1. Local Anaesthetic Toxicity in High Dose Regimens Dr. John Martin MBBS FANZCA

2. Scenario 1: Patient #1 delivered to PACU – stable 64 y.o. Female had multiple orthopaedic procedures – CTR, knee scope, shoulder arthroscopic procedures (Common situation with this particular surgeon) Commenced seizure – nurse activated the Emergency Alarm – myself & attending anaesthetist arrived. Attending anaesthetist stated immediately he suspected local anaesthetic toxicity because surgeon had used L.A. in all sites at “normal” doses. ABC management and Intralipid 20% commenced – seizure stopped. About 5 minutes later – Seizure recommenced – another bolus Intralipid given and infusion commenced. Midazolam added and seizure stopped. Seizures recurred – more midazolam given and seizure settled Patient transferred to ICU. Total dose 2.5 times accepted maximum safe dose of L.A. given.

3. Scenario 2: WHILE Scenario 1 was happening Emergency Alarm went off again. Staff stated there was a second emergency Cardiac Catheter Lab! Second event was a cardiac arrest. Cath Lab patient (#2): 73 y.o. Male having a pacemaker insertion under local anaesthesia and sedation (by proceduralist). Prolonged insertion with complete repositioning of generator. Multiple extra injections of LA given. Patient noted to become unco-operative – assumed to be in pain and more LA given. Suddenly went into VF. Resuscitated successfully after an anaesthetist attended and commenced Intralipid. Final calculated L.A. dose approx. 2 times maximum dose

5. Spectrum of Unwanted Reactions: Toxicity (Local Anaesthetic Systemic Toxicity LAST) (related to blood concentration) Anaphylaxis (Immune mediated and can occur with small doses) Local Toxic Effects ( Intra-neuronal Injection High neuronal concentration)

6. Relative Toxic Concentrations

7. Disadvantage of Bupivacaine

8. Variation on this pathway common: Just over 40% of cases do not follow classic sequence. Includes: Simultaneous presentation of CNS and CVS signs and symptoms. 40% of cases occurring during sedation had no CNS effects at all. “Severe “ CNS symptoms only in 68% cf: “Mild” symptoms in 18% G. Di Gregorio, J. M. Neal, R. W. Rosenquist, and G. L. Weinberg, “Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009,” Regional Anesthesia and Pain Medicine, vol. 35, no. 2, pp. 181–187, 2010.

9. Published Local Anaesthetic Safe Doses From various texts over last 10 – 30 years Now manufacturers hesitate to give maximum doses Lignocaine3 - 5 Lignocaine with Adrenaline5 - 7 Bupivacaine (& with Adrenaline)2 Ropivacaine 3 Prilocaine6 -7 Prilocaine with Adrenaline7 -9

10. Published Local Anaesthetic Maximum Doses Initially from animal studies (usually sheep). Give Intravenous doses and see what doses cause events. Then cut down the dose by an amount and call that the recommended safe limit. Since “absorption” (bioavailability) is 100% this gives reasonable buffer if made an inadvertent intravenous injection. Absorption from clinical sites is going to be less (variably) so should in theory always be in a safe concentration.

12. The Road to Supramaximal Dose Regimes 1990's - Plastic Surgeons in USA (predom.) begin using “Tumescent Analgesia” for Liposuction. - Originally used “safe doses” of Lignocaine diluted in high volumes (up to a litre) which was then injected under pressure via a long needle into the fat to be suctioned. Late 1990s – Early 2000's - Doses increased to supramaximal dosages. Studies showed limited absorption and doses up to 35 mg/kg had safe circulating concentrations. Late 2000's – Current Surgeons of all types use more L.A. for post operative analgesia Initially used in “safe” doses Use of “tumescent analgesia” copied but with variations.

13. The Road to Supramaximal Dose Regimes Why Tumescent Analgesia appears to be safe. - L.A. Is injected into fat which is poorly vascular and has limited absorption. - The L.A. is very dilute so takes long time to absorb. - Tumescence causes compression of tissues which further limits absorption. - Part of the normal plastic surgical management of liposuction is immediate postoperative use of compression garments which further limits absorption. - L.A. used is Lignocaine - Rapidly metabolised in the healthy liver - Large conc. range from initial onset to catastrophe - Toxic events usually short lived & require limited duration of resuscitation

14. The Road to Supramaximal Dose Regimes Why Surgical Pseudo-Tumescent Analgesia is less safe. Major problem is complete uncertainty in rate of absorption. - L.A. Is injected into variable tissues with varied rates of absorption. - The L.A. is not as dilute and tissues compression variable. - Orthopaedic and general surgical patients have highly variable co morbidity states. - L.A. used is Bupivacaine or Ropivacaine - Not Rapidly metabolised even in the healthy liver - Lower conc. range from initial onset to catastrophe - Toxic events can be long lived & require longer duration of resuscitation - Highly protein bound – paradoxically can be riskier (small changes in binding produce large changes in free L.A.)

