Local Anaesthetic Systemic Toxicity PDF

Local Anaesthetic Systemic Toxicity =================================== ***Life Threatening* [adverse event] which takes place after the administration of a local anaesthetic through a variety of routes.** ---------------------------------------------------------------------------------------------...

Local Anaesthetic Systemic Toxicity =================================== ***Life Threatening* [adverse event] which takes place after the administration of a local anaesthetic through a variety of routes.** ------------------------------------------------------------------------------------------------------------------------------------------------- - Symptoms usually occur within the first 10-minutes but could take place within an hour. Why Local anaesthetic drugs? What are they made of? =================================================== - Water soluble salts (Na+) of lipid (fats) soluble alkaloids (This means they contain salts which dissolve in water (like sodium) of alkaloids (this is the part of the drug which serves the purpose of whatever its being given for) that dissolve in fat)-in other words local anaesthetics have chemicals which can easily dissolve in water and fats. That's why they are called **lipophilic.** This structure allow [local anaesthetics](https://www.sciencedirect.com/topics/medicine-and-dentistry/local-anesthetic) to cross the cell membrane in their unionized form with ease. Think about why local anaesthetics are given?? Usually to numb an area so the patient does not feel pain. In essence-the drug spreads around that area because its 'lipophilic' and blocks Na+ channels so message of pain doesn't reach brain and kick-start a load of physiological responses like HR going up etc. - Something to remember: different local anaesthetics have different abilities of dissolving in lipids-so it will be easier to remove ones that are more lipid soluble (dissolve in fat more easily-like bupivacaine-but these ones can cause fast toxicity too). All local anaesthetics target the voltage-gated Na^+^ channel and carry the risk of toxicity. They block sodium channels which interferes with signals to the brain. But wasn't sodium also important for cardiac conduction?? Well exactly! they also prevent the [rapid] early depolarization stage of an action potential from occurring (so a big problem for the heart-which needs to contract) - What is sodium? Sodium is a mineral that carries an electrical charge, known as an electrolyte. Electrolytes facilitate muscle contraction and nerve cell transmission. How does **[systemic]** toxicity happen?? ===================================================== - Toxicity occurs when the concentration of the LA reaches a level that affects organs dependent on sodium channel conduction, mainly excitable neural tissue within the **heart** and **CNS** (central nervous system) - The effects can be mild (progressive inhibition/stop of function) to life-threatening seizures and cardiac arrest. STEP-BY-STEP: 1. When local anaesthetic is given peri-neurally (inside nerves), they are absorbed into the systemic circulation. 2. Rate of absorption depends on **how much LA** was given and the **vascularity of the structures around** where it was given. 3. LA tends to bind to the plasma (watery part of blood)-since LA are made up of soluble salts. Body System: Blood Components 4. Each LA binds to plasma differently. For example, bupivacaine has a high percentage of binding (dissolving) so longer duration of action-but also makes it more risky because if something binds really well to plasma it becomes dissolved in a large part of your blood and its pretty difficult to get something out from a watery base. So, the toxicity can happen fast and for a longer duration. 5. In other words: Once plasma is saturated with the LA, the level of free drug in the systemic circulation will rise rapidly, leading to the sudden onset of symptoms associated with severe, life-threatening toxicity. Remember some tissues such as heart and brain and liver are more perfused with blood, so it will effect these the most. 6. Another problem is: In order to get the LA out of your system, you need to metabolise it. But metabolism is dependant on enzymes in the plasma, and any dysfunction to these will reduce the metabolism of the LA. But how we gonna metabolise without ATP (energy) 7. LAST occurs when Mitochondria cannot generate adenosine triphosphate (ATP) for energy (to metabolise)- anaerobic metabolism The Key Toxicity Effects (Brain & Cardiac) ========================================== Brain (CNS Toxicity) -------------------- 1. LA drugs cross the blood-brain barrier with ease. 2. Local anaesthetic interferes with nerve impulses being sent to the brain by blocking sodium channels, in the nerve plasma membrane (axons) 3. The LA