Ropivacane:

A Breakthrough in

REGIONAL &

NEURAXIAL BLOCKADE

Dr. Mridul M. Panditrao

ConsultantDepartment of Anesthesiology

& Intensive careRand Memorial Hospital

Freeport, Bahamas

Formerly:

PROFESSOR & HEAD

Department of Anaesthesiology &

Critical Care

Padmashree Dr. D.Y. Patil Medical

College

Pimpri, Pune

History: It all started with cocaineIncas in South Americas chewed coca leaves as a

euphoriant, dating back to 3000 B.C. (Erythroxylum

coca, Coca Plant)

Numbness of tongue was considered as a temporary

side-effect

1860: cocaine isolated coca leaves by Paolo

Mantegazza, who tested it on himself.

1860: cocaine formulated into “Dr. Mariani's French

Tonic”, for which Dr. Mariani received a gold medal

from Pope Leo XIII.

1884: cocaine used for topical ophthalmic anesthesia

by Carl Koller (at the suggestion of Freud).

1885 Advertisement !

History: more cocaine1884: cocaine used for peripheral nerve

block (Halstead) 1886: John S. Pemberton invented Coca

Cola, combining cocaine with Cola nitida extract (kola nut).

1898: cocaine first for spinal anesthetic (Karl Gustav August Bier)

Personally developed PDPH, which he correctly diagnosed!

Modern local anesthetics 1932: Tetracaine1943: Lignocaine (Lofgven and Lundquist)1957: Mepivacaine1960: Prilocaine1963: Bupivacaine1972: Etidocaine discovered

1973: Etidocaine lost

1996: Ropivacaine1999: Levobupivacaine

Two types of linkages give rise to 2 chemical classes of local anesthetics.

ESTER LINKAGE (1 EYE!)

AMIDE LINKAGE (2 EYES!!)

PROCAINE

procaine (Novocaine)

tetracaine (Pontocaine)

benzocaine

cocaine

LIGNOCAINE

lignocaine (Xylocaine)

mepivacaine (Carbocaine)

bupivacaine (Anavin)

etidocaine (Duranest)

ropivacaine (Ropin)

Lignocaine (Lignocaine)

NN

O

Amide Linkage

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME AMIDE - type LAAs

LIGNOCAINEMost widely used LA

Effective by all routes.

Faster onset, more intense, longer lasting, than

procaine.

Good alternative for those allergic to ester type

More potent than procaine but about equal toxicity

More sedative than others

Bupivacaine (Anawin)

N

N

O

N N

O

S Bupivacaine R Bupivacaine

*

*

Enantiomer: levobupivacaine, ChirocaineEquipotent, but less cardiotoxic than bupivacaine

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME AMIDE - type LAAsBupivacaine

No topical effect

Slower onset and one of longer duration agents

Unique property of sensory and motor

dissociation can provide sensory analgesia with

minimal motor block

has been popular drug for analgesia during labor

More cardiotoxic than other LA

Acute Toxicity

Main concern is CNS and Cardiac toxicity

CNS Tinnitus, dizziness, lightheadedness are early signs Anxiety disorientation loss of consciousness

seizures respiratory arrestCardiac

Hypotension All local anesthetics are negative inotropes

PVC wide QRS Multiform vtach vfib, or Pattern with bupivacaine

Bradycardia asystole Pattern with bupivacaine + lignocaine

Acute ToxicityWith most drugs like Lignocaine, CNS

toxicity precedes cardiac toxicity,

providing a warning of impending disaster.

With bupivacaine, acute toxicity rapidly

progresses to cardiovascular collapse.

Pregnancy enhances the risk of cardiac

toxicity.

NeurotoxicityLignocaine

Initially seen with formulation in 10%

dextrose

Now seen with all formulations

No longer recommended for spinal

anesthesia

Bupivacaine appears free of neurotoxicity

Treatment of overdoseAirway:

100% oxygenIntubate if necessary to ventilate

CNS:Break seizure with propofol, thiopental, or

midazolamCardiovascular

Amiodarone has demonstrated efficacy. Use 300 mgLidocaine would be a particularly poor choice!Resuscitation difficult with bupivacaine, more

frequently successful in animal studies following ropivacaine and levobupivacaine overdose.

