Division of Anesthesiology, Balgrist University Hospital, Zurich
Forchstrasse 340, CH-8008 Zürich
www.balgrist.ch
José A. Aguirre, MD, MSc
See-Spital, Kilchberg
12th June 2013
Adjuvants for regional anesthesia
– is there still a need for
peripheral nerve catheters?
Disclosure
Agenda
• Why this lecture?
• The evidence of peripheral nerve catheters
• The evidence for adjuvants in peripheralregional anesthesia
• Are local anesthetics / adjuvantsneurotoxic?
• Future directions
• Conclusions
• 50 - 70 % of in hospital patients suffer from
moderate to severe pain after surgery.
• 40% of ambulatory surgical patients have
moderate / severe pain during the first 24–48h.
• Chronic pain after hip arthroplasty: 28%
• Chronic pain after knee arthroplasty: 33%
Power I et al. BJA 2005; 95:43-51Apfelbaum JL et al. Anesthesia and Analgesia 2003; 97:534-40Pavlin DJ et al. Anesthesia and Analgesia 2002; 95: 627-34Wu CL et al. Anesthesiology 2002; 96:994-1003Wilder-Smith OHG B et al. Eur J Pain 2002; 6:89-201Nikolajesen L et al. Acta Anaesthesiol Scand 2006; 50:495-500Puolakka P et al. EJA 2010; 27:455-460
Post surgical pain: a problem?
Severity of acute postoperative pain
CPSP: chronic postsurgical pain Kehlet H et al. Lancet 2006; 13:1618-25
Most striking predictive factor for
CPSP?
• Not one single published study showing that
postoperative acute pain treatment with regional
anesthesia has a negative impact on direct or
indirect costs:
– with RA better analgesia, less side effectsRichman JM et al. A&A 2006; 102:248-57, Aguirre J et al. Anesthesiol Res Pract 2012; Epub June:1-20
– with RA positive impact on CPSPBlumenthal S et al. Anesthesiology 2005; 102:392-97; Aguirre J et al. A&A 2012; 114:456-61
– with RA earlier discharge due to better analgesiaIlfeld BM et al. RAPM 2011; 36:116-120
– with RA better early joint mobilizationIlfeld et al. Anesthesiology 2006; 105:999-1007
Post surgical pain as important cost
factor?
RA: regional anesthesiaCPSP: chronic postsurgical pain
RA: regional anesthesiaGA: general anesthesia
Perhaps you might want
to update your Facebook status
to “unconscious” before we start?
Bingham AE et al. RAMP 2012; 37:583-94Ilfeld BM; A&A 2011; 113:904-25Le-Wendling L et al. Curr Opin Anaesthesiol 2008; 21:602-09
Peripheral catheters: the evidence
• Systematic review: 9 metaanalyses, 14 RCTs for regional anesthesia; > 3‘000 articles and 4 metaanalyses for systemic analgesia.
• Outcomes: satisfaction, quality of life, quality of recovery, length of stay, pain
Liu SS et al. A&A 2007; 105:789-808RCT: randomized controlled trial
Effect of analgesic technique on
postoperative patient-reported outcomes
• Results:
• Regional anestesia offers better postoperative analgesiacontrol with reduction of opioid-related side-effects.
• Insufficient and inconsistent data to support subsequentimprovement in quality of life and quality of recovery, satisfactionand length of stay.
• These results are due in part to some significant methodologicalissues.
Only 2 RCTs compared CFNB with single-injection FNB:
Currently there is no evidence supporting the use of either a SSNB or CFNB in addition to a single-injection FNB!
23 RCTs (1’106 patients) comparing FNB with opioid-based PCA or epidural analgesia:
SFNB / CFNB (+ PCA) are a good alternative for PCA or epidural analgesia for postoperative analgesia in patients after TKA.
