Safe local anesthetic dosing

ropivacaine


Patrick Tapley and Michael Fredrickson


Many factors influence safe local anaesthetic dosing for regional anaesthesia, whether as single injection or catheter techniques. These factors include patient factors (age extremes, weight and medical comorbidities such as liver or renal dysfunction and heart failure) and block factors (site and rate of LA administration).

Maximum LA doses are guided by both pharmacodynamic and pharmacokinetic studies and case reports. The former involve escalating doses of LA by intravenous infusion,1-3 documenting plasma concentration at the onset of toxicity such as CNS symptoms. These studies have formed the basis of drug company data sheets and formularies. Nevertheless, inconsistencies exist between different sources. For example, a popular pharmacology textbook recommends a maximum ropivacaine dose of 3mg.kg.4 Dosing on a mg.kg basis has repeatedly been shown to have low correlation with LA plasma concentrations, an observation highlighted in a review article by Rosenberg et al,5 who concluded that in line with other anaesthetic drugs, LA dosing should be block and site specific. The Astra Zeneca data sheet 6 supports a block specific approach by recommending a maximum absolute dose (irrespective of weight) depending on block site, varying from 150mg for caesarean section epidural top up, to 300mg for brachial plexus block.

Table A and B details LA doses that result in plasma concentrations above and below toxic thresholds for mild central nervous system toxicity. These doses were derived from 178 studies involving 4651 patients in which plasma LA concentrations after a regional block were measured.

 

Table A

 

 

Recommended dose

Dose producing toxic plasma conc

Recommended dose

Dose producing toxic plasma conc

Recommended dose

Dose producing toxic plasma conc

Recommended dose

Dose producing toxic plasma conc

Area

Block

Ropivacaine

 

Bupivacaine

Levobupivacaine

Lignocaine

Upper Limb

Interscalene

225mg 

300mg

200mg +A

200mg

 

 

386mg

450mg

ISB Bolus

        +infusion

225mg

18mg x48hr

 

150-210mg

19.15mg x24hr

 

 

 

 

 

Axillary

175-225mg

300mg

175-225mg

 

225mg

225mg*

600mg + A

 

Infraclavicular

277.5mg

 

 

 

 

 

 

 

Supraclavicular

 

 

300mg + A

 

 

 

 

 

Subclavian perivascular

(??ISB v supra)

190mg

 

 

 

 

 

 

 

 

Lower limb

Femoral Nerve

60mg

225mg

75mg

 

 

 

 

 

Femoral Nerve Bolus

+ infusion

 

 

74mg

12.95mg x 48hr

134mg

23.5mg x48hr

 

 

 

 

3in1

114mg

 

 

 

 

 

420mg + Norad

 

3in1 Bolus + infusion

150mg

24mg x24hr

150mg 24mg.hr x48hr

 

 

 

 

 

 

3in1 + SNB

 

 

168.75mg

+adr

 

 

 

650mg + Adr

 

SNB (labat)

150mg

 

100mg

 

 

 

 

 

SNB (labat) + LuPl

300mg

+ adr

214mg

150mg

+adr

 

150mg

 

 

 

LuPl

175mg

 

 

 

 

250mg

 

 

LuPl Bolus

+infusion

150mg

24mg x24hr

+adr

150mg

24mg x48hr

+adr

 

 

 

 

 

 



Table B

Area

Block

Ropivacaine

Bupivacaine

Levobupivacaine

Lignocaine

Recommended maximum dose

Dose producing toxic plasma conc

Recommended maximum dose

Dose producing toxic plasma conc

Recommended maximum dose

Dose producing toxic plasma conc

Recommended  maximum dose

Dose producing toxic plasma conc

Lumbar Epidural

Non obstetric single shot

 

200mg

250mg

187.5mg

225mg + adr

 

127.5mg

 

460mg

400mg + adr

 

Non obstetric infusion

B=30mg

I=30mg x21hr

B=50-75mg

I=20mg x72hr

B=25mg

I=25mg x21hr

 

 

 

B=90mg

I=90mg x5hr

 

 

Thoracic Epidural

Infusion studies

B=50mg

I=20mg x24hr

 

