the minimum local analgesic concentration for labor analgesia · • ec50 - ed50 and relative...
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The minimum local analgesic concentration for labor analgesia
Giorgio Capogna
Department of Anesthesiology
Città di Roma Hospital
• The up-down sequential allocation model is the first
systematic application of dose-response pharmacodynamics
to regional anesthesia
• Comparison of drugs relative potency
(the ratio of equieffective concentrations) (EC50)
• Potency should not be confused with efficacy
• Efficacy: the maximum effect of a drug (Emax)
% e
ffect
% e
ffect
PotencyEfficacy
• is ideally suited to sensitivity experiments and
has had applications in engineering,
psychology, industrial chemistry and
anesthesia (MAC)
• the response must be binary (yes/no,
dead/alive, effective/ineffective) in an up-down
manner with each subsequent patient's dose
varying according to the previous patient's
response
Up-down sequential allocation method
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effective
ineffectivedru
g c
once
ntration %
w/v
EFFECTIVE:• requires a VAPS of 10 mm or less at the height of painful uterine contraction within 30 min• directs a decrement of the concentration of the study drug for the next woman.
INEFFECTIVE:INEFFECTIVE:• requires a VAPS greater than 10 mm that responds to a rescue bolus with a high concentration of local anesthetic • directs an increment of concentration of the study solution for the next woman.
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effective
ineffective
dru
g c
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ntration %
w/v REJECTREJECT :
• failure of the rescue bolus (failure of the spread of the solution)• progression of laborsame concentration for the next woman
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effective
ineffective
conce
ntration %
w/v
mlac
• testing is eventually concentrated around the median
• allows the reduction (30-80%) in the sample size
• increases the accuracy with which the median is estimated
• EC50 - ED50 and relative potencies of local anesthetics
• Analgesia
• Motor block
• Sensory – motor separation
• ED50 and relative potencies of opioids
• Sparing effect
• Obstetric factors influencing local anesthetic requirements
• Stage of labor (cervical dilatation)
• Dystocia
• Induction of labor
• EC50 - ED50 and relative potencies of local anesthetics
• Analgesia
• Motor block
• Sensory – motor separation
• ED50 and relative potencies of opioids
• Sparing effect
• Obstetric factors influencing local anesthetic requirements
• Stage of labor (cervical dilatation)
• Dystocia
• Induction of labor
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patient number
Ropivacaine
Bupivacaine
Conce
ntration %
EC50 for Analgesia of Epidural
Bupivacaine & Ropivacaine
Capogna G et Al. BJA 1998
0.156% (0.136-0.176)
0.093% (0.076-0.110)
Potency ratio: 0.60 (0.47-0.75)
Concentration-response plots for analgesia Bupivacaine vs Levobupivacaine
Lyons G et Al. BJA 1998
Potency ratio: 0.98 (0.67-1.41)
Molar Potency ratio: 0.87 (0.60-1.25)
EC50
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Concentration (%)
Cum
ula
tive
Resp
onse
Bupivacaine
Levobupivacaine
Bupivacaine 40% > Ropivacaine
Capogna G et Al. BJA 1998; Polley LS et Al. Anesthesiology 1998
Bupivacaine 2-13% > LevobupivacaineLyons G et Al. BJA 1998
Levobupivacaine > Ropivacaine?
Levobupivacaine ≥≥≥≥ Ropivacaine
Polley LS et Al. Anesthesiology 2003; Benhamou D et Al. Anesthesiology 2003
MLAC for Analgesia: Ropivacaine vs Levobupivacaine
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Number
Conce
ntration (%
)
Levobupivacaine
Ropivacaine Polley LS et Al. Anesthesiology 2003
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Number
Conce
ntration (%
)
Levobupivacaine
Ropivacaine
Benhamou D et Al. Anesthesiology 2003
Potency ratio: 0.98 (0.8-1.2)
Potency ratio: 0.84
Methodological confounding variables
– Cervical dilatation up to 7 cm Polley L et Al Anesthesiology 2005
Threefold increase in EC50 from 2 to 5 cm dilatation Capogna G et Al. BJA 1998
– Cervical dilatation assessed 30 min before the study
Possible progression of labor Polley L et Al. Anesthesiology 2005
– High % Rejects (second stage of labor before completion of the study)
Polley L et Al. Anesthesiology 2005
– Low VAPS at inclusion Benhamou D et Al. Anesthesiology 2005
– Mixed sample (Parity & Oxitocin?)
