Inhalational Agents 4th year MBChB tutorial

Synonyms Inhalational Agents Anaesthetic gases Anaesthetic Agents Volatiles

History of Anaesthesia

How it all began... October 1846 – Dr William Morton first demonstrated the use of Ether to induce anaesthesia First use of ether in South Africa – 1847 in Grahamstown!

Ether dome Surgeon: John Collins Warren Comment: “Gentleman, October 16th 1846  First successful public demonstration of anaesthesia Massachusetts General Hospital, Boston  Anaesthetist: William Thomas Green Morton Agent: Diethyl Ether Patient: Gilbert Abbott Operation: Excision of tumour under jaw Surgeon: John Collins Warren Comment: “Gentleman, this is no humbug!”

Older volatiles Ether Chloroform John Snow designed the first inhaler (forerunner to the modern vaporisers) Administered chloroform to Queen Victoria for delivery of her last 2 children, lead to the birth of obstetric anaesthesia! What else is John Snow famous for? Chloroform The first fatality from anaesthesia was a 15-year- old girl called Hannah Greener, who died on January 28, 1848 during surgery to remove an ingrown toenail!!! Respiratory or Cardiac side-effects from overdose

Schimmelbusch Mask narcosis mask for dripping liquid ether now obsolete, it was a mask constructed of wire, and covered with cloth.

Modern volatiles and vapourisers

Modern Volatiles 1930–1956 - introduction of cyclopropane and trichloroethylene Halothane - The first modern non-flammable hydrocarbon was introduced in 1960 By the 1980s, the anaesthetic vaporiser had evolved considerably with several modifications and safety features

Vapourisers Colour coded vapourisers and bottles Colour and key-filler system Anaesthetic back-bar interlocks so you can’t switch on more than one vapouriser at a time

Vapouriser cassettes

Pharmacology of Volatiles

Uptake and Distribution The speed at which you “go to sleep” depends on the anaesthetic agent’s partial pressure in the BRAIN Delivery to the lungs Uptake of agent from the lungs Uptake of the agent into the tissues

1) Delivery to the Lungs Inspired concentration Alveolar Ventilation The higher the concentration of the agent, the faster the induction Alveolar Ventilation Induction is increased by increased ventilation Induction in decreased by reduced ventilation eg respiratory depression obstructed airway

2) Uptake of anaesthetic agent from the lungs Solubility for the agent in the blood (blood/gas solubility co-efficient) The more soluble the agent – the slower the induction! The less soluble the agent – the more rapid the induction! Why does this occur? Very difficult concept to grasp If the circulation constantly carries the agent away, the alveolar concentration does not have a chance to build up and as a result the concentration in the brain rises slowly too Cardiac output If CO increased, increased agent uptake from alveoli, therefore slow inuction ..... And vice versa

Alveolar to mixed venous partial pressure difference Initially during induction, the tissues take up a large amount of the AA - anaesthetic agent (due to the concentration gradient) The blood returning to the lungs i.e. the mixed venous blood therefore has a low concentration of the AA Uptake of the AA from the alveoli to the blood in lungs is high ( also due to the concentration gradient) Shunting Blood that bypasses the alveoli will not come into contact with AA Intrapulmonary or intracardiac shunts

3) Uptake by the Tissues Tissue solubility Tissue bloodflow Concentration gradient between blood and tissues Greatest uptake – vessel-rich organs (heart, brain, lungs, kidneys, liver) receive the largest portion of the CO once equilibrium is achieved ... Second phase – uptake by the muscle group equilibrium is achieved within 1-3 hours Last phase – uptake by the poorly vascularised tissues (fat, bone) equilibrium takes many hours

Stages of Anaesthesia 1 Analgesia: From induction to LOC 2 Description 1 Analgesia: From induction to LOC 2 Excitement: LOC to automatic breathing; characterised by excitement, breath-holding, vomiting, coughing, swallowing, hiccoughing 3 Surgical anaesthesia Light Until eyeballs become fixed Medium Increasing intercostal paralysis Deep Diaphragmatic respiration 4 Overdose: From diaphragmatic paralysis to apnoea and death. All reflex activity is lost and pupils are widely dilated. Medullary paralysis

Recovery from Anaesthesia The same factors that affect “going to sleep” affect “waking up” in reverse order! Recovery is slow from soluble agents eg halothane Recovery is fast from poorly soluble agents eg Desflurane and Sevoflurane

Metabolism of Volatile Agents At the end of an anaesthetic, the major route of removal of the AA is via the lungs (via alveolar ventilation) A small percentage of the AA will be metabolised in the liver “Rules of 2’s” Halothane 20% Enflurane 2% Isoflurane 0.2% Sevoflurane 3-4% Desflurane 0.02% Harmful metabolites Halothane Hepatitis Fluorides from Methoxyflurane and Enflurane Compound A from Sevoflurane Carbon monoxide from Desflurane

Potency of Volatiles MAC (%) Minimum Alveolar Concentration required to prevent 50% of young adults from moving in response to a standard surgical stimulus (skin incision) at sea level. MAC is ↓ed by: MAC is ↑ed by: Sedatives N2O Analgesics Elderly Hypotension Hypothermia Myxoedema Less effect: Hypoxia, anaemia, pregnancy Alcoholism Children Hyperthermia Thyrotoxicosis

Specific Inhalational Agents

What is this?