B=50-75mg

I=15mg x72hr

+adr

 

 

 

B=200mg

I=200mg x5hr

+adr

 

 

Obstetric Epidural

LSCS

150mg

?187.5mg

 

164mg

 

150mg

 

493mg

540mg +adr

401mg + adr+ NaHCO3

 

Epidural top up LSCS

 

 

100mg +/-adr

following 121mg labour

 

 

 

 

 

Labour analgesia

B=25mg

I=25mg x6.7hr

 

B=25mg

I=25mg x7.7hr

 

 

 

B=150mg

I=75mg.hr

767.2mg total

 

 

Abdomen

TAP block

150mg

200mg

 

 

50mg +/-adr

 

400mg

 


Table Key

Bold text =mean dose 3in1= 3in 1 femoral nerve block
Italic text = median dose / infusion time SNB= Sciatic nerve block
B= Bolus dose LSCS = Lower segment caesarean section
I=infusion dose +adr = adrenaline added to LA solution
*= patients with pre dialysis renal failure LuPl = Lumbar plexus block


These data highlight that current dosing recommendations of LA for certain blocks are excessive. For example, the recommended 300mg of ropivacaine for brachial plexus block may result in toxic plasma concentrations, and even symtoms and signs of mild neurological toxicity (circumoral numbess/tingling, lightheadness, muscle rigidity and twitching). These data also support block specific LA dosing. Table C lists other factors that should be considered due to their effects on LA pharmacokinetics.

 

Table C

Plasma LA conc

Factor

Explanation/notes

 

Increased

Post-operative

-Increased Alpha 1 Acid Glycoprotein (A1AG) (increases total not free conc)

Extremes of age (neonates,elderly)

- Multiple kinetic factors

Cardiac output extremes

-Increased C.O (Hyperdynamic states e.g. renal failure)

-Reduced C.O (Cardiac failure)

Liver Cirrhosis e.g. Chlids Pugh B/C

-Reduced A1AG

Renal dysfunction e.g. end stage renal failure (not dialysed)

- reduction suggested for infusions, but not single shot blocks

Pregnancy

-Increased cardiac output and reduced A1AG

Concomitant drug administration

-CYP450 inhibitors (OCP, fluvoxamine, Ciprofloxacin)

 

Reduced

Adrenaline containing LA

Single shot block only (tachyphylaxis demonstrated during infusions)

Concomitant drug administration

-CYP inducers (dexamethasone, barbiturates)


Safe repeat administration of LA remains contentious. There is relatively little data in the literature to support a time frame for the “safe” administration of a repeat LA dose. Whilst data sheets state a maximum dose of LA per 24 hr period (e.g. bupivacaine 400mg, ropivacaine 675-800mg), it is unclear when it is safe to administer a repeat  “large dose” LA bolus.   Five elimination half lives is a commonly quoted pharmacokinetic parameter to describe “complete” elimination of a drug from the body. Using the t1/2 obtained from the studies described above, table D highlights these in relation to each block.

 

Table D

Block

Ropivacaine

Bupivacaine

Levobupivacaine

Lignocaine

t1/2

5x t1/2

t1/2

5x t1/2

t1/2

5x t1/2

t1/2

5x t1/2

Datasheet

1.8h IV

4.2h E

9h

21h

2.7h IV

13.5h

1.3h IV

6.5h

1.5-2h IV

7.5h

ISB

3.9h

19.5h

           

Axillary

7.7h

38.5h

17.1h

85.5h

   

2.86h

14.3h

SNB

5.8h

29h

           

Lu Epi N.O

12.5h

62.5h

       

3.15h

15.75h

Obs Epid CS

5.2h

26h

7.25h

36.25h

       

TAP block

2.1h

10.5h

           

 

Table Key

Lu Epi E N.O = non obstetric epidural
Obs epid CS: obstetric epidural caesarean section
IV = intravenous administered
h=hours
SNB = sciatic nerve block
ISB = interscalene block

 

These data have confidence intervals, thus drawing conclusions about a safe time to repeat dose is difficult. However the five t1/2 time could theoretically be used as a safe dosing interval, as 97% of LA will have been eliminated from the body, meaning a repeat large dose of LA will be unlikely to result in toxic plasma concentrations.