15. The Road to Supramaximal Dose Regimes Are These Other High Dose Delivery Techniques Safe? - Some studies have shown some regimens produce low circulating concentrations from specific sites and with specific concentrations of injectate. - Some orthopaedic studies have shown very low maximum blood concentrations when the solution is diluted significantly (same mass of drug). - Adjuvents can be added (NSAIDs and Adrenaline) which increase the analgesic effect while limiting need for bigger masses of L.A. Answer: A guarded “Yes, they can be …..........but ”

16. Are Supramaximal Dose Regimes Safe Enough? “In selected situations – Yes But …..........” 1. Proceduralists have to have a thorough understanding of the factors that will control the final circulating concentrations. 2. Have a thorough appreciation of factors that affect the rate of absorption. 3. Have an understanding of the patient co-morbities and situations that will alter circulating concentrations for given delivered doses. 4. Be able to diagnose early and manage the toxic events that will inevitably happen from time to time.

17. Factors Which Effect Final Concentrations. 1. Site of Injection - Highly vascular tissues have higher rates High - Intercostal Spaces - Perineum (and further increased in pregnancy) - Paracervical Blocks - Head and neck Medium - Epidural Space - Thorax, Abdomen and Shoulders Low - Proximal Limbs - Distal limbs Special - Some Subcutaneous Field Blocks > Nerve Trunk Blocks Situations - Tissues behind tourniquets – low absorption till tourniquet removed (acidic tissues – less binding)

18. Factors Which Effect Final Concentrations. 2. Patient Selection Age - Adults have highly variable tissue perfusion - Obesity – probably protected due to adiposity - Emaciated – higher risk of  absorption - Children - much more constant perfusion – usually higher absorption - Dose to Weight errors more likely - More blocks done under GA  Early CNS signs missed. Pregnancy - Decreased circulating protein – less binding more free L.A. - But diluted volume so lowered conc. From that. - Final Effect in an individual – uncertain Concomitant Medications – Amide L.A.s are metabolised by Liver Cytochrome P 450 system. Liver insufficency or drugs which inhibit this system may  L.A. Conc. - Many drugs can  the L.A. effect on CVS cells – Digoxin, Calcium Channel Blockers, Beta Blockers

19. Factors Which Effect Final Concentrations. 2. Patient Selection (cont.) Co-Morbidities – Low volume states – From fasting, illness, iatrogenic. -  movement of interstitial fluid to vascular Compartment - takes drug with it. -  dilution of drug in plasma - Cardiac Disease – High output states -  Absorption - Ischaemic Cardiac Tissues may be more susceptible to arrhythmias - Any disorder with  Protein levels – Liver Disease, Malignancy, - Renal Failures, Immune Deficiencies

20. Factors Which Effect Final Concentrations. 2. Patient Selection (cont.) Co-Morbidities – Low volume states – From fasting, illness, iatrogenic. -  movement of interstitial fluid to vascular Compartment - takes drug with it. -  dilution of drug in plasma - Cardiac Disease – High output states -  Absorption - Cardiac Tissues may be more susceptible to arrhythmias - Any disorder with  Protein levels – Liver Disease, Malignancy, - Renal Failures, Immune Deficiencies

22. Management of Local Anaesthetic Toxicity Basic Life Support - ABC is paramount Fitting may make oxygen requirements increase but ability to secure an airway harder. May need paralysis and Intubation. General Treatment: CNS & CVS Effects can be much more resistant to treatment than same events from other causes. - CNS - “Usual” acute seizure management - Benzodiazepines - CVS – Can't use Lignocaine (which is the first line treatment for many of the same CVS events.)

23. Specific Management of Local Anaesthetic Toxicity Intravenous Emulsified Lipid: Appears to act a specific sink. Lipid soluble end of the L.A. binds with the lipid. Originally thought to just dilute L.A. But studies using other agents to give the same dilution did not support this. Intralipid 20% most commonly used because of availability. Although Propofol has almost same vehicle can't use it. Cardiac and sympathetic depressant effect makes situation worse

24. Specific Management of Local Anaesthetic Toxicity