Dosing Guidelines(nerve block)

Drug Onset Local custom DurationMaximum With epinephrine

AmidesLidocaine Rapid 4.5 mg/kg 7 mg/kg 900 mg with epi 1-2 hMepivacaine Medium 6 mg/kg not given 750 mg 2-3 hEtidociaine Rapid 6 mg/kg 8 mg/kg N/A 4 - 8 hPrilocine Medium 8 mg/kg 8 mg/kg N/A 1-2 hBupivacaine Slow 2.5 mg/kg 3 mg/kg 200 mg 4 - 12 hRopivacaine Slow 4 mg/kg No effect N/A 4 - 9 hLevobupivacaine Slow 2 mg/kg (!) not given 300 mg 4 - 8 h

EstersProcaine Rapid 10 mg/kg 15 mg/kg N/A 15-30 minChloroprocaine Very rapid 10 mg/kg 15 mg/kg 10 mg/kg 30-60 minTetracaine Slow 1.5 mg/kg 2.5 mg/kg N/A 3 h

Per Package Insert

What is Ropivacaine Hydrochloride?

Ropivacaine is a long-acting, local anesthetic with

both anesthetic and analgesic effects. At high

doses it produces surgical anesthesia and at

lower doses it produces analgesia (sensory block)

with limited motor block..

0.75% is indicated for surgical anesthesia

0.2% is indicated for postoperative pain relief .

What is ROPIN?®

Ropivacaine hydrochloride

Solution for injection in 7.5 mg/ ml

&

2.0 mg/ml in 20 ml ampoule

Now in 7.5 mg/ ml in 4 ml ampoule

N

N

O

*

Ropivacaine (Ropin)®

N

N

O

*

Only available as pure S isomerCauses vasoconstrictionLess motor block than bupivacaineOtherwise, equipotent anesthesia, but less cardiotoxic

S bupivacaine

SELECTIVE PHARMACOLOGICAL PROPERTIES OF SOME AMIDE - type LA

Ropivacaine

Enantiomer of propivacaine (S stereoisomer)

Structurally very similar to bupivacaine

No topical effectiveness

Clinically ~ equivalent to bupivacaine

Similar sensory versus motor selectivity as

bupivacaine with significantly less CV toxicity

(allegedly)

PHARMACOLOGY OF ROPIVACAINE

Ropivacaine is less lipid solubleLess penetration in nerve fibers Less motor block Early mobilizationEarly recovery

PHARMACOLOGY OF ROPIVACAINE

cardio toxicity Less toxic effects to CVS

Does not cause arrhythmias

Does not cause ECG Changes

neurotoxicity Less toxic effects to CNS

Ropivacaine will not cause seizures, convulsions

Visual and hearing disturbances, paraesthesia rarely

Comparison of LA characteristicsRelative lipid solubility

Relative potency

onset pKa Local duration

vasodilation Plasma protein binding

lignocaine 4 4 rapid 7.9 moderate +++ 55%

bupivacaine 130 16 slow 8.1 long + 90%

ropivacaineRopivacaine

N/A 12 rapid 8.1 long ± 94%

Plasma protein binding may be used as an indirect measure of tissue binding tendencies

L A As in Sub- Arachnoid Block ?Name Concen

tration (%)

Onset(min.)

Duration(min.)

RecommendedMax. dose

pH (pKa)

Uses Toxicity

Lignocaine 5With dextrose

1-5 30-90 100mg

5.0-7.0 (7.9)

No longerused

More Neuro than Cardiac

Bupivacaine

0.5 With dextrose

1-15 75-200 20mg

4.0-6.5(8.1)

Drug of choice at present

More cardiac than Neuro

Ropivacaine

0.75 ???? ???? ????In epi.4mg/kg

N.D. (8.1)

Epi/infiltration

?????

Ropivacaine intrathecally ???

To find out the efficacy of 0.75%

Ropivacaine isobaric given

intrathecally for lower abdominal

& lower limb surgeries : A

prospective feasibility study

Aims & Objectives :To study the efficacy of 0.75% isobaric

ropivacaine in sub-arachnoid block

To observe any side- effects of 0.75%

isobaric ropivacaine in sub-arachnoid

block

MATERIALS & METHODS

Stringent Inclusion & Exclusion Criteria Age Range of 20 - 75 yearsInformed ConsentASA I- IILower Limb/Abdominal & Gynaecological

