BUPIVACAINE epidural effectiveness has a clearly scientific evidence for perioperative analgesia Bupivacaine epidural still safe in a wide range dose to cause systemic toxicity We always reduce the risk of LA toxicity by our usually practice procedures

1. Curriculum Vitae
Nama : dr. Andi M.Takdir Musba, Sp.An-KMN
Tempat,Tanggal Lahir : Pare-Pare, 31Oktober 1974
Pangkat / Golongan : Penata MudaTk I / III-d
Alamat rumah : JL. Datuk Ditiro II No. 15 Makassar 90214, Indonesia
Telp / Hp : 0411-452113 / 0811463304
Email : takdir1974@yahoo.com
Alamat kantor : Bagian Ilmu Anestesi, Perawatan Intensif & Manajemen Nyeri
Fakultas Kedokteran UNHAS / RS. Dr.Wahidin Sudirohusodo
Jl. Perintis Kemerdekaan Km.11Tamalanrea Makassar-90245
Telp/HP/Fax/Email : 0411-582583-589777 /Fax. 0411-590290 /
anestesiologi_unhas@yahoo.co.id
Riwayat Pendidikan :
- Dokter Umum tahun 1999 Fakultas Kedokteran Universitas Hasanuddin
- Spesialis Ilmu Anestesi tahun 2007 Fakultas Kedokteran Universitas Hasanuddin
Pelatihan / Kursus :
-Tahun 2003 : Kursus Perioperative, Surabaya, Indonesia
-April 2006 : Pain ManagementWorkshop and Refresher Course, Makassar
- November 2006 : Acupuncture andTCMWorkshop, Makassar oleh Fakultas Kedokteran
Universitas Hasanuddin dan Xiamen University, China
- Februari - April 2008 : Course on Clinical Pain Management Program, Siriraj Hospital,
Mahidol University, Bangkok,Thailand
- Maret 2008 : Interventional Pain ManagementWorkshop, Bangkok

2. SAFETY PROFILE OF BUPIVACAINE
IN NEURAXIAL ANALGESIA
A.M.TAKDIR MUSBA
DEPARTMENTOF ANESTHESIOLOGY, INTENSIVECARE
AND PAIN MANAGEMENT
FACULTY OF MEDICINE, HASANUDDIN UNIVERSITY
MAKASSAR - INDONESIA

3.  Regional Anesthesia and analgesia can
greatly enhance the comfort of our patients
 Epidural Analgesia clearly evidenced as
effective perioperative analgesia
 LOCAL ANESTHETIC drugs have their own
risk. But …
The phobia of LA Safety profile will reduce
using regional analgesia for perioperative
analgesia ???

4. LOCAL ANESTHETIC
Ekenstam, 1957

5. Long Acting Amide-LA
 Due to their three- dimensional structure, local
anesthetics molecules can also have a
stereospecificity with two enantiomer molecules
that may exist in two different spatial
configurations, like left- and right-handed
gloves.
 Enantiomers can be differentiated by their
effects on the rotation of the plan of a polarized
light into dextrorotatory [clockwise rotation
(R+)] or levorotatory [counterclockwise rotation
(S-)] stereoisomers

6.  A solution of Bupivacaine is a racemic solution
 Solutions containing only one enantiomer of a
chiral molecule, which is optically pure 
Ropivacaine and levobupivacaine
 R- and S- enantiomers of LA  different affinity
for the different ion channels of sodium,
potassium, and calcium
 a reduction of central nervous system and
cardiac toxicity ?

7. Old Vs New
 When new molecules are introduced into the
market, it is not always simple to
understand whether their potential
advantages are really relevant to the daily
practitioner and worthy of the increased
costs of the newest agents compared to the
previous ones
Leone S. Et al , ACTA BIOMED 2008; 79: 92-105

8. Physiochemical LA
 Onset of Action : lower pKa, site of
administration
 Potency : higher partition coefficient , lipid
solubility
 Duration of action : higher protein binding,
addition vasoconstrictor

