ropivacane: a new break through in regional and neuraxial blockade
DESCRIPTION
Prof. Mridul M. Panditrao, discusses the merits and demerits of all the three, local anaesthetics, viz; loidocaine, bupivacaine and the new comer, Ropivacaine, their pharmacology, structual differences, comarison, dosing guide and his own experince and a controlled comparative trialTRANSCRIPT
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!