causes blockage directly in the brain (Cortical inhibitory pathways)-which cause an initial excitation (nervousness, confusion, agitation, tinnitus, visual disturbance, paraesthesia, peri-oral tingling and muscle fasciculation) 4. Sometimes seizures can happen (usually from 1 part of brain overly contracting)- followed by CNS depression, decreased conscious level and respiratory arrest. Heart (Cardiac Toxicity) ------------------------ 1. LAs have bio-chemical effects on cardiac tissue, such as: - block ion channels - inhibit (hinder/refrain) ***Oxidative Phosphorylation*** in mitochondria. The OXPHOS/TCA cycle---also known as the citric acid cycle (CAC) or the Krebs cycle---is a series of enzymatic chemical reactions that oxidize acetyl-CoA derived from carbohydrates, fats, and proteins, into ATP and carbon dioxide (CO2). **In simple words:** **LA prevents chemical reactions in the mitochondria which stops the production of ATP + C02 (we know that these are needed for energy). But without them we lose the ability to break displace and manipulate H+ ions and we know that the accumulation of these will cause an acidic PH-We will switch to anaerobic metabolism when the kidneys find it difficult to produce enough bicarbonate to buffer excess H+. This could lead to cell death-organ damage & failure.** **Wanna know more?? Try this:** **** - Without ATP transportation capability, leads to a reduction in systemic vascular resistance, cardiac conduction and myocardial contractility (all of which needs ATP-cellular energy). - Ion channel blockades lead to shortened refractory period (between PQRST intervals), leading to conduction defects in the heart (prolongation of both PR and QRS intervals classically observed on ECG). But did you know that by blocking sodium channels, potassium and calcium also get effected. Calcium becomes more and this is involved in contraction remember. Sodium balances these, especially in the cardiac cycle. See CIRCULATION Slides.  **Prolonged PR** - Might start with Hypotension (conduction is needed for the heart rhythm-pacemaker cells and also contractility (stroke volume)-without these the cardiac output cannot be maintained, tachycardia and arrhythmias (hearts effort to compensate & arrythmias from the inhibition of conduction-sodium channels in particular) then progressing to severe hypotension, bradycardia and ultimately cardiac arrest. Heart cannot keep up without the correct ions for conduction. Recommended interventions in the **prevention** of local anaesthetic systemic toxicity (LAST) ============================================================================================= - - - - - - - Treatment: ========== 1. Discontinue Local anaesthetic (if possible) 2. Call for help and request lipid rescue pack (LAST BOX) as this is an emergency requiring an MDT and lipid emulsion will be required for treatment 3. Give 100% Oxygen (O2) and ensure adequate ventilation to prevent hypoxia (02 to brain and main organs) caused by depletion of ATP, hypercapnia and the resultant acidosis which accentuates the effects of toxicity. If there is decline in consciousness level then tracheal intubation is indicated. 4. Confirm or establish intravenous (IV) access --for emergency lipid emulsion (fast treatment) 5. Give an initial bolus of 20% Intralipid/lipid emulsion - If you think about it: The job of lipid emulsions is to separate the sodium (Na+) (which are positive ions) from the tissue (since local anaesthetics will dissolve easily in tissue) into negatively charged particles so that they can move from tissue to plasma and into the lipid thus draining and retaining the free unbound anaesthetic agent alongside scavenging it from tissues. - ??? Think about what emulsions actually are! Look at this pictureEmulsion - QS Study So the lipid emulsion serves to separate the sodium from the lipid (tissues/fat). **In Systemic Toxicity (where the LA is in the plasma already):** By administering **lipid emulsion** we expand the volume which to some extent manages the vasodilation caused by LAST and also increases the preload. Hence, improving cardiac output and blood pressure. Also, the lipid emulsion provides substrate for direct energy delivery to the myocardium and this improves cardiac function. 6. If NO circulatory arrest: Treat hypotension and arrythmias-benzodiazepines may be given. *Benzodiazepines: For seizures, delirium, muscle relaxant, opiate effect.* 7. If YES circulatory arrest-Start CPR-but avoid the larger dose of adrenaline as this gives an ALPHA effect working on vasoconstriction and we want contractility (to raise stroke volume) in LAST. 8. Don't forget: AFTERCARE-may need HDU/ICU for extra observation or if intubated with controlled ventilation (to correct PH). Extra reading: ============== Basic pharmacology of local anaesthetics - PMC (nih.gov)