Hadzic A et al. Anesthesiology 2010; 113:1014-5Barrington MJ et al. Anesthesiology 2011; 114:1494-5Ilfeld BM et al. Anesthesiology 2008; 108:703-13Salinas FV et al. Anesth Analg 2006; 102:1234-9
RCT: randomized controlled trial(C/S) FNB: (continuous/single injection) femoral nerve blockSSNB: single injection sciatic nerve blockPCA: patient controlled analgesia
Blumenthal S et al. Anesthesiology 2005; 102:392-97
• 21 RCTs, 702 patients; study quality: 8 good, 13
fair (ISC: 9, IFC:1, Fe:4, P:4, PVB:1, LPB:2)
• cPNBs associated with
– Decreased worst pain score on day 0, 1, 2
– Decreased overall opioid use
– Decreased nausea
– Higher patient satisfaction scores
• Unclear: complications, long-term
functional outcomes and costs
Aguirre J et al. Anesthesiol Res Pract 2012 (online)Ilfeld BM. A&A 2011; 113:903-24
cPNB: continuous perineural blockISC: interscalene blockIFC: infraclavicular blockFe: femoral nerve block
P: popliteal blockPVB: paravertebral blockLPB: lumbar plexus block
Aguirre J et al. accepted by Anesthesiology (2013)Aguirre J et al. Anesthesiol Res Pract. 2012 (online)Ilfeld BM; A&A 2011; 113:904-25Ilfeld BM Anesthesiol Clin. 2011; 29:193-211
Peripheral catheters: the advantages
• Technically demanding but possible and cheap
• Positioning prior to surgery with the option to start after neurological control
• Possibility to stop in the case of problems(ACS)
• Possibility to stop prior to removal � patient-centered pain management
ACS: acute compartment syndromePCRA: patient controlled regional anesthesia
Peripheral catheters: the advantages
• Possibility to adapt (drug, dose, flow rate, concentration, continuous, PCRA…) to therapy / clinic
• Possibility to restart after break
• Possibility to use for home therapy
ACS: acute compartment syndromePCRA: patient controlled regional anesthesia
Aguirre J et al. accepted by Anesthesiology (2013)Aguirre J et al. Anesthesiol Res Pract. 2012 (online)Ilfeld BM; A&A 2011; 113:904-25Ilfeld BM Anesthesiol Clin. 2011; 29:193-211
• Problems of ambulatory surgery
– Unplanned hospital visits due to pain and
PONV
– Readmission rate after general anesthesia:
7-27%
– Readmission rate after regional anesthesia:
4-13%
Williams BA et al. Anesthesiology 2004; 100:697-706Hadzic A et al. Anesth Analg 2005; 100:976-81
Peripheral catheters: the advantages
PONV: post anesthesia nausea and vomiting
Aguirre J et al. Anesthesiology (Case Scenario) 2013…Aguirre J et al. Anesthesiol Res Pract 2012 (online)Ilfeld BM; A&A 2011; 113:904-25Ilfeld BM Anesthesiol Clin. 2011; 29:193-211
Peripheral catheters: the
disadvantages
• Demands technical skills and good regional anesthesia understanding
• Demands an „acute pain service“
• Demands continuous education and instruction of medical and nurse staff
• Demands a 24/7 telephone contact, out-patient protocoll and patient education forhome therapy
ACS: acute compartment syndromePCRA: patient controlled regional anesthesia
• RA in anesthetized
patient
• Winnie technique
• Bolus prior to catheter
insertion
• 5cm catheter over needle
tip
• Bolus injection on the
ward without test
• First nurse control 6h after bolus
Are local anesthetics / adjuvants
neurotoxic?
• Neurological complications of pain catheters
Central catheters: 0.01% / 2 - 4.2: 100‘000Cook TM et al. BJA 2009; 102:179-90 (707‘445 central blocks)
Pöpping DM et al. BJM 2008; 101:832-840 (14‘223 patients)
Peripheral catheters: 0.4 – 2%Barrington MJ et al. RAPM 2009; 34:534-541 (7‘000 patients)
Capdevila X et al. Anesthesiology 2005; 103:135-45 (1‘416 patients)
Auroy Y et al. Anesthesiology 2002; 97:1274-80 (43‘946 patients)
• Infectious risk of pain catheters
Local infection: 0 - 3.2%
Proven systemic infection: 0 – 0.9%Capdevila X et al. Anesthesiology 2009; 110:182-88 (12‘078 patients)
Regional anesthesia and
complications
Goetz MB et al. Z Orthop Unfall 2010; 148:163–167 Beller J et al. Orthopäde 2008; 37:475-480Broex EC et al. J Hosp Infect 2009; 72:193-201Sessler DI et al. Anesthesiology 2010; 113:265-67Chang CC et al. Anesthesiology 2010; 113:279-84
Regional anesthesia and
complications
Gadsden J et al. Int Anesth Clin 2010; 48:107-15
All commonly used local anesthetics induce neuronal apoptosis in clinically used concentrations.
The neurotoxicity correlates with lipid solubility and thus with
the conduction blocking potency of the local anesthetic, but is
independent of the chemical class (ester/amide).
Moderate correlations for cytotoxicity with lipophilicity and clinical potency of LA.
Structural factors such as ester or amide linkage orstereospecificity do NOT have any influece on cytotoxicity.