Controversial results with levobupivacaine
Bupi=Levo=Ropi ?Bupi>Levo>Ropi ?
• Traditional comparisons: high/equal concentrationbupi=levo=ropiBurke D et Al. Br J Anaesth 1999; Gaiser RR et Al. J Clin Anesth 1997; Writer et Al. Br J Anaesth 1998
• Comparisons at equipotent concentrations bupi ≥ levo> ropi Fernandez-Guisasola J et Al. Anesth Analg 2001; Camorcia M et Al. Eur J Anaesth 2003; Sah N et Al. J Clin Anesth 2007
• MLAC potency ratio studies: bupi ≥ levo>ropi
Analgesic Concentration - Response Curve
Potency
% E
ffect
Concentration
Comparisonsat highconcentrations
MLAC comparison
Relative Potencies of Epidural Pipecoloxylidines
Relative potencies (95%CI)Analgesia
0.98 (0.67- 1.41)
0.87 (0.60-1.25)
Bupivacaine: Levobupivacaine
0.60 (0.47- 0.75)Bupivacaine: Ropivacaine
Polley L et Al. Anesthesiology 1998; Lyons G et Al. Br J Anaesth 1998; Lacassie HJ Anesth Analg 2002; Lacassie HJ Anesth Analg 2003
Relative potencies (95%CI)Motor Block
0.87 (0.77- 0.98) Bupivacaine: Levobupivacaine
0.66 (0.52- 0.82)Bupivacaine: Ropivacaine
Epidural Sensory - Motor Separation
EC50 for Analgesia EC50 for Motor Block
Polley LS et Al Anesthesiology 1998 and Lacassie HJ et Al. Anesth Analg 2002 & Anesth Analg 2003
0.0625 0.125 0.25 0.5
Log2 concentration (%)
Ropivacaine
Levobupivacaine
Bupivacaine
IT Analgesic potency ratio
0.76 (0.50- 0.96)Levobupivacaine: Ropivacaine
0.80 (0.70- 0.92)Levobupivacaine: Ropivacaine
0.81 (0.69-0.94)Bupivacaine: Levobupivacaine
Relative potencies (95%CI)
0.65 (0.56- 0.76)Bupivacaine: Ropivacaine
Camorcia M et Al. Anesthesiology 2005
Sia AT et Al. Anesthesiology 2005
IT motor block potency ratio
0.71 (0.51-0.98)Bupivacaine: Levobupivacaine
Relative potencies (95%CI)
0.83 (0.64- 1.09)Levobupivacaine: Ropivacaine
0.59 (0.42-0.82)Bupivacaine: Ropivacaine
Camorcia M et Al. Anesth Analg 2007
Spinal Sensory - Motor Separation
ED50 for Analgesia ED50 for Motor Block
Camorcia M et Al Anesthesiology 2005 and Camorcia M et Al. Anesth Analg 2007
Log2 Dose (mg)
1 2 4 8
Ropivacaine
Levobupivacaine
Bupivacaine
Epidural / Spinal Separation ratios
0 1 2 3
Ropivacaine
Levobupivacaine
Bupivacaine
1 2 4 8
Motor Block: Analgesia Ratio
Capogna G et Al. Br J Anaesth 1998; Lyons G et Al. Br J Anaesth 1998; Polley L et Al Anesthesiology 1999; Camorcia M et Al Anesthesiology 2005; Camorcia M et Al. Anesth Analg 2007; Lacassie HJ et Al. Anesth Analg2002 & Anesth Analg 2003
• EC50 - ED50 and relative potencies of local anesthetics
• Analgesia
• Motor block
• Sensory – motor separation
•• ED50 and relative ED50 and relative potenciespotencies of of opioids opioids
•• SparingSparing effecteffect
• Obstetric factors influencing local anesthetic requirements
• Stage of labor (cervical dilatation)
• Dystocia
• Induction of labor
Sparing effect
• Previous studies: No differences in analgesic efficacy with the
addition of epidural fentanyl to bupivacaine Youngstrom P et Al Anesthesiology 1984; Scriutton M et Al. IJOA 1998; Asik I et Al. EJA 2002
• Fentanyl and Sufentanil: up to 91% reduction in the EC50 for
epidural & intrathecal local anesthetics Polley LS et Al. Anesth Analg 1996; Lyons
