Local anestheticst systemic toxicity

FEATURES ABOUT LOCAL ANESTHETIC SYSTEMIC TOXICTY

1. LOCAL ANESTHETIC SYSTEMIC TOXICTY ( LAST ) Chairperson- Presented by - PROF. DR. L.D. DASH DR. RAMKRISHNA Head of Dept. 2 ND YEAR PG DEPT. OF ANESTHESIOLOGY DEPT. OF ANESTHESIOLOGY

2. LOCAL OR REGIONAL ANESTHESIA Local anesthetics produce a transient and reversible loss of sensation ( analgesia ) in a circumscribed region of the body without loss of consciousness . Normally, the process is completely reversible .

3. MECHANISM Interrupting nerve conduction – alpha subunit of Na+ channel & prevent Na+ influx Activated Na+ channel are more sensitive than the resting one

4. STRUCTURE LA has 2 domain with either an ester or amide linkage - hydrophilic - lipophilic Greater the lipid solubility greater the potency and duration of action More potency means increase toxicity and decreased therapeutic index

5. STRUCTURAL CLASSIFIACTION AMINOESTERASE Procaine, chloroprocaine , tetracaine , benzocaine , cocaine Metabolised by pseudocholinesterase , except cocaine in liver High incidence of allergy PABA Soln are not stable AMINOAMIDES Lignocaine , bupivacaine , ropivacaine , mepivacaine , etidocaine Metabolised in liver Less chance of allergic rxn Soln are stable

6. CLASSIFICATION DURATION OF ACTION SHORT ACTING- procaine, choloroprocaine (shortest) INTEREMEDIATE – Lignocaine , mepivacaine , prilocaine , cocaine LONG ACTING- Bupivacaine , levo - bupivacaine , tetracaine , ropivacaine , etidocaine , dibucaine (longest )

7. PROPERTIES OF LA POTENCY- increase with lipid solubility ONSET - Dose – fastens the onset Conc.- fastens the onset PH – LA are weak bases, so pKa closer to physiological pH gives more unionized drug diffuses axonal membrane – quicker onset so NaHco3 is added to increase pH

8. Types of Nerve Fibres - Diameter – thin diameter fibres more sensitve diameter type A>B>C sensitive C>B>A - Myelination - Mylinated fibres more sensitive fibre type A & B are mylinated

9. DURATION OF ACTION Mainly depends on extent of LA remains vicinity of nerve, depends of factors LIPID SOLUBILITY - increases duration VASCULARITY OF TISSUE – more vascularity decrease duration by increase in metabolic uptake VASOCONSRICTOR- decreases vascular uptake – increase duration e.g adrenaline, more the intrinsic vasodilatory effect more prolongation by addition of vasoconstrictor METABOLISM- esters have shorter duration as metabolized by pseudocholineasteraes

10. DOSE - increases duration but not significant PLASAMA PROTEIN BINDING –alpha 1 acid glycoprotein binding agents have longer duration like bupivacaine NaHCO3 – increases duration by releasing CO2 into axon making acidic medium, more ionic form to Na+ channel binding

11. LAST (LOCAL ANESTHETIC SYSTEMIC TOXICITY) Adverse rxn proportional to plasma conct . LA Dose of drug administered Rate of absorption Site of injection Vasoactivity of drug use of vasoconstrictor Biotransformation & elimination

12. TOXIC DOSES OF LA EASTERS Prilocaine – 12mg/kg Chloroprocaine - 12mg/kg Cocaine- 3mg/kg Tetracaine - 3mg/kg

13. TOXIC DOSES OF LA AMIDES Lignocaine - 4.5mg/kg (max300mg, without Adr ) 7mg/kg (max 500mg, with Adr .) Bupivacaine – 2.5mg/kg (175mg max) Levobupivacaine - 2.5mg/kg (max175mg) Ropivacaine - 3mg/kg ( max 225mg) Prilocaine – 8mg/kg Dibucaine – 1mg/kg Etidocaine - 4.5mg/kg

14. RATE OF ABSORPTION Drugs injected rapidly and in bolus have high LA plasma concentration SITE OF INJECTION LA used in more vascular tissue poses risk of systemic toxicities , intercostals block more than epidural than brachial

15. VASOACTIVITY OF DRUG Esters LA being metabolized by Psuedocholineasterse are short acting & safer Amides are long acting , more potent less therapeutic index risk for toxicities Peak plasma level of ester – rate of biotransformation & elimination In case of amides – on rate of absorption

16. USE OF VASOCONSTRICTOR Vasoconsrictors decreases the vascular uptake of LA and increases the safety dose . Efficiency of vasoconstrictor depends on intrinsic vasodilatory effect of LA E.g. Toxic dose of ligno . 4.5mg/kg without Adr 7mg/kg with Adr

17. BIOTRANSFORMATION & ELIMINTION Ester are safer than amides Liver dysfunction increases toxicity Elderly and neonates prone to toxicities Shock increase the toxicity risk as circulation is diverted to CNS & CVS ,more LA binds

