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This presentation is about Local Anaesthetic Systemic Toxicity, causes and management

1. LAST Dr. Ashok Jadon, MD, DNB, MNAMS, FIPM, FIPP, FAMS Senior Consultant Anaesthesia & Pain Relief service Tata Motors Hospital, Jamshedpur Local Anaesthetic Systemic Toxicity

2. Local anesthetic systemic toxicity (LAST) It is a life-threatening adverse event. Occurs after the administration of local anesthetic drugs through various routes. 

3. Incidence 0.03%, or (1 episodes/3,000 peripheral nerve blocks) This is an understatement How many of us have reported so far

4. Why and How it occurs? Inadvertent intravascular injection High-volume fascial plane blocks Continuous catheter techniques Multiple LA techniques in the same patient Use of tumescent anesthesia

5. Mechanism? Underlying mechanisms of LAST are multifactorial, LAST has diverse cellular effects in the central nervous system and cardiovascular system.  

6. Chemical Structure of LA

7. Sodium Channel

8. Non-ionized Ionized

9. Pharmacokinetic Considerations <2–3 % of an injected dose enters the target nerve. A large fraction of the drug is absorbed by the surrounding tissue. More than 90 % of an injected dose is taken up by the systemic circulation within 30 min of injection. The rate of absorption into the bloodstream is a major determinant of systemic toxicity.

10. Factors Contd … Peak plasma concentration of LA (the time taken to attain peak levels are governed by the ) Rate of systemic absorption. Determined by the vascular supply of injection sites Mass of drug deposition LA distribution to organs is determined by perfusion Well-perfused tissues such as the brain, heart, liver, and lungs receiving the bulk of LA mass initially

11. Relation with site of injection The cephalic parts of the body have a more rapid rate of absorption for example, A cervical epidural leads to higher plasma levels of LA than a caudal epidural . Absorption rates are directly related to local blood flow and inversely related to local tissue-binding Axillary block Vs Caudal block Fastest absorption in Intercostal block

12. Protein binding & Role of Liver Three principal blood components are involved in local anesthetic binding: T he plasma proteins alpha-1-acid glycoprotein(AAG), Human serum albumin (HSA), and RBCs (erythrocytes). Local anesthetics bind tightly to serum proteins, greatly limiting the free fraction of available drug. Free or unbound fraction which is active.

13. Role of liver contd.. Most absorbed local anesthetic is cleared from the liver. Hepatic clearance dependent on the ratio of free to protein-bound drug Lidocaine, being moderately protein-bound, has a high hepatic extraction ratio (70–75 %). Clearance is reduced by factors that limit hepatic blood flow, e.g. cardiac failure, intravascular volume depletion, and upper abdominal surgery. Bupivacaine and ropivacaine, being highly protein-bound, are cleared by less than 50 % per pass

14. Clinical Presentation Neurological presentation is most common, One-fifth of the reported cases presented with isolated cardiovascular disturbance . LAST often presents atypically

15. Distribution of toxicity type Isolated cerebral toxicity in 50 % of cases, Combined cerebral and cardiac in 36 % of cases, 14 % of cases exhibited cardiac toxicity alone.

16. Time of toxicity presentation 26 % within 1 min 48 % within 5 min of injection 22% after 30 min or more

17. Mechanism of CNS & CVS Toxicity

18. Central nervous system (CNS) toxicity Increasing plasma concentrations of LA initially affects cortical inhibitory pathways Inhibiting these pathways leads to E xcitatory clinical features of sensory and visual changes, M uscular activation, and Seizure activity. As the plasma concentrations of LA rises further.. excitatory pathways are affected, Producing a depressive phase of neurological toxicity, Loss of consciousness, coma, and respiratory arrest.

19. Mechanism contd.. Most LA drugs readily cross BBB Effects of these drugs on the CNS are dose dependent They vary depending on the individual drug and unbound plasma concentration . Example lidocaine toxicity signs at various plasma levels

20. Lidocaine toxicity CONC(mcg/mL) EFFECT 1–5 Analgesia 5–10 Lightheaded , Tinnitus, Tongue numbness 10–15 Seizure , Loss of consciousness 15–25 Coma , Respiratory arrest >25 CV depression

21. Neural toxicity; time to act 40 % of all LAST cases reported Prodromal manifestations, i.e . confusion, dizziness, tinnitus, dysarthria, limb twitching , tremor, and eye movement abnormalities. With increasing plasma concentrations, muscle twitching and tremors involving facial musculature and distal parts of the extremities

22. Neural Toxicity cont.. Seizure was the other commonest reported sign of CNS toxicity in ( Vasques et al, series 54 % of reported LAST cases ). When levels of local anesthetic in the CNS increase further, leading to CNS depression, a reduced level of consciousness, and eventually coma . Excitatory pathways are more resistant to the effects of local anesthetic toxicity.

23. CVS toxicity It typically follows a two-stage pathway. In the early stages, sympathetic nervous system activation during the CNS excitatory phase indirectly leads to hypertension and tachycardia . A direct myocardial depressant effect occurs at higher concentrations.