9. Physiochemical and Pharmacokinetic
properties of long acting LA
Leone S. Et al , ACTA BIOMED 2008; 79: 92-105

10. Comparisons of the 3 LALA
Potency
Racemic Bupivacaine > Levobupivacaine > Ropivacaine
CasatiA., Best Pract Res Clin Anaesthesiol. 2005
MLAC of Bupivacaine (0.081%) and levobupivacaine (0.083%) and
nearly 50% higher MLAC values for ropivacaine
Lyons G, et al. Br J Anaesth 1998; 81: 899-901
Polley LS, et al. Anesthesiology 1999; 90: 944-50
Capogna G, et al. BrJ Anaesth 1999; 82: 371-3
Thoracic epidural analgesia with 0.125% bupivacaine was more
effective than 0.125% ropivacaine when used in combination with
0.5 μg/ml sufentanil
PouzeratteY, et al. Anesth Analg 2001; 93: 1587-92

11. Potency (scientific evidence )
 At concentrations of 0.5% or greater, there
were no significant differences in onset time and
intensity or duration of sensory blockade between
bupivacaine, levo- or ropivacaine used for
epidural analgesia (Level II)
 No consistent differences between ropi-, levo- and
bupivacaine when given in low doses for regional
analgesia (epidural and peripheral nerve blockade)
in terms of quality of analgesia or motor blockade
(Level II)
Acute Pain Management: Scientific Evidence, 3rd edition, ANZCA, 2010

12. Toxicity
 Cardiovascular and central nervous system
toxicity of the stereospecific isomers Ropivacaine
and Levobupivacaine is less severe than with
racemic bupivacaine (Level II)
Acute Pain Management: Scientific Evidence, 3rd edition, ANZCA, 2010
 Levo and Ropi considered more well tolerated
than Bupivacaine but not as totally well
tolerated , as they still capable of inducing
systemic toxicity
ZinkW., Graf BM. Curr Opin Anaesthesiol, 2008

13. Determinants of Systemic
Toxicity
 Pharmacokinetic Factors
 Pharmacodynamic Factors
Tasch MD., Butterworth JF.Toxicity of Local Anesthetics, ASA, 2006

14. Pharmacokinetic Factors
 Circulating concentration of the drug in a form
that is not protein-bound
LAs are, as a rule, not (intentionally) administered directly
into the bloodstream, so systemic drug levels are the
result of interplay among dosage, additives, and site of
injection.
Paracervical > Intercostal > Epidural > PNB
 Patient-specific conditions can influence the
systemic uptake and toxicity of appropriately
administered
 Plasma protein binding , pregnancy, renal failure, hepatic
and heart failure

15. Pharmacodynamic Factors
 Increased lipid solubility
 Increased ability to permeate cellular
membranes and increased binding affinity for
ion channels
 Increased potency for local anesthesia and
systemic toxicity
 Stereoisomers
(S−) enantiomer (levobupivacaine) < (R+)
enantiomer or the standard racemic mixture

16. Convulsive Dose of LA
as a sign of Toxicity
Groban L. Reg Anesth Pain Med 2003; 28: 3-11

17. Cumulative Dose and Plasma Conc LA
at Cardiovascular Collapse

18. How much plasma concentration
can cause cardiac depression ?
 Can reduce 35% EF in anesthetized canine
 Ropivacaine 3 mg/ml
 Levobupivacaine 1.3 mg/ml
 Bupivacaine 2.1 mg/ml
 Also find in awake sheep and isolated rabbit
heart
Chang DH, et al. BrJ Pharmacol 2001; 132: 649-58
Pitkanen M, et al . Reg Anesth Pain Med 1992; 17: 182-92
Zapata-Sudo G, et al. Anesth Analg 2001; 92: 496-501
Groban L, et al . Reg Anesth Pain Med 2002; 27: 460-8

19. But ………..
Its often difficult to compare and extrapolate the
results of animal studies to human patients.
Leone S. Et al. Pharmacology, toxicology, and clinical use
of new long acting local anesthetics, ropivacaine and
levobupivacaine. ACTA BIOMED 2008; 79: 92-105
Its must be also considered that specie to specie
variability, and differences between human and
animal models can affect the strength of external
validity
Groban L. Central nervous system and cardiac effects
from long-acting amide local anesthetic toxicity in the intact
animal model. Reg Anesth Pain Med 2003; 28: 3-11.

