Lidocaine anestehsia and liposuction

La lidocaina come anestetico
locale nella chirurgia del contorno
corporeo
Il punto di vista dell’anestesista
Claudio Melloni
libero 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 lidocaine

concentration 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 injection
Plasma 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

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 1acid 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,

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
Servizio
Anestesia e Rianimazione
adrenals,diheart and liverOspedale di isolated. The adrenals' relative weight
were Faenza(RA)

Ma La lidocaina tissutale residua
contribuisce alla analgesia
postoperatoria?


Livelli tissutali 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 and Monoethylglycinexylidide in Liposuction: A

Regione mammaria

Peak local tissue concentrations of lidocaine were in the 0- to 4-hour collection, immediately
Area mammaria
postoperatively in both left and right femurs [18.5 (7.89) microg/ml mean (SEM) and
27.7 (13.18)microg/ml, respectively]. Lidocaine levels decreased exponentially from the initial
peak, 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 to
tissue distal from the infiltrated sites. In contrast,peak levels in the control probe occurred
in the 8- to 12-hour collection [3.94 (2.4)mirog/ml].

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

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 antinocicettiva

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 which

samples 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 cerebrospinal
fluid (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 anesthesia
can alter the pharmacokinetics of
disparate
drugs through direct effects on drug
elimination mechanisms
and/or indirect effects on hemodynamics.


Livelli plasmatici di lidocaina
e
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. Anesthesiainduced 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.

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.

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

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

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

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

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
Tmax
CL
Vss
T1/2
MRT

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).


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
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 Servizio di Anestesia e Rianimazione Ospedale di exacerbated by all local anesthetics,
general anesthesia, was Faenza(RA)

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).

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


recovery without
sequelae;


associated with polymorphic
ventricular tachycardia


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


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


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


Contr Bupi Levo Ropi Lido Mepi Prilo


Contr Bupi Levo Ropi Lido Mepi Pril

Contr Bupi Levo Ropi Lido Mepi Prilo


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


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


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


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


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


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,


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
lmather@med.usyd.edu.au.

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
Servizio

2008;106:1440

di Anestesia e Rianimazione Ospedale di Faenza(RA)

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 and
Thermoregulation in Liposuction
Plast. Reconstr. Surg. 114: 503, 2004

Hemodynamic Physiology and
Thermoregulation 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 of
Lidocaine-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 lidocaineinduced 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
Servizio di Anestesia e Rianimazione Ospedale in systemic lidocaine concentrations.
slow, progressive increase di Faenza(RA)

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 sedation
in spontaneously breathing rats receiving no
other anesthetics exerts a protective effect against
lidocaine-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

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.


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 highand 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

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 di Anestesia e Rianimazione Ospedale di Faenza(RA) and the free fraction of the drug.4 In the
Servizio the binding to a1-acid glycoprotein (AAG)

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


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;109:12671272


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;109:12671272


Rygnestad T, Brevik B, Samdal F. Plasma Concentrations of
Lidocaine and [alpha]1-Acid Glycoprotein during and after
Breast Augmentation.Plast Reconstruct Surg., 1999;109:12671272


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

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


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