G et Al. BJA 1997; Polley LS et Al. Anesthesiology 1998; Palm S et Al. Anaesthesia 2001; Stocks G
et Al. Anesth Analg 2001; Robinson AP et Al. Anesth Analg 2001, Van De Velde M et Al. IJOA 2007
• Epinephrine, Clonidine, Neostigmine: statistical but not clinical
sparing effect Kenneth NE et Al. Anesthesiology 1999; Aveline C et Al. Anesth Analg 2002;
Polley LS et Al. Anesthesiology 2002
Sparing effect of opioids
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control 1 mcg/mL 2 mcg/mL 3 mcg/mL 4 mcg/mL
Bupivaca
ine
%
Lyons et Al. BJA, 1997
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control 0.5 mcg/mL 1 mcg/mL 1.5 mcg/mL
Bupivaca
ine
%
Polley et Al. Anesthesiology 1998
Fentanyl
Sufentanil
EC50
8 16 32 64 128 2560.00
0.25
0.50
0.75
1.00SufentanilFentanyl
Log2 dose (µg)
Cum
ula
tive
resp
onse
Relative analgesic potency ratioEpidural Opioids
Potency ratio: 5.9 (5.6-6.3)Capogna G et Al. Anesth Analg 2003
• EC50 - ED50 and relative potencies of local anesthetics
• Analgesia
• Motor block
• Sensory – motor separation
• ED50 and relative potencies of opioids
• Sparing effect
• Obstetric factors influencing local anesthetic requirements
• Stage of labor (cervical dilatation)
• Dystocia
• Induction of labor
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bupiv
aca
ine c
once
ntration %
MLAC of Epidural Bupivacaine increases with progression of labor
0.048% (0.037 -0.058) early labor
Capogna G et Al. BJA 1998
0.14% (0.132- 0.150) late labor
LA LA requirementsrequirements increaseincrease in in earlyearly laborlabor in in womenwomen withwith dystocicdystocic laborslabors
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Vaginal delivery CS for dystocia
Panni MK & Segal S. Anesthesiology 2003
Bupivacaine EC50
Capogna G et Al. Anesthesiology 2002
Prostaglandin induction of labor
increases analgesic requirements
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patient number
SpontaneousInduced
27.3 µg (23.8-30.9)
21.2 µg (19.6-22.8)
Epidural sufentanildose (µg)
Future perspectives
Anesthetic potency and
• Intrathecal Dose & Concentration
• Gender & Pregnancy
• Genetic Factors
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Ropivacaine 0.1%
Ropivacaine 1%
Dose
(m
g)
Less concentrated intrathecal solutions cause less motor block
9.1 mg (5.1-7.1)
6.1 mg (7.8-10.3)
Camorcia M et Al. Anesth Analg 2004 Motor block efficacy ratio: 1.5 (1.2-1.9)
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male female pregnant
ITBupivaca
ine
dose
Pregnancy and Gender may affect local anesthetic potency
Camorcia M et Al. IJOA 2007
Potency Ratio:Male-Female 1.45 (1.13-1.86)
Female-Pregnant 1.52 (1.18-1.95)
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A118 A118G, G118
ITFenta
nyl
dose
(µg
)
µ-opioid receptor polymorphism and interindividual opioid requirements
26.8 µg (22.7-30.9)
17.7 µg (13.4-21.9)
Landau R et Al. Anesthesiology 2005
• Comparison between local anesthetics at
equipotent concentrations/doses
• Contribution of opioids to analgesic mixtures
• Pharmacological rationale for labor analgesia
• Tool for assessing the effects of interindividual
and labor variables on LA requirements and
potency
Conclusions
Thank You!