierman C, Rosow CE, Arthur GR, Chang Y,

Courtiss EH, May JW Jr. The purpose of this work was to determine the effect of tissue pressure during tumescent injection and presence of low

concentration epinephrine on the absorption of lidocaine from subcutaneous tissues in human volunteers. Twenty healthy female human volunteers were randomized into four study groups. After body fat measurements, all

subjects received an injection of 7 mg/kg of lidocaine into the subcutaneous tissues of both lateral thighs. The injected solution consisted of 0.1% lidocaine and 12.5 meq/liter sodium bicarbonate in normal saline with or without 1:1,000,000 epinephrine. Tissue pressure was recorded during injection using a specially designed double-barreled needle. The time required for injection was also recorded. Subjects in group 1 received lidocaine with epinephrine injected by a high-pressure technique. Group 2 subjects received lidocaine with epinephrine injected by a low-pressure technique. Group 3 subjects received lidocaine without epinephrine injected under high pressure. Group 4 subjects received lidocaine without epinephrine injected under low pressure. Following injection, sequential blood samples were drawn over a 14-hour period, and plasma lidocaine concentrations were determined by gas chromatography. No suction lipectomy was performed.

Maximum tissue pressure during injection was 339 ± 63 mmHg and 27 ± 9 mmHg using high-and low-pressure techniques, respectively. Addition of 1:1,000,000 epinephrine, regardless of the pressure of injected fluid, significantly delayed the time to peak plasma concentration by over 7 hours. There was no significant difference in the peak plasma concentration of lidocaine among the four groups. Peak plasma concentrations greater than 1 mcg/ml were seen in 11 subjects.

Epinephrine (1:1,000,000) significantly delays the absorption of lidocaine administered by the tumescent technique. High pressure generated in the subcutaneous tissues during injection of the solution does not affect lidocaine absorption. The delay in absorption may allow time for some lidocaine to be removed from the tissues by suction lipectomy. In addition, the slow rise to peak lidocaine concentration in the epinephrine groups may allow the development of systemic tolerance to high lidocaine plasma levels.


Rygnestad, T, Samdal F.Plasma Concentrations of Monoethylglycinexylidide during and after Breast

Augmentation.Plast reconstruct Surg 2000;106:728-31

MEGX is pharmacologically active,and its potential for adverse effects has been confirmed in man.13 In the present study, we found that the maximal plasma concentration of MEGX occurred as late as 8 to 12 hours after the end of the injection. In three patients, the concentration was still increasing after 12 hours.

The maximal concentration of MEGX+lidocaine occurred 5 to 12 hours after the end of the injection. The magnitude of the MEGX peak suggests that MEGX will contribute to the risk of developing toxicity when high doses

of lidocaine are used.

Lidocaine is present in plasma both in a protein bound pharmacologic inactive fraction and as a free active fraction. MEGX is probably not protein bound 10 and, thus, only exists in the free and pharmacologically active form. This finding further underlines the pharmacologic significance of MEGX with regard to potential lidocaine toxicity. It should also be noted that after an intravenous bolus injection, the clearance of lidocaine is reduced in the presence of MEGX.13

In previous studies, we have found a significant variation in peak plasma concentrations of lidocaine in patients undergoing liposuction14 as well as in patients undergoing breast surgery.4 Moreover, we have reported that it is difficult to assess the risk of lidocaine toxicity without taking into consideration the binding to a1-acid glycoprotein (AAG) and the free fraction of the drug.4 In the present study, we have also found a substantial interindividual difference in the peak plasma concentrations of MEGX. This finding shows that there are significant differences from person to person in the pharmacokinetics of lidocaine,at least when applied in breast surgery and liposuction. 4,14–16 The variation in the pharmacokinetics strongly indicates that recommendations about maximum safe dose should be made with caution



Rygnestad, T, Samdal F.Plasma Concentrations of Monoethylglycinexylidide during and after Breast

Augmentation.Plast reconstruct Surg 2000;106:728-31

Kenkel JM,Lipschitz , A H,Shepherd G,Armstrong VW,Streit F,Oellerich M, Luby M, Rohrich R,Brown

SA.D.Pharmacokinetics and Safety of Lidocaine and Monoethylglycinexylidide in Liposuction: A Microdialysis

Study.J Plast Surg . 114,2004, 516-524


More information would be desirable on the factors controlling the resorption of lidocaineduring liposuction therapy to improve durationof effect. Perry et al.43 studied postoperativepain at 5, 30, 60, and 120 minutes and on the first postoperative day after liposuction and found that there was no statistically significant

difference between paired, mirrored sides of 10 subjects when lidocaine was used on only one side. The study concluded that lidocaine is not necessary in liposuction. Further research into diminishing the dose of lidocaine in wetting solution is warranted, as the safety profile of liposuction may be significantly improved by

eliminating lidocaine toxicity as a potential complication. Lidocaine’s impact on diminishing intraoperative general anesthesia deserves

further exploration.