Nitrous Oxide MAC: 105% Also known as Laughing gas Entonox (50% O2 & 50% N2O) Potent ANALGESIC, but poor anaesthetic Reduces MAC When used as a carrier gas, induction is pleasant and rapid (paediatrics) Adverse Effects: Negatively inotropic Augments respiratory depression of other anaesthetic drugs Diffuses into air-filled cavities of body (more soluble than N2) – increase volume and pressure Bowel, middle ear, eye, lungs (tension pneumothorax) PONV Teratogenic – controversial Bone Marrow Suppression

N2O in history Davy and N2O “prescription for scolding wives”

Diffusion Hypoxia N2O is much more soluble than NITROGEN (in air) Diffusion Hypoxia can occur when you finish an anaesthetic where you used N2O in high concentration 70% N2O and 30% O2 The N2O enters the alveoli, from the blood, FASTER than NITROGEN enters the blood, from the alveoli (if you were giving the patient AIR only). This reduces the partial pressure of O2 in the alveoli Diffusion Hypoxia is not usually detectable in young fit patients Safe Practice – give O2 (e.g. 40%) when switching off an anaesthetic with N2O

Halothane MAC: 0.75 % Halogenated hydrocarbon Colourless liquid decomposed by light, stored in amber bottles Non-irritant Pleasant smell Suitable for gas induction

Pharmacodynamics of Halothane Respiratory Dose-dependent respiratory depression bronchodilator Skeletal Muscle Muscle relaxation Trigger for MH (malignant hyperthermia) Uterus ↓es uterine tone Liver ↑ed liver enzymes post-op Halothane Hepatitis CNS Potent hypnotic, no analgesia ↑ed CBF and ICP (minimised by hyperventilation) CVS Myocardial depression and vasodilatation ↓ed BP Arrhythmias

Enflurane MAC: 1.68 % Halogenated Ether Colourless liquid, more pungent than halothane, not suitable for gas induction No longer available at GSH Expensive Adverse effects

Pharmacodynamics of Enflurane Respiratory Irritant to airways Breath-holding Laryngospasm Skeletal Muscle Greater relaxation than halothane Enhances effects of muscle relaxants Triggers MH Liver Less effect on liver enzymes CNS Epileptiform changes on EEG in epileptics ↑ed CBF and ICP CVS Bigger BP drop than Halothane Tachycardia

Isoflurane MAC: 1.14 % Halogenated ether Colouless More expensive

Pharmacodynamics of Isoflurane Respiratory Irritant to airways Not suitable for gas induction Bronchodilator Skeletal Muscle Relaxant Potentiates NDMR Triggers MH Uterus Relaxes uterus Liver Low potential for toxicity CNS Least effect on ICP Least effect on CBF ↓ed CMRO2 consumption ↓ed CSF production Ideal for neurosurgery CVS Vasodilator Coronary Steal phenomenon Drops the BP Tachycardia More CVS stable than H

Sevoflurane MAC: ±2% Halogenated methyl isopropyl ether Very pleasant and sweet-smelling Best for gas induction Expensive

Pharmacodynamics of Sevoflurane CNS Slight ↑ed CBF and ICP ↓ed CMRO2 consumption Also good for neuro CVS Mild depression of cardiac contractility Slight drop in BP, but less than with I or D No increase in HR, so CO not as well maintained as with others Respiratory Dose-dependent depression bronchodilator Skeletal Muscle Adequate muscle relaxation for intubation in children Liver No increased liver enzymes Renal Nephrotoxic endproducts Fluoride Compound A

Desflurane MAC: ±6 % Fluorinated methyl ether Boiling point is very close to room temperature so it needs a special vapouriser Very expensive Limited availability at GSH Most rapid induction and emergence of all the volatiles due to it’s low blood-gas solubility co-efficient Not suitable for gas induction as very irritant and pungent Similar effects on CNS, CVS, Respiratory and Skeletal Muscle Triggers MH Carbon monoxide production

Malignant Hyperthermia Rare 1:15000 Pharmacogenetic disorder Triggers: 2 drug classes All volatiles Suxamethonium Acute hypermetabolic state within muscle tissue with induction of GA Defect: Abnormal Ca receptor in muscle Clinical signs Tachycardia (& other CVS signs) Hypercapnia (3 x ↑ ) Tachypnoea (if not paralysed) High temperature (late!) Skeletal muscle rigidity (early) Arterial blood gas: Metabolic & Respiratory acidosis ↑ed K+, Ca++, creatine kinase Myoglobinuria Acute Renal Failure Treatment: DANTROLENE iv and supportive in ICU