24. CVS toxicity contd.. Normal conduction is disrupted by direct sodium channel blockade, Resting membrane potential become more negative, Action potential propagation is impaired, at SA node & at the bundle of His. L eading to prolonged PR, QRS, and ST intervals. Re-entrant tachyarrhythmias and bradyarrhythmias occurs Further potassium channel blockade worsened the condition by, prolonging the QT interval.

25. Cellular mechanism of toxicity

26. Typical Cmax after Commonly Used Blocks & Local Anesthetics

27. Temporal relationship with Neural and cardiac toxicity Neurologic toxicity occurs at lower concentrations followed by cardiac toxicity at higher concentrations. This is not always true for bupivacaine, which has a narrower margin between the cerebral and cardiac toxicity

28. Relative Potency for Toxicity (CVS:CNS) Toxicity This table is from Barash 5th.

29. Treatment of Toxicity Immediate intervention at the earliest sign of toxicity improves the chances of successful treatment Prominent display of a treatment checklist in locations where regional anesthesia nerve blocks are frequently performed may be helpful

30. Recognition & Management of LAST

31. Intralipid use 1) A bolus Intralipid® 20% 1.5 ml/kg of over 1 min, Followed by a continuous infusion 0.25 ml/kg/min continuously infused for at least 10 min after hemodynamic stability is obtained; 2 ) if hemodynamic stability is not obtained, two repeated boluses of Intralipid® (1.5 ml/kg) followed by continuous infusion of Intralipid® ( 0.5 ml/kg/min) should be considered; and 3) Recommended upper limit of the initial dosage 10 ml/kg for 30 min

32. The mechanism of action of lipid emulsions The first hypothesis circulating lipid sink extracts lipophilic local anesthetic from either plasma or tissues. The second hypothesis is reversal of the local anesthetic inhibition of the myocardial fatty acid oxidation. Third mechanism could be a direct stimulation of the voltage-gated calcium channels ( CaV ) of cardiomyocytes by long-chain fatty acids . Intralipid 20% solution contains mainly long-chain fatty acids

33. Do’s and Don'ts Use vasopressor like ephedrine for hypotension Avoid Vasopressin Use small dose of epinephrine, Avoid large dose. These results suggest that high doses of epinephrine and vasopressin inhibit lipid emulsion-mediated resuscitation because high-dose epinephrine causes acidosis and less sustained ROSC Use Amiodarone Avoid Calcium channel and β-adrenergic receptor blocking drugs

34. Results of Resuscitation

35. Other concerns of CVS toxicity Characteristics of Channel blockade Lidocaine blocks sodium channels in a “ fast-in fast-out ” fashion, Bupivacaine blocks these channels; in “ slow-in slow-out” manner in low concentrations “fast-in slow-out” manner at higher concentrations.

36. Other concerns of CVS toxicity The dissociation constants for the R(+) and S(−) bupivacaine Dextrorotatory isomer is seven times more potent in blocking the potassium channel than the levorotatory isomer The levorotatory isomer (S −) of bupivacaine has less potential for cardiac toxicity than the dextrorotatory one (R+) or racemic mixture of both This led to the development of the single stereoisomers levobupivacaine and ropivacaine. Ropivacaine blocks sodium channels in a “fast-in medium-out” fashion.

37. Remember Acute morbidity from seizure activity is due to airway complications; Hypoxia, Hypercarbia, and Acidosis Maintain the Oxygenation at any cost Use of relaxant if ventilation is necessary

38. Prevention Precautions is better than CURE Vigilance is most important. START- STOP & GO Frequently aspirating the injectate for signs of blood return. D ividing the dose of the local anesthetics Knowledge of Pharmacokinetic profile and anatomy of concerned area of the block

39. Prevention is better than CURE The use of a vasoconstrictor will serve to reduce the rate of uptake in addition to prolonging the block. Addition of epinephrine (1:200,000) to a dextrose solution , the primary purpose of which is ultrasonography observation of spread of injectate. This is used in 0.5–1 mL increments as a test dose prior to injection of local anesthetic. A rise in heart rate of ten beats per minute or more is indicative of intravascular injection

40. Refinement in the Technique Use of Ultrasound Use of Blunt needles Use of adequately large needle Appropriate concentration and dose

41. Cautions during assessment Early signs of cerebral toxicity are subjective (dizziness, drowsiness, and tinnitus). These will not be related by the heavily sedated or anesthetized patient. Moreover , general anesthesia itself raises the cerebral toxicity threshold, and neuromuscular blockade will preclude the onset of generalized tonic- clonic seizures. Consequently, the first manifestation of an accidental intravascular injection or rapid absorption may be cardiovascular collapse

42. Conclusions Vigilance during the performance of regional anesthesia and immediate intervention at the earliest sign of toxicity improve the chances of successful treatment. Intralipid helps in early and successful resuscitation If long action of LA is desired Ropivacaine is safer than Bupivacaine in regards to safety profile and success of resuscitation

43. PvPI (Pharmacovigilance Programme of India) It is an Indian government organization which identifies and responds to drug safety problems. Its activities include receiving reports of adverse drug events and taking necessary action to remedy problems.

44. Thank You!