SurgeriesProper Pre-op. evaluation & preparation

&I E C Approval

MATERIALS & METHODS

NBM overnightAll Monitoring DevicesPre-loading with Lactated Ringer – 10 ml/kg

(nearly 500ml.) 15 min. priorAll aseptic PrecautionsL2-L3 / L3- L4 space26 Gz. Quinke’s Spinal needleSitting or Lateral PositionMidline intra-thecal approach

MATERIALS & METHODS

3.0 ml of Ropivacaine 0.75% isobaric after free flow of C S F Supine with 10°-15° Head DownA pillow under the headPulse/ NIBP/ SpO2 X 5 min. for first 30 min.No interference by surgeons permitted till

the desired level is achievedInfusion of R/L continued as per the

requirement

MATERIALS & METHODSAssessment of Neuraxial Blockade

Sensory Block: Pin-Prick testObserved till T5- T6 level is achievedThen permitted for surgical interventionMotor Block: Bromage Scale

Grade Criteria Degree of block

I Free movement of legs and feet Nil (0%)

IIJust able to flex knees with free movement of feet

Partial (33%)

IIIUnable to flex knees, but with free movement of feet

Almost complete (66%)

IV Unable to move legs or feet Complete (100%)

Bromage PR. Philadelphia: WB Saunders; 1978: 144

MATERIALS & METHODS

Intra-operative ManagementContinuous MonitoringIntake according to Blood loss/ Urinary outputSide effects: N/V, Pain, Shivering, Pruritus,

Sedation, Respiratory discomfort, Sensorium etc....,if any

Residual neuraxial/ Wearing off of blockade noted

Visual Analog Scoring (VAS)VAS More than 7 ….. Rescue Analgesia...

Inj. Diclofenac Na 75mg I.M.

MATERIALS & METHODSReadings of Blockade : Observations

To Time of Giving Spinal Analgesia

T1 Time of Onset of Sensory Blockade

T2 Time of Onset of Motor Blockade

T3 Time to reach Maximum Sensory level

T4 Time to two segment regression of sensory block

T5 Time of Wearing off of Sensory Block

T6 Time of Wearing off of Motor Block

T7 First dose of rescue Analgesia

Optimal Surgical Conditions Score (self-devised)

MATERIALS & METHODS

No.

Conditions 2 1 0

1 Intra-operative Muscle relaxation

Pronounced

Minimal Nil

2 Intra-operative Bleeding Minimum Moderate

Excessive

3 Post-operative Bleeding Minimum Moderate

Excessive

ResultsTotal Number of ASA I-II patients (N) = 40

Age Range = 23- 72 yrs.

Sex : M = 26, F= 14

Specialty wise distribution:

Gen. Surg.= 15, Ortho.=14 , Gyne. =

6, Uro.= 5

ResultsNO. Parameter Range Value Mean ± SD

1 Onset of Sensory block 10-300sec 69.9 ± 69.8 sec

2 Onset of Motor block 10-660sec 165.8 ± 161.7 sec

3 Peak of Sensory block 120-1320 sec 578.2± 298.0 sec

4 2 Segment Regression 60-177min 132.6 ± 36.97 min

5 Wearing off of Sensory block 62-180min 135.8 ± 34.63 min

6 Wearing off of Motor block 45-346min 118.8 ± 46.81 min

7 Time from Spinal to Rescue (1st Dose of Rescue)

110-525min 255.32 ± 88.54 min

ResultsOnset of Sensory block = 1.5 min. average

Onset of Motor block = 3.5 min. average

Peak of Sensory block = 10min. average

2 Segment Regression = nearly 2hrs. 30min.

Wearing off of Sensory block = nearly 2hrs. 30min.

Wearing off of Motor block = nearly 2hrs.

Time from Spinal to Rescue (1st Dose of Rescue) =

nearly 4.5 hrs.

Results Intra-operative Vitals Profile &

EventsPulse = minimal bradycardia ,< 2 - 5% of

baselineNIBP = minimal Fall, < 3.5- 6.8% of baselineSpO2 = 100% , No change, either on room air

or on O2 1 - 2 liters /min.No extra Fluid requirementNo Pharmacological support requiredNo specific side effects attributable to Spinal/

drugNo sedation & comfort level of patients =

adequate Optimal Surgical Conditions Score = 5 - 6

Post-operative Follow-up

No Problems specific to Spinal/ Drug in

first 24 hrs,

next 72 hrs. or

till the patients were discharged!

On Follow-ups : No Complaints till now!

