adjuvants for regional anesthesia – is there still a need ... · adjuvants for regional...

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


• Possibility to adapt (drug, dose, flow rate, concentration, continuous, PCRA…) to therapy / clinic

• Possibility to restart after break

• Possibility to use for home therapy


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


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


• 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


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


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


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


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


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


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.



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


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).


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


• 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

adjuvants for regional anesthesia – is there still a need ... · adjuvants for regional...

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