----start---- anesth 3/23 klide when using inhaled anesthetics, some of the inhaled anesthetics get into the environment. if you don't have a scavenging device on the popoff valve, excess enters the operating room. if the popoff valve does have a scavenging device, it won't, but there are other sources of pollution in the OR. anesthetic is dissolved in the rubber of the anesthesia machine, and can leach out into the air. if the machine is on but not connected to patient, anesthetic gets into room. anesthetic can come out of the incision. when the patient goes to the recovery room, it will be exhaling anesthetic. when you fill vaporizers, some of the liquid gets into the air. consider effects of inhaled anesthetics on people with chronic exposure and also on the world. vaisman survey, 1967 an unusually high prevalence of headache, fatigue, nausea, irritability and pruritis was found in anesthetists working in poorly ventilated ORs. chronic inhalation of waste (excess) anesthetic gas MAY cause: spontaneous abortion genetic defects cancer functional impairment other dysfunctions - liver disease - some people react to very low concentrations of inhaled anesthetics. one student from here can't walk through a room with low concentrations of inhaled anesthetics without becoming jaundiced (this was one student in the past 30 yrs). many studies have looked into this kind of thing. it's hard to know if the problems are caused by exposure to the gas. the major concern was and is the incidence of spontaneous abortion. there clearly is an increased incidence of spontaneous abortion among women who work in OR or women who are impregnated by men who work in OR. could be due to anesthetic but also could be scrub solution, surgical glue solvents, electrocautery electromagnetic radiation, radiographs, etc. you can't isolate out the anesthetic. also it could just be stress, or proximity of worker to surgeon. the studies done looked at incidence of abortion in women working in OR vs women working elsewhere, that's all. there is no way to know it is the inhaled anesthetic that causes the problem. it's unlikely at this time that any study will be done to try to clearly define if it is the problem - you can't set up an unscavenged machine and have someone use it for 30 yrs. also, as the concern was evolving, people started using scavenging systems, minimizing exposure, and it became a moot point, because exposure became very very small. consider relative risks for spontaneous abortion, working in OR carries a 30% increase in risk smoking during pregnancy carries an increase in risk of 80% drinking alcohol causes increases of 100-200% from previously available evidence, it's reasonably clear that you should try to minimize exposure. the other concern is for the environment.. there are substances that are fluorinated, chlorinated carbon compounds, like freons, used as refrigerants. these things are very stable in the environment. they escape from their devices and get out into world and rise higher and higher in altitude over time - at high altitude they are exposed to more UV light. when these molecules get up there, they break down due to UV light, releasing the halogen. free Cl catalyzes breakdown of ozone to oxygen. so these compounds cause depletion of the ozone layer. nitrous oxide can do that, too. potent volatile liquid inhalants have some hydrogens on the molecule. when there are hydrogens on there, substances are less stable, so they break down much sooner, before reaching the ozone layer. when they do break down, they form compounds with water, and halogen acids - and cause acid rain. there are some gases in the environment that reflect radiated heat, preventing heat from leaving the earth - CO2 is one of these "greenhouse gases" and the volatile liquid anesthetics also produce CO2 when they break down, adding to the greenhouse effect. nitrous oxide is also a greenhouse gas. two main sources of nitrous - microbial breakdown of fertilizers, and anesthesia. if one is interested in measuring the amount of inhaled anesthetic i the environemnet, there are services - you can collect a sample, mail it out, and get an answer. this isn't the greatest method - only a single sample - but can give you an idea. a better way is for people to wear a little pack with a vacuum pump on it, that collects air samples during the day, extracts the anesthetic, and allows it to be measured. how do you prevent pollution? on p 39 is a list of things you can do to check the equipment. you can try to do this in the lab. when you work with the machine it will make more sense. go over the list during the lab. at the bottom it mentions low leakage practices - trying to avoid spilling liquid while you fill the vaporizor. also recap the bottle after it is empty to keep vapor in. try to remember not to have flow meter and vaporizor on when machine isn't connected to the patient (at the end of a case,when you