LAST local anaesthetic systemic toxicity

Local anaesthetic systemic toxicity

1. Local Anaesthetic Systemic Toxicity (LAST) Understanding the Risks and Management

2. LOCAL OR REGIONAL ANAESTHESIA Local anaesthetics 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. Local Anaesthetic Systemic Toxicity (LAST) refers to the systemic effects resulting from the absorption of local anaesthetic agents into the bloodstream, leading to potential toxic reactions. Importance of understanding LAST : It is crucial for healthcare professionals, especially those involved in anaesthesia and procedural medicine, to be aware of LAST due to its potentially life-threatening consequences.

3. MECHANISM OF LOCAL ANAESTHETICS Local anaesthetics block nerve conduction by inhibiting sodium influx through sodium channels in nerve cell membranes. Interrupting nerve  conduction – alpha subunit of Na+ channel & prevent Na+ influx. Activated Na+ channel are more sensitive than the resting one.

4. Mechanism of Action of Local Anaesthetics Modes of Administration of Local Anaesthetics: Topical Administration Infiltration Nerve Block Epidural Each mode of administration offers distinct advantages and is chosen based on factors such as the type and location of the procedure, patient preference, and the desired duration of anaesthesia. Proper selection of the administration route, along with accurate dosing and technique, is essential for achieving effective anaesthesia while minimizing the risk of systemic toxicity.

5. STRUCTURE Different classes of local anaesthetics: Local anaesthetics are classified based on their chemical structure and mechanism of action. Local anaesthetics 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. Understanding the differences between these classes of local anaesthetics is essential for selecting the most appropriate agent for a given clinical situation, taking into account factors such as duration of action, onset time, and potential for systemic toxicity or allergic reactions

6. STRUCTURAL CLASSIFICATION AMINOESTERASE – Procaine, Chloroprocaine , Tetracaine , Benzocaine Cocaine Metabolised by pseudocholinesterase , except cocaine in liver. High incidence of allergy PABA. Solution are not stable. AMINOAMIDE – Lignocaine Bupivacaine Ropivacaine Mepivacaine Etidocaine Metabolised in liver. Less chance of allergic reaction. Solution are stable.

7. CLASSIFICATION AS PER DURATION OF ACTION SHORT ACTING – Procaine Choloroprocaine (shortest) INTEREMEDIATE – Lignocaine Mepivacaine Prilocaine Cocaine LONG ACTING – Bupivacaine Levo-bupivacaine Tetracaine Ropivacaine Etidocaine Dibucaine (longest)

8. PROPERTIES OF LOCAL ANAESTHESIA POTENCY: increase with lipid solubility. ONSET: Dose: fastens the onset. Concentration- 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.

9. Diameter – thin diameter fibres more sensitve diameter type A>B>C sensitive C>B>A. Myelination - Myelinated fibres more sensitive fibre, type A & B are myelinated . Types of Nerve Fibres

10. 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 . 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. DURATION OF ACTION

11. LAST (LOCAL ANESTHETIC SYSTEMIC TOXICITY) Adverse reaction is proportional to plasma concentration of LA. Dose of drug administered. Rate of absorption. Site of injection. Vasoactivity of drug. Use of vasoconstrictor. Biotransformation & elimination.

12. Factors Contributing to LAST Patient-related factors: Age, weight, comorbidities, concurrent medications, and genetic predispositions. Drug-related factors: Type of local anaesthetic, concentration, dose, and additives such as vasoconstrictors. Technique-related factors: Injection site, rate of injection, accidental intravascular injection, and use of adjuvants. Other contributing factors: Hypoxia, hypercarbia, acidosis, and electrolyte imbalances.