Results

Results

Encouraged by these observations &

results

Used In Lower Segment Caesarian sections

(LSCS)

Specific Modification in Protocol was:

2.0 ml of intra-thecal injection

Strict watch was kept on APGAR of the

neonate

No fall in scores have been observed till now!

DiscussionComparative with other LAA

Parameter Lignocaine Ropivacaine Bupivacaine

Onset of Sensory block 1 - 5 min. 0.6 - 5 min. 1 – 15 min.

Onset of Motor block 2 - 6 min. 0.6 - 11 min 3 – 20 min

Peak of Sensory block 2 – 8 min. 2 - 22 min. 3 – 30 min

2 Segment Regression 30 -90 min. 60 - 180 min 75 – 200 min.

Wearing off of Sensory block 35 - 105 min. 60 - 180 min 80 - 210 min.

Wearing off of Motor block 45 – 120 min. 45 - 346 min 80 – 240 min.

Time from Spinal to Rescue (1st Dose of Rescue)

45 – 135 min. 110 - 525 min. 130 – 700 min.

DiscussionRopivacaine as Ropin® is available in 0.75%, 20 & 4 ml.

Ropivacaine as Ropin® is available in 0.2%, 20 ml.

Has been used for Peripherral Nerve Blocks & Epidurally ＊

Has been used for Labour Analgesia epidurally ＊

Proven to have a very wide safety margin and safety profile ＊

＊

Emanuelsson B.M. Ekblom A. Olofsson  C. Reventlid H.: Ropivacaine 7.5 mg/ml for elective Caesarean section. A clinical and pharmacokinetic comparison of 150 mg and 187.5 mg. Acta anaesthesiologica scandinavica   1997, 41, 9, . 1149-1156 ;

Kanai.A, Kinoshita S., Suzuki A., Okamoto H., Hoka S Advantage of ropivacaine for postoperative epidural analgesia following leg orthopedic surgery [Article in Japanese] . Masui. 2005 Jan;54(1):8-13.

Turner, G.; Blake, D.; Buckland, M. Continuous Extradural Infusion of Ropivacaine for Prevention of Postoperative Pain After,Major Orthopedic surgery :; Survey of Anesthesiology:Regional Anestheisa and Pain Control, 1997, 44, 4, 213-219

Emmanuel A, Fabienne B:Patient-Controlled Epidural Analgesia Versus Continuous Epidural Infusion with Ropivacaine for Postoperative Analgesia in Children, Anesth Analg 2003;97:1608–11

Discussion

SDERTEaL J E , Article: AstraZeneca's Local Anaesthetic Naropin Announced an Additional Approval for a New Route of Administration, Intrathecal (Spinal) use in the European Union (EU). http://www.highbeam.com/doc/1G1-113834425.html, Jan-Mar 2004

Simpson D, Curran M, Oldfield V, Keating G : Ropivacaine

A Review of its Use in Regional Anaesthesia and Acute Pain Management, Drugs 2005; 65 (18): 2675-2717

ConclusionRopivacaine Intra-thecally : A feasibility study

3.0 ml. appears to be a safe doseUseful in all types of surgical proceduresOnset of Sensory Block comparable to that of

LignocaineOnset of Motor Block comparable to that of BupivacainePeak of Sensory Block comparable to that of

Bupivacaine2 segment regression & Wearing of Sensory and Motor

Block, Intermediate between both the drugs!Motor Recovery appears to be earlier than Sensory

recoverySafety Profile appears to be adequate

ConclusionRopivacaine has All the Advantages of both Lignocaine

and Bupivacaine combined

Although structurally it is similar to bupivacaine, some of

the actions are like Lignocaine

Being a Chiral Drug (S-enantiomer) there is definitely no

Cardio-vascular toxicity

Lesser Motor and Autonomic blocking action

Provides Excellent Intra-operative conditions for both

Surgeon as well as Anaesthesiologist

Appears to be safe for both Mother as well as Newborn

ConclusionPost-operative course- early, intermediate as well as

late : appears to be smooth, uneventful and adequate!

No neurological, both short term as well as long term

problems seem to have happened till now in any of

the nearly 80 patients , we have studied (as confirmed

by the follow up!)

The dose of 3.0 ml used may be slightly on lower side!

Peculiarly Motor block wears off earlier than Sensory!

Take Home Message !We recommend 0.75% isobaric

Ropivacaine for intra-thecal use, with all

proper precautions & patient selection,

in-depth & vigilant intra-operative

monitoring and sincere post-operative

follow-up, of short as well as long term!