disconnect animal - don't forget to turn it off) use ET tubes with cuffs to prevent leakage out of animal. two biggest areas of pollution - one you can do most about - relates to excess gas coming out of the popoff valve. in small buildings, the scavenging hose is often vented out a window or out through a wall to the outside world. this shouldn't be near your air conditioning intake! if the distance is >15 ft, there will be increased resistance to movement of the gas through the tubing, building up pressure in the circle. there are devices to add to prevent this- gas comes into an open container with a fan in it, which helps to push gas out the tubing. you need a device like this, not a suction pump, b/c if you put suction on the tubing you invert the patient's lungs. another device used is f/air. it's a container of charcoal. the volatile liquid inhaled anesthetic is adsorbed to the surface of the charcoal, removed from gas flowing through the container. the container isn't transparent, and there is no indicator. the only way to know when it's used up is to weigh the container. weigh when new, then weigh periodically. amount of charcoal can remove 50 g of halothane. when wt increases by 50 g, throw it away. a third method is to take gas from popoff valve, connect it to exhaust system in the room. this is what human hospitals do. it's a passive system. turnover of air in room is high enough to carry away gas without letting it accumulate. this depends on adequate gas turnover in the room. you have to know that it is adequate. Dr.klide was concerned about this when VHUP was built - he knows the temperature control sucks, and gas movement probably sucks too. so they use a different system - there is a suction outlet with a known negative pressure and a breathing bag within the scavenging system - this bag will collapse if suction is too hard, and will get big if suction is too little. so you can control it and get it to the right amount. this is a more expensive, more complex system with valves in it to prevent accidents. if the system sucks too hard, negative pressure opens a valve and sucks in room air instead of sucking out the lungs. also if pressure builds up, it will vent to the room instead of inflating the patient. the other place where pollution occurs is the recovery room. try to have this area as well ventilated as possible so that exhaled anesthetic is carried away. all the scavenging systems other than charcoal and closed circuit anesthesia put the excess gas into the world environment. the way to reduce the overall pollution, then, would be using closed circuit anesthesia to reduce waste. if you don't use nitrous, you can use lower flows and minimize pollution. last thing in handout: advice to breeding couple. what if you get pregnant? in general, it's hard to answer that question. with reasonable scavenging, the amount of inhaled anesthetic is really small. the federal gov't has some standard that is considered to be safe, and with reasonable scavenging it is easy to reach that - so exposure should be small - but people's attitudes about it vary a lot. knowing the facts, people worry a lot, and the stress can be more of a problem than the (alleged) exposure. therefore the attitude is key. both extremes are reached. some pregnant women have worked up til delivery, and others won't come to the third floor. if one is really concerned, though, it should probably be during the first trimester - so often, a rotation may be put off til the second or third trimester. ---break--- soma note: exam is comprehensive. it has to be. (i have no idea what he's talking about!) stop compartmentalizing your information. you have to integrate it. so the exam is comprehensive. he will give us a case. we will describe things that are happening during the case. you have to answer it. if BP goes to hell, you need to know how to modify it. if you have to change flows, you have to remember what that agent does when you change flow. also how quickly it does it. there will be review sessions before the final. ephedrine - what do you use it for? it increases cardiac output. can use it if patient becomes hypotensive. Dr Soma will talk today about kinetics. Where do drugs go, how do they get there. basic principles are the same- how fast does it get where it's going, how does it get there,where is it going. if you take a drug, and inject it into the venous system, if it's rapidly distributed into the central compartment/vascular compartment, it doesn't go anywhere, and it's eliminated through the kidneys -this is a one compartment model. very few drugs match this model. the slope of the rate of elimination is a straight line. the half life of the drug is as long as it takes for the concentration to drop in half. this approximates your clearance - it takes about 5 or 6 half lives to clear your drug from plasma. this doesn't mean the effects take that long to clear. but the