In the clinical setting, a repeat full dose of LA is often administered sooner than the 5x t1/2 time periods outlined above. This is also suggested to be feasible in some drug company data sheets. This is unlikely to lead to toxic plasma concentrations of LA, as washout of LA will be 50% complete after one half life, and a large amount of LA will have been distributed to moderate and poorly perfused tissues further reducing plasma concentrations. Repeat administration of LA (presuming accidental IV injection is avoided), will take time (dependent on injection site) to reach the systemic circulation, allowing further distribution, metabolism and excretion of in-situ LA.  Additionally, an increased concentration of A1AG, common in the postoperative period, will lead to a reduced free fraction of LA in plasma.  These factors combined should result in subtoxic plasma concentrations being avoided after repeat LA dosage administration, albeit after a sensible time period (e.g. >6hours)

Toxic plasma concentrations can also result during LA infusions. The studies we have reviewed support current dosing recommendations. One exception is the potential for accumulation during of prolonged LA during infusions (e.g. 72hrs 20mg.hr ropivacaine).

The doses recommended here should be used in conjunction with sound clinical judgement, as numerous methodological limitations exist with reviews of this type.


LA systemic toxicity (LAST)

If plasma LA concentrations continue to rise, major neurological signs and symptoms may occur (convulsions, coma, and apnoea) progressing to cardiovascular toxicity with arrhythmias, myocardial depression and cardiac arrest. Vigilance is required, as presentation can be delayed (in 35% of cases, LAST is delayed by over five minutes 7 after LA injection). This suggests excessive LA absorption, rather than direct intravascular injection as the causative mechanism.

Guidelines exist 8,9 to aid the management of LAST, with the mainstays of treatment being supportive (airway, breathing, circulation, and seizure control), and lipid emulsion.  Lipid emulsion should be administered as a bolus dose (1.5ml.kg of 20% lipid emulsion), followed immediately by infusion (15ml.kg.h). Further bolus doses can be administered every 5minutes, with a doubling of the infusion rate after 5 minutes if cardiovascular stability has not been restored or deteriorates. The maximum recommended cumulative dose is 12ml.kg.  There is much debate as to the exact mechanism of action of lipid emulsion, but the “lipid sink” theory is the most quoted. 10 Since its introduction, lipid emulsion has led to a reduction in mortality associated with severe LAST, and together with guidelines detailing the management of LAST, lipid emulsion should be readily available in all areas where local anaesthetics are administered.

 

References

 

1. Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997;78:507-514

2. Bardsey H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol 1998;46:245-9

3. Mather LE, Tucker GT, Murphy TM,  Stanton-Hicks Md’A, Bonica JJ. Cardiovascular and subjective central nervous system effects of long-acting local anaesthetics in man. Anaesth Intens Care 1979;7:215-221

4. Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. Fourth Edition. Oxford University Press 2013. Page 320.

5. Rosenberg PH, Veering B, Urmey WF. Maximum Recommended Doses of Local Anesthetics: A Multifactorial Concept. Reg Anesth Pain Med 2004;29:564- 75

6. Naropin data sheet 230412. Astra Zeneca. Accessed at www.medsafe.govt.nz/profs/datasheet/n/Naropininj.pdf. Accessed 5th November 2013

7. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anaesthetic Systemic toxicity. A Review of Published Cases, 1979 – 2009. Reg Anesth Pain Med 2010;35: 181-7

8. AAGBI safety guideline; Management of Severe Local Anaesthetic Toxicity. Available at http://www.aagbi.org/sites/default/files/la_toxicity_2010_0.pdf and http://www.aagbi.org/sites/default/files/la_toxicity_2010_0.pdf. Accessed 28th October 2013.

9. American Society of Regional Anaesthesia nad Pain Medicine checklist for treatment of Local anaesthetic systemic toxicity. Available at http://www.asra.com/checklist-for-local-anesthetic-toxicity-treatment-1-18-12.pdf, accessed 28th October 2013

10. Weinberg G.L Lipid emulsion Infusion. Resuscitation for Local Anesthetic and Other Drug Overdose. Anesthesiology 2012;117(1): 180- 7