Although S-Enantiomers may be advantageous with regard to
systemic toxicitiy they have NO advantage in respect of LA cytotoxicity in vitro.
Buerkle H. Best Pract Res Anaesth 2000; 14:411-18Niemi G. Best Pract Res Anaesth 2005: 19:229-45Buvanendran A et al. Best Pract Res Anaesth 2007; 21:31-49Christiansson L. Period Biol 2009; 11:161-170
Why adjuvants for LA?
• Shorten the onset time of LA action
– Only for central blocks?
• Limit the absorption of LA
– Decrease of spinal cord blood flow?
– Risk of peripheral neuropathy?
– Nausea and vomiting ?
• Improvement of block intensity/duration
– Clinical evidence?
LA: local anesthetic
Affinity of local anesthetic
Hyperpolarization
closed open inactivated
intracellular
extracellular
Depolarization Depolarization
Shorten the onset time
Aguirre J et al. Practical Pharmacology in Regional Anesthesia; 2012 Springer, New York: 121-156
• ↑ the pH of the LA solution (3.0 → 6.5)
• ↑ concentration of the base form of the LA used���� LA and technique dependent
• Addition of sodium bicarbonate forperipheral nerve blocks is obsolete
• No effect on block duration
Sinnott CJ et al. Anesthesiology 2000; 93:1045–52Contreras-Dominguez V et al. Rev Esp Anestesiol Reanim 2006; 53:532–537
Given the lack of significant efficacy, the use of sodium bicarbonate in peripheral nerve blocks
cannot be recommended
Shorten the onset time
Limit the absorption of local
anestheticsAims:
• To increases the number of anestheticmolecules to diffuse through the nerve membrane
• To improve of block intensity and duration
• To limit plasma peak level
Niemi G. Best Pract Res Anaesth 2005: 19:229-45Neal JM et al. Reg Anesth Pain Med. 2003; 28:124–134Weber A et al. Anesth Analg. 2001; 93:1327–1331
Nerve
Artery
VeinNeedle
LA
97- 98%
2-3%
Systemic resorption depends on local blood flow!
Heavner JE. Curr Opin Anaesthesiol 2007; 20:336-42. ReviewCox B et al. Best Pract Res Clin Anaesthesiol 2003; 17:111-36
- 30%
Limit the absorption of local anesthetic
Limit the absorption of local
anestheticsLimitations:
• Block prolongation for drugs of low to moderate lipid solubility (lidocaine, mepivacaine)
• Minimal or no block prolongation for drugsof high lipid solubility (ropivacaine, bupivacaine)
Niemi G. Best Pract Res Anaesth 2005: 19:229-45Neal JM et al. Reg Anesth Pain Med. 2003; 28:124–134Weber A et al. Anesth Analg. 2001; 93:1327–1331
Sinnott CJ et al. Anesthesiology 2003; 98:181-88
Me
an
intr
an
eu
rallid
oca
ine
(±S
D)
(nm
ol/m
g w
et)
Time after injection (min)
Lidocaine&epinephrine
Lidocaine
120min60min30min10min4min
022.35.811Lido
(nmol/mg)
26.26.4*8.414.5Lido&epi
(nmol/mg)
Initial vasoconstriction retards the rapid removal of LA
allowing more LA to enter the deeper perineural structures
Limit the absorption of local
anestheticsClinical implications:
• The use of epinephrine for peripheralnerve blocks is only done (if at all…) as a safety measure to detect intravascularinjection
Brummett CM et al. Int Anesthesiol Clin. 2011; 49: 104–16
Improvement of block intensity:
opioids
Peripheral effects of opioids ?
• Evidence and recognition of opioid receptors on sensory nerve terminals
• Opioid effects more pronounced in inflamed tissue
• increased numbers of nerve terminals due to nerve sprouting
• up-regulation of opioid receptors
• disruption of perineurium
Buvanendran A et al. Best Pract Res Anaesth 2007; 21:31-49Christiansson L. Period Biol 2009; 11:161-170
RCT, 30 patients, hallux valgus surgery; sciatic-femoral nerve block with 30 ml ropivacaine 0,75% vs 30ml ropivacaine 0,75%
+ 1mcg/kg/fentanyl. No systemic application of fentanyl.
No difference between the groups concerning :
Onset time
Duration of postop. analgesia
Quality of postop. analgesia
O2 saturation
Degree of sedation
Magistris L et al. Eur J Anaesth 2000; 17:348-53
Improvement of block intensity:
opioids
Bouaziz H et al. Anesth Analg 2000; 90:383-87
40ml mepivacaine 1.5%
RCT, 60 patients, axillary brachial plexus block
40ml mepi/tetra/epi (=LA) + buprenorphine 0,3mg + saline i.m.
vs LA + 0,3mg buprenorphine i.m.
vs LA + saline i.m.
