Curriculum VitaeNama : dr. Andi M. Takdir Musba, Sp.An-KMNTempat, Tanggal Lahir : Pare-Pare, 31 Oktober 1974Pangkat / Golongan : Penata Muda Tk I / III-dAlamat rumah : JL. Datuk Ditiro II No. 15 Makassar 90214, IndonesiaTelp / Hp : 0411-452113 / 0811463304Email : takdir1974@yahoo.comAlamat kantor : Bagian Ilmu Anestesi, Perawatan Intensif & Manajemen Nyeri

Fakultas Kedokteran UNHAS / RS. Dr. Wahidin Sudirohusodo Jl. Perintis Kemerdekaan Km.11 Tamalanrea Makassar-

90245Telp/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 Management Workshop and Refresher Course, Makassar- November 2006 : Acupuncture and TCM Workshop, 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 Management Workshop, Bangkok  

SAFETY PROFILE OF BUPIVACAINE IN NEURAXIAL ANALGESIA

A.M.TAKDIR MUSBA

DEPARTMENT OF ANESTHESIOLOGY, INTENSIVE CARE AND PAIN MANAGEMENT FACULTY OF MEDICINE, HASANUDDIN UNIVERSITY MAKASSAR - INDONESIA

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 ???

LOCAL ANESTHETIC

Ekenstam, 1957

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

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 ?

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

Physiochemical LA

Onset of Action : lower pKa, site of administration

Potency : higher partition coefficient , lipid solubility

Duration of action : higher protein binding, addition vasoconstrictor

Physiochemical and Pharmacokinetic properties of long acting LA

Leone S. Et al , ACTA BIOMED 2008; 79: 92-105

Comparisons of the 3 LALA Potency Racemic Bupivacaine > Levobupivacaine >

RopivacaineCasati A., Best Pract Res Clin Anaesthesiol. 2005

MLAC of Bupivacaine (0.081%) and levobupivacaine (0.083%) and nearly 50% higher MLAC values for ropivacaineLyons G, et al. Br J Anaesth 1998; 81: 899-901Polley LS, et al. Anesthesiology 1999; 90: 944-50Capogna G, et al. Br J 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 sufentanilPouzeratte Y, et al. Anesth Analg 2001; 93: 1587-92

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

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 Zink W., Graf BM. Curr Opin Anaesthesiol, 2008

Determinants of Systemic Toxicity

Pharmacokinetic Factors Pharmacodynamic Factors

Tasch MD., Butterworth JF. Toxicity of Local Anesthetics, ASA, 2006

Pharmacokinetic Factors Circulating concentration of the drug in a

form that is not protein-boundLAs 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

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

Laboratory animal

models

Convulsive Dose of LA as a sign of Toxicity

Groban L. Reg Anesth Pain Med 2003; 28: 3-11

Cumulative Dose and Plasma Conc LA at Cardiovascular Collapse

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. Br J Pharmacol 2001; 132:

649-58Pitkanen M, et al . Reg Anesth Pain Med 1992; 17: 182-92Zapata-Sudo G, et al. Anesth Analg 2001; 92: 496-501

Groban L, et al . Reg Anesth Pain Med 2002; 27: 460-8

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.

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

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

The difference between Ropivacaine and Bupivacaine was not statistically significant

Britt-Marie K. Emanuelsson, et al. Anesth Analg 1995;81:1163-8

Bupivacaine Epidural Infusion free plasma concentration reach lower than that can cause CNS toxicity

Britt-Marie K. Emanuelsson, et al. Anesth Analg 1995;81:1163-8Knudsen K., et al, British Journal of Anesthesia 1997;78

Knudsen K, 1997

Subjects Reporting Adverse Events Related to the 21-h Epidural Infusion

Britt-Marie K. Emanuelsson, et al. Anesth Analg 1995;81:1163-8

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 Systemic Toxicity Sign has been report !!!

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

SISTEMIC TOXICITY OF LA ACCIDENTAL RAPID IV INJECTION RAPID ABSORPTION OVERDOSES

EXCESSIVE BLOOD CONCENTRATION

SIGN OF TOXICITY CNS, CV, GI, etc

Reducing the risk

TEST DOSE INJECTION USE VASOCONSTRICTOR PATIENT MONITORED CLOSELY USE LOWER DOSE IN FRAIL PATIENT CONCENTRATION AND VOLUME

LcHv Vs HcLv

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

THANK YOU FOR YOUR KIND ATTENTION