20. Intravenous LA in Human Study
 CNS and CV effect after infusion iv in human
volunteer
 Bupivacaine or Ropivacaine 0.5 %, 2 ml/iv
continuous infusion and was discontinued at
definite sign and symptoms CNS effect or at the
request of subject
 Maximum tolerated dose 103 mg for Bupivacaine
and 117 mg for ropivacaine
 A threshold for CNS toxicity was apparent of mean
plasma concentration 0.6 mg/L for Ropivacaine and
0.3 mg/L for Bupivacaine
Knudsen K., et al, British Journal of Anesthesia 1997;78

21. Study in Epidural Human Volunteer
 Thirty-seven male volunteers, mean age 27 yr (range 20-42), mean body
weight 80 kg (range 60-98), mean height 182 cm (range 170-190) were
included in the study and written, informed consent was obtained from
each participant
 Judged healthy based on a routine medical/physical examination,
laboratory screening (hematology, blood chemistry, coagulation, and
liver function), and ECG
 The subjects received 10 mL/h of the study drug ropivacaine 1,2, or 3
mg/mL (0.l%, 0.2%, or 0.3%) for 21 h corresponding to infusion
rates of 10, 20, or 30 mg/h, respectively, or 25 mg/h bupivacaine 2.5
mg/mL (0.25%)
 Plasma concentration at time 0, and 30,60, and 90 min, and
2,3,4,5,6,8,10,12,19,21 (end of infusion), 21.5, 22, 23,24, and 25 h after
the start of injection of the bolus dose.
Britt-Marie K. Emanuelsson, et al.Anesth Analg 1995;81:1163-8

22. The difference between Ropivacaine and
Bupivacaine was not statistically significant
Britt-Marie K. Emanuelsson, et al.Anesth Analg 1995;81:1163-8

23. Bupivacaine Epidural Infusion free plasma
concentration reach lower than that can
cause CNS toxicity
Britt-Marie K. Emanuelsson, et al.Anesth Analg 1995;81:1163-8
Knudsen K., et al, British Journal ofAnesthesia 1997;78
Knudsen K, 1997

24. Subjects Reporting Adverse Events
Related to the 21-h Epidural Infusion
Britt-Marie K. Emanuelsson, et al. Anesth Analg 1995;81:1163-8

25. Our APS Report
Epidural postoperative analgesia using mostly
Bupivacaine 0,0625 – 0.125% combined with
opioid via epidural continuous ( 4-8 ml/hr )
intermittent 6-10 ml/6 hrs
 2004 -2011 : 4648 cases
No SystemicToxicity Sign has been report !!!

26. If CV collapse happen,
what evidences say ?
 No differences in the number of successfully
resuscitated animal were reported between
Ropi-, Levo- and Bupivacaine
 Cumulating dose producing cardiac arrest was
greater in Ropivacaine than Levobupicaine and
Bupivacaine
 Less adrenaline (epinephrine) was required to
treat ropivacaine-induced cardiac arrest than for
levobupivacaine- or bupivacaine-treated rats
Ohmura S, et al . Systemic toxicity and resuscitation in bupivacaine-,
levobupivacaine-, or ropivacaine-infused rats. Anesth Analg 2001; 93: 743-8

27. SISTEMIC TOXICITY OF LA
 ACCIDENTAL RAPID IV INJECTION
 RAPID ABSORPTION
 OVERDOSES
EXCESSIVE BLOOD CONCENTRATION
SIGN OFTOXICITY
CNS, CV, GI, etc

28. Reducing the risk
 TEST DOSE INJECTION
 USEVASOCONSTRICTOR
 PATIENT MONITORED CLOSELY
 USE LOWER DOSE IN FRAIL PATIENT
 CONCENTRATIONANDVOLUME

29. LcHv Vs HcLv

30. Conclussion
 BUPIVACAINE epidural effectiveness has a
clearly scientific evidence for perioperative
analgesia
 Bupivacaine epidural still safe in a wide
range dose to cause systemic toxicity
 We always reduce the risk of LA toxicity by
our usually practice procedures

31. THANKYOU
FORYOUR KIND ATTENTION