18. CLINICAL PRESENTATION All system are affected but specially CNS & CVS CNS fibres are more sensitive than CVS Usually CNS symptoms appear earlier, as plasma level increases CVS symptoms appears

19. CNS TOXICITY LA produces stimulation followed by CNS depression as inhibitory neurons are blocked first CLINICAL FEATURES ( Excitatory) SUBJECTIVE- lightheadedness, Dizziness – difficulty in focusing - parasthesia in mouth & tongue – Tinnitus & auditory hallucinations , confusion OBJECTIVE – shivering ,tremors, muscle contraction Seizure , convulsion

20. SEIZURES – appears due to initial blockade of inhibitory neurons 10-12 mc/ml plasma level for lignocaine & 4 mc/ml for bupivacaine Seizures – causes hypoxia – metabolic acidosis further increases toxicity by increase in cerebral blood flow- increasing LA conct . For binding

21. CNS DEPRESSION cessation of seizures ,coma respiratory depression & respiratory arrest Plasma level 20mic/ml lignocaine & 4mic/ml bupivacaine Respiratory depression cause hypercarbia – increase cerebral circulation, intracellular acidosis- increase in ionic form LA – increase duration of Na+ channel binding – increase LA toxicity

22. CVS TOXICITY All LA can induces dysrythmia except Cocaine – myocardial depression All LA are vasodilator except cocaine, levobupivacaine & ropivacaine are vasoconstrictor Negative ionotropic action on myocardium – conduction delays – increase PR interval, increase QRS duration, even sinus arrest, complete heart block Toxic dose ratio CNS:CVS = 1:7 ( lignocaine ) & 1:3 for ( bupivacine )

23. Low dose LA – increase BP, HR & cardiac output by sympathetic activity & direct vasoconstriction Increase in Plasma LA- vasodilatation due to vascular smooth muscles relaxation – hypotension – decrease peripheral vascular resistance Reduced cardiac out put – extreme hemodynamic instability – arrythmia and cardiac arrest CVS toxic plasma level – 30 mic /ml lignocaine 6mic/ml bupivacaine

24. ALLERGIC RXN Easter LA contains allergens PABA derivative ( para aminobenzoic acid) Preservatives used in LA Symptoms – rashes , urticaria Anaphylaxis – wheeze, anxiety, hyperventilation, shock, bronchospasm, respiratory distress Methemoglobinemia – conversion of prilocaine to ortholuidine which changes HBS to MethHBS – treated with inj methylene blue 1mg/kg i.v .

25. DIAGNOSIS OF LAST LAST can occur any time from during administration of LA to 45 minutes after admist . High degree of suspicion ( most imp for diagnosis ) CNS excitation – agitation, confusion, twitching, seizures , convulsions CNS depression – drowsiness, coma, apnea , NON specific CNS- metallic taste, circumoral parathesia , tinnitus, dizziness

26. CVS SIGN – initially – hypertension, tachycardia or hypotension or bradycardia CVS hallmark - ventricular ectopic, multi form ventricular tachycardia, ventricular fibrillation, Progressive hypotension and bradycardia leading to Asystole and latter to cardiac arrest

27. TREATMENT Early recognition Immediately stop LA administration Call for help Secure airway & 100% O2 supplement – intubate if required Control seizures – benzodizepines (preferred) inj. Midazolam 0.2mg/kg bolus repeat after 5 min infusion 2mg/kg/hr or inj propofol @ 1mg/kg or inj. Thiopentone 2-5mg/kg, muscle relaxant use intractable seizures.

28. Shocks – use IV fluid and vasopressin Ventricular arrhythmia – inj amiadarone 150mgover 10 minutes followed by 360mg in 6 hours and 540mg in next 18 hours CVS Dysrythmia – cardiopulmonary resususitation avoid calcium channel blocker, beta blocker

29. INTRA-LIPID TREATMENT Mechanism- lipid sink – increase clearance by extraction of LA from cardiac tissue Lipid counteract LA inhibition of myocardial fatty acid oxidation , release energy – reverse cardiac depression Inj. 20% intralipid – 1.5ml/kg over 1 minutes (100ml) infusion @ 0.25ml/kg/min ( 500ml over 30 mins ) Repeat bolus every 5 mins for persistent cvs collapse Double the infusion rate if BP returns but remain low Infuse for minimum 30 mins

30. PREVENTION Maintain vigilance, suspicion Monitor ECG, NIBP, Aterial 02 sat. Communicate with patient if feasible Be conservative in dosing of LA – low concentration but optimum dose Aspirate in every 3-5ml of LA Inject slowly (<20ml/min) avoid high pressure injection Use additives to decrease dose of LA

31. Use of Benzopdiazipines premedication can prevent mild CNS toxicity Monitor the patient atleast 30 mins BE prepared with – emergency airway , drugs 20% intralipid is highly recommend and kept ready

32. THANK YOU