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

14. 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. RATE OF ABSORPTION

15. 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 VASOACTIVITY OF DRUG

16. 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 lignocaine 4.5mg/kg without Adr , 7mg/kg with Adr USE OF VASOCONSTRICTOR

17. 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. BIOTRANSFORMATION & ELIMINATION

18. 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. CLINICAL PRESENTATION

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

20. 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. SEIZURES

21. Cessation of seizures ,coma. Respiratory depression & respiratory arrest. Plasma level 20 mcg/ml lignocaine & 4 mcg/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. CNS DEPRESSION

22. 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 ). 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 mcg/ml lignocaine and 6mcg/ml bupivacaine . CVS TOXICITY

23. 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 . ALLERGIC REACTION

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

25. Initially – hypertension, tachycardia or hypotension or bradycardia . CVS hallmark- ventricular ectopic, multiform ventricular tachycardia, ventricular fibrillation Progressive hypotension and bradycardia leading to asystole and latter to cardiac arrest. CVS SIGN

26. 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. TREATMENT

27. Use iv fluid and vasopressin. Ventricular arrhythmia – Inj. Amiadarone 150mg over 10 minutes followed by 360 mg in 6 hours and 540 mg in next 18 hours. CVS Dysarrythmia – cardiopulmonary resusitation . Avoid calcium channel blocker, beta blocker. Shocks

28. 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 . INTRA-LIPID TREATMENT

29. AAGBI Safety Guidelines Management of Severe Local Anaesthetic Toxicity 1. Recognition: Signs of severe toxicity: Sudden alteration in mental state, severe agitation or loss of consciousness, with or without tonic- clonic convulsions. Cardiovascular collapse: sinus bradycardia , conduction blocks, asystole and ventricular tachyarrhythmias may occur. Local anaesthetic (LA) toxicity may occur some time after an initial injection.

30. 2. Immediate Management Stop injecting the LA. Call for help. Maintain the airway and, if necessary, secure it with a tracheal tube. Give 100% oxygen and ensure adequate lung ventilation (hyperventilation may help by increasing plasma pH in the presence of metabolic acidosis). Confirm or establish intravenous access. Control seizures: give a benzodiazepine, thiopental or propofol in small incremental doses. Consider drawing blood for analysis, but do not delay definitive treatment to do this.

31. 3. Treatment: IN CIRCULATO RY ARREST: Start cardiopulmonary resuscitation (CPR) using standard protocols. Manage arrhythmias using the same protocols, recognising that arrhythmias may be very refractory to treatment. Consider the use of cardiopulmonary bypass if available. GIVE INTRAVENOUS LIPID EMULSION (following the regimen overleaf ): Continue CPR throughout treatment with lipid emulsion. Recovery from LA-induced cardiac arrest may take >1h. Propofol is not a suitable substitute for lipid emulsion. Lidocaine should not be used as an anti-arrhythmic therapy. WITHOUT CIRCULATO RY ARREST: Use conventional therapist to treat: hypotension bradycardia tachyarrhythmia CON SIDER INTRAVENOUS LIPID EMULSION (following the regimen overleaf ): Propofol is not suitable substitute for lipid emulsion. Lidocaine should not be used as an antiarrhythmic therapy.

32. 4. Follow-up: Arrange safe transfer to a clinical area with appropriate equipment and suitable staff until sustained recovery is achieved. Exclude pancreatitis by regular clinical review, including daily amylase or lipase assays for two days. Report cases as follows: in the United Kingdom to the National Patient Safety Agency (via www.npsa.nhs.uk). in the republic of Ireland to the Irish Medicines Biard (via www.imb.ie). If Lipid has been given, please also report its use to the international registry at www.lipidregistry.org. Details may also be posted at www.lipidrescue.org

33. An approximate dose regimen for a 70kg patient would be as follows:

34. Maintain vigilance, suspicion. Monitor ECG, NIBP, Arterial oxygen saturation. 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. Use of Benzopdiazipines as premedication can prevent mild CNS toxicity. Monitor the patient atleast 30 mins . BE prepared with – emergency airway, drugs etc. 20% intralipid is highly recommend and kept ready. PREVENTION

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