Rygnestad T, Brevik B, Samdal F. Plasma Concentrations of Lidocaine and [alpha]1-Acid Glycoprotein during and after Breast Augmentation.Plast Reconstruct Surg., 1999;109:1267-1272


The mean lidocaine dose was 18.2 mg/kg (range 16.3 to 21.9 mg/kg). The mean injection time was 23.3

minutes (range, 16 to 35 minutes). Rygnestad T, Brevik B, Samdal F. Plasma Concentrations of Lidocaine and [alpha]1-Acid Glycoprotein during and after Breast

Augmentation.Plast Reconstruct Surg., 1999;109:1267-1272


Rygnestad T, Brevik B, Samdal F. Plasma Concentrations of Lidocaine and [alpha]1-Acid

Glycoprotein during and after Breast Augmentation.Plast Reconstruct Surg.,

1999;109:1267-1272


0 pioid-insensitive neuropathic pain due to nerve injury is one of the most difficult problems in pain management. Therapeutic approaches for these painful sensations, which can be evoked by thermal or mechanical stimuli, include the use of sodium channel blockers such as carbamazepine, tocainide,

phenytoin, mexiletine, or lidocaine (1,2). Lidocaine and mexiletine alleviate consistent neuropathic pain states (3-5). Local anesthetics act in both the peripheral and the central nervous systems (6-9). At the peripheral level, local anesthetics inhibit neuronal transduction, decrease the release of inflammatory mediators, inhibit migration of leukocytes, and suppress albumin extravasation (10). At the central site,local anesthetics block neuronal activity at the spinal


Effetti periferici degli anestetici locali

Inibizione della trasduzione neuronale Riduzione dei mediatori nfiammatori Inibizione della migrazione leucocitaria Soppressione dello stravaso albuminico Inibizione della generazione di impulsi a

livello del nervo leso,neuromi inclusi


Effetti centrali degli anestetici locali

Riduzione della scarica a partenza dal ganglio della radice dorsale

Blocco della attività neurale spinale a livello del corno post.

Modulazione della liberazione di neurotrasmettitori

Soppressione della attività delle fibre C


dorsal horn level, thus modulating the release of excitatory neurotransmitters (6,ll). However, the underlying mechanisms for the analgesic action of systemically administered lidocaine remain controversial.

Some preclinical studies provide evidence for a predominant inhibition of impulse generation arising from injured nerve segments or any associated dorsal root ganglion (12,13). Devor et al. (14) found a selective blocking effect for systemically delivered lidocaine by inhibiting ectopic discharges from experimental neuromas without affecting axonal conduction.


However, several investigators propose a predominant central site of action for the use of systemic lidocaine or other sodium channel blockers (3,6,15).

Sotgiu et al. (16) found that systemically administered lidocaine preferentially acts on the hyperactive, wide dynamic-range neurons found in the dorsal horn, resulting in analgesia. This type of sensitized neuron is often found in hyperalgesic pain states. Further important evidence regarding a central site of action was demonstrated by the spinal suppression of C-fiberevoked activity seen with low concentrations after systemic lidocaine (17).


Hyperalgesic pain states occur after surgery, trauma,and metabolic disorders, and they are also related to sympathetically maintained pain syndromes (3). As a result of continuous C-fiber stimulation, hyperalgesia represents a state of facilitated sensory processing at the level of the spinal dorsal horn (3,12). As a clinical symptom of nerve injury, hyperalgesic pain often leads to protective immobilization, which may result in malformation or loss of function in the affected body region. Preclinical and clinical studies have shown that sodium channel blockers such as lido- Caine, given systemically or spinally, effectively inhibit this pain (18-20). This analgesic effect can be achieved with small doses of lidocaine, which do not alter acute nociceptive pain thresholds or axonal conduction.

This was reported by Wallace et al. (21), who revealed no prominent effects by systemic lidocaine infusions on acute heat, cold, or mechanical thresholds.


Their findings are in accordance with those ofBach et al. (22), who showed that IV lidocaine decreases neuropathic pain without affecting the neurosensory system. The administration of a bolus dose of 2 mg/kg IV lidocaine produced plasma concentrations of lidocaine similar to those for which Wallace et al. (17) demonstrated a decrease in pain scores and a concomitant reduction in the size of the receptive field to which the pain was referred. The onset of the inhibition of spinal dorsal horn neuron activity after IV lidocaine occurs within 5-7 min, as shown in a preclinical model. The antihyperalgesic action of systemic lidocaine is mainly attributed to the spinal cord. Lido- Caine has a plasma half-life of approximately 90 min after bolus injection, an octanol to water distribution coefficient of 110 at 36”C, and pH 7.4; it rapidly accesses the central nervous system after systemic delivery (l&23). At the spinal cord, systemically applied lidocaine blocks the release of substance I’ (24), inhibits the discharge of wide dynamic neurons (25), and suppresses the discharge induced by the release of the excitatory amino acid glutamate (7). Previous studies of IV bolus delivery of lidocaine recorded inconsistent plasma levels (26,27


). This finding is supported by our observation of a very fast decay in plasma lidocaine concentrations and an interindividual difference for the plasma peak obtained after IV lidocaine injection. As demonstrated in our present study, there was no linear relationship between plasma and CSF levels of lidocaine after the systemic bolus delivery of lido- Caine. In addition, the CSF levels of lidocaine obtained after this IV bolus injection did not reach the proposed therapeutic range. However, the faster decay of plasma levels of lidocaine compared with the sustained and constant lidocaine levels in the CSF suggests that the analgesic effects are mediated through the central site. Thus, the spinal cord seems to contribute greatly to the alleviation of neuropathic pain after a systemic lidocaine injection. This analgesic effect might be enhanced further not only by inhibition of sodium channels, but also by blocking of N-methyl-Daspartate and neurokinin receptors with a subanesthetic dose of lidocaine (28). Continuous administration of lidocame maintains constant plasma levels after IV administration. It also enhances the bloodbrain transfer of lidocaine into the CSF (29). Ferrante et al. (2) suggest that the analgesic response to IV lido- Caine is best characterized by a precipitous break in pain over a narrow dose range and concentration. This study reveals that a single bolus IV injection of lidocaine results in concentrations of lidocaine prevailing long enough in the CSF to act at the spinal dorsal horn. Thus, we suggest that a systemic bolus of lido- Caine suppresses nociceptive impulses at a central site of action. References


Lidocaine anestehsia and liposuction

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