Duration of postop. analgesia Buprenorphine + LA 22.3h
Buprenorphine i.m. 12.5h
Saline 6.6h
Conclusions: Buprenorphine prolongs postoperative analgesia.
Opioid-peripheral receptor site of action suggested.
Axonal transport cannot be excluded.
Candido KD et al. RAPM 2002; 27:162-67
Improvement of block intensity:
opioids
LA: local anesthetic
Analgesic efficacy of Tramadol whenadded to LA in brachial plexus block
0,011,3 ± 1,71,9 ± 22,6 ± 2,13,5 ± 2,4VAS 1 - 10
0,026 (30)12 (60)15 (68)13 (76)
Patients requiring analgesia n/(%)
NS
NS
220 ± 41
205 ± 43
217 ± 46
204 ± 71
247 ± 96
222 ± 89
183 ± 43
171 ± 51
Duration (min)
Sensory block
Motor block
p
ValueT200mg
(n=20)
T100mg
(n=20)
T40mg
(n=22)
Placebo
(n=17)
RCT, 4 groups, axillary plexus with 1,5% mepivacaine 40ml and tramadol
Conclusions: Tramadol extends the duration and improves quality of
analgesia in a dose-dependent fashion.
Incidence of adverse effects increases with the dose.
Robaux S et al. A&A 2004; 98:1172-77LA: local anesthetic
Improvement of block intensity:
opioids
Tramadol
- Tramadol (100mg) added to ropivacaine0.75% for axillaryblock does not improve the speed of block onset or increase the duration of sensory or motor block or postoperative analgesia.
- Tramadol (200mg) added to lidocaine 1.5% (epinephrine 1/200’000) prolongs block duration and analgesia but delays onset of anesthesia.
Kesimci E et al. Acta Anaesthe Scan 2007; 51:736-41Kaabachi O et al. A&A 2009: 108:367-70
Improvement of block intensity:
opioids
Clinical implications
• There is little future for tramadol and buprenorphine as a single adjuvant in peripheral nerve blocks. Their usecannot be recommend for clinicalpractice.
Brummett CM et al. Int Anesthesiol Clin. 2011; 49: 104–16
Improvement of block intensity:
clonidine
Analgesic benefit from the addition of clonidine to
local anesthetics? YES
Mechanisms of action?
- Centrally mediated analgesia?
- α2-mediated vasoconstriction in the periphery?
- Clear: not α2-mediated block prolongation but
inhibition of hyperpolarization-action current.
Effect more profound in C-fibers.
Buerkle H. Best Pract Res Anaesth 2000; 14:411-18Brummett CM et al. Int Anesthesiol Clin. 2011; 49: 104–16Pöpping DM et al. Anesthesiology 2009; 111:406-15McCartney CJ et al. RAPM 2007; 32:330-338Leem JW et al. RAPM 2000; 25:620-25
RCT, 30 patients, hallux valgus repair; sciatic-femoral
nerve block with 0,75 % ropivacaine 20 ml vs. ropivacaine +
clonidine 1 µg/kg.
Conclusions:
• Adding 1 mcg/kg clonidine to 0,75 % ropivacaine has noeffect on onset time and quality of the block but provides athree hours prolongation of postoperative analgesia.
Mild, short increase in the degree of sedation.
No hemodynamic side effects.
Casati A et al. Anesth Analg 2000; 91:388-92
Improvement of block intensity:
clonidine
Side effects :
• Hypotension
• Bradycardia
• Sedation
Less side effects compared to epidural/spinal administration.
Related to the dose and to plasma levels.
Optimal dose: 150µg (adults).
Improvement of block intensity:
clonidine
Buerkle H. Best Pract Res Anaesth 2000; 14:411-18Brummett CM et al. Int Anesthesiol Clin. 2011; 49: 104–16
PNB: peripheral nerve blocks
For opioids little evidence for brachial plexus block
Clonidine seems to have an analgesic benefit with little side effects up to a dose of 150 µg
Murphy DB et al. A&A 2000; 90:1122-28Pöpping DM et al. Anesthesiology 2009; 111:406-15
Recommendations for the use of
adjuvants
Epinephrine: no use (as test dose??)
Clonidine: up to 150µg for adults
Dexmedetomidine: wait for better data
Buprenorphine / Tramadol: little efficacy
Dexamethasone: CAVE: dose-response-related neurotoxicity
Midazolam: CAVE: dose-response-related neurotoxicity
Brummett CM et al. Int Anesthesiol Clin. 2011; 49: 104–16
• Lidocaine and tetracaine maintain/increaseblood flow; bupivacaine and levobupivacainedecrease blood flow.
• Addition of epinephrine / phenylephrine mightfurther reduce blood flow.
– Laboratory: blood flow alteration with / withoutchanges in histology.
– Clinical studies: only case reports blamingvasoconstrictors for neurological deficits.
Are adjuvants neurotoxic?
Brummett Ch Int Anesthesiol Clin 2011; 49:104-16Neal J et al. RAPM 2003; 28:124-134Dahlgren N et al. Acta Anaesthesiol Scand 1995;39:872-80
• However,
– addition of vasoconstrictors might potentiate
peripheral nerve ischemia specially in patients
with microvascular disease
– and potentiate the neurotoxic effects of LAs
also if the acutal risk of significant
neurological ischemia with neurological
compromise is very low.
Are adjuvants neurotoxic?
Brummett Ch Int Anesthesiol Clin 2011; 49:104-16Neal J et al. RAPM 2003; 28:124-134Hashimoto K et al. Anesthesiology 2001; 94:876-81
EDA: epidural anesthesiaLA: local anesthetic
� avoid in selected patients
Candido K et al. RAPM 2011; 36:211-12
M: MidazolamD: DexamethasoneC: ClonidineB: BuprenorphineR: Ropivacaine
Sprague-Dawley rat sensory neurons
Exposure to clinically used concentrations
for 24 hours.
M: Midazolam
D: DexamethasoneC: ClonidineB: BuprenorphineR: Ropivacaine
Results with ropivacaine reaffirm the need to identify ways to mitigate local anesthetic induced neurotoxicity.
While having no protective effect on ropivavaine-induced neurotoxicity in vitro, future research with adjuvants should
address if the clonidine + buprenorphine + dexamethasone combination can lead to a reduction of ropivavaine
concentrations (and/or provide equal or superior duration) in preclinical in vivo models.
M: Midazolam
D: DexamethasoneC: ClonidineB: BuprenorphineR: Ropivacaine
Future directions
Extended release liposomes:
- Encapsulated forms of bupivacaine
- Superior compared to placebo
- Comparable to bupivacaine tissueinjections
- Systemic toxicity? Neurotoxicity?
Smoot JD et al. Surg J 2012; 32:69–76Gorfine SR et al. Dis Colon Rectum 2011; 54:1552–1559Golf M et al. Adv Ther 2011; 28:776–788Davidson EM A&A 2010; 110:1018-23
Chahar P et al. Journal of Pain Research 2012; 5:257-64
Future directions
Sensory block without motor effect
A charged lidocaine derivative (QX314)
which has a quaternary nitrogen cannot
diffuse across the cytoplasmic membrane of
motor nerves. However, it can block action
potential propagation if introduced into the
axon cytoplasm via direct injection.
Frazier DT et al. J Pharmacol Exp Therap 1970; 171:45–51Roberson DP et al. Br J Pharmacol 2011; 164:48-58
Conclusion: shall we abandon RA?
Conclusions
• Limited evidence for any analgesic benefit of using opioids for peripheral nerve blocks over systemic administration.
• Clonidine can prolong the post-block analgesia with a limited risk of predictable side-effects at a dose up to 150 µg.
• Use the least toxic drug
– Spinal anesthesia: bupivacaine, chloroprocaine,
prilocaine.
– Peripheral: ropivacaine / bupivacaine (?), mepivacaine,
lidocaine.
• Avoid unnecessary risk with adjuvants
– NO epinephrine & lidocaine for central nerve blocks.
– NO tramadol / bicarbonate for peripheral nerve blocks.
– NO midazolam for peripheral neve blocks.
– NO adjuvants to ropivacaine. Clonidine??
Conclusions
Lirk P et al. RAPM 2012; 37:601-606Cuvillon P et al. BJA 2013; ahead of print
• Use perineural catheters for:
– extremely painful surgery (rotator cuff repair, total kneearthroplasty): ≥ 48h
– painful joint mobilisation (capsulotomy, synovectomy): ≥
5d
– chronic pain patients and expected moderate to severe
postoperative pain: ≥ 48h
– repetitive surgery (diabetic foot, wound controls): ≥ 5d
• Use perineural catheters only if:
– you and your team can manage them!!!
Conclusions
Aguirre J et al. Anesthesiol Res Pract 2012 (online)Borgeat A, Aguirre J. Unintended Destinations of Local Anesthetics; 2012 Lippincott W&W, Philadelphia:196-204