physical elimination of the drug takes that long. if you know the starting concentration and you know the dose you gave you can calculate the volume of the compartment. this is pretty straightforward - very simple. drugs do not work that way. when you have an alpha and a beta phase, it gets more complex. when someone says the halflife of a drug is say 5 hrs, they usually are talking about the beta phase - when you inject the drug into the central compartment, the initial phase involves redistribution into tissue. the second phase is the removal of drug from those tissues by some mechanisms- metabolism or elimination. can involve renal system, liver, respiratory system, biliary excretion. so this beta phase is after drug has equilibrated with second compartment. if you give an inhalational agent, you're putting it into the lung and getting a high enough concentration to cause an effect. the first phase is distribution into tissues, and second phase is elimination from tissue (and further distribution). the alpha phase tells you how quickly drug gets to where it is going in the body. if it is highly plasma bound, has low lipid solubility, doesn't move out of vascular compartment, etc, how do you describe phase a? slow. if it is very lipid soluble, uncharged, then distribution phase is very rapid. this doesn't tell you where drug is going, though. you want to know where initial distribution is going, and how long it takes to get to CNS, and what influences speed of distribution. if a dose of thiopental is given IV, what happens? patient will start licking, head drops, gets a little sleepy - maybe some excitement. drug can be tasted at time of injection before patient falls asleep. probably takes about 5 seconds to lose consciousness. that means that the drug that you've injected into vascular compartment is very rapidly distributed into tissues, as opposed to another drug like pentobarbital, which isn't as lipid soluble, and when you inject it, the distribution to other tissues is slower. so it takes longer to fall asleep. so for thiopental, slope in alpha phase is steeper. slide of graph for flunixin which has rapid distribution phase and slow elimination phase. you're injecting into central compartment, removing drug from C1 into C2, and eliminating drug from C1. this tells you nothing about what is in C1 or C2. normally, for as far as the anesthetic agent is concerned, the target organs are in C1 - the brain, heart, lungs. if you give thiopental into vascular compartment, in that compartment you find the CNS, heart, lung, highly perfused tissue- and in C2, you might have muscle, other tissues less highly perfused. the early rapid elimination causes rapid decline in plasma concentration and rapid uptake into tissues - what tissues? the initial rapid distribution of a drug goes into highly perfused tissues. then, in the second phase, there is a slower uptake into muscle, fat if animal is on the table, and you think it is anesthetized, and you stimulate it, and it begins to move, what happens to the muscle? blood flow increases, it picks up more anesthetic, some of drug in highly perfused tissue shifts into muscle, decreasing amount of drug in initial compartment, decreasing concentration in brain. bad news. you want to achieve some steady state. when you give a thiobarbiturate, you give a bolus, get some level of anesthesia which from then on is decreasing continually. when you give inhalational anesthetic, you want to maintain some steady state. for thiobarbiturate you would give a bolus and then maintain on a continuous infusion. with an inhalant, you can't give a bolus, but through the lung you are giving a continuous infusion. if you know, you can calculate , if you give a thiobarbiturate bolus and know halflife and so forth you can calculate an infusion rate. you do not give infusions of thiobarbiturates because recovery would take forever. but with inhalational agents, animals recover really quickly when drug is no longer given. they will exhale the drug at the same rate that it was given. [i'm having a hard time with this lecture...] so recovery is kind of the mirror image of induction. ---break--- ok, we're back. a constant infusion of a drug is given, as in inhalation anesthesia. what then determines how quickly you get a rise in tissue concentration? pick a tissue, any tissue. what determines how fast you acheive a rise in that concentration? ability of drug to cross membranes - lipid solubility. this is how you define solubility. also, blood flow to that tissue. when the organ is equilibrated at the concentration you're infusing, we're talking about. also, the volume of the tissue (blood flow relative to volume). if you have brain, muscle, and fat, there are three different volumes, but if they have the same blood flow relative to their volume, which tissue will equilibrate more quickly? brain. this is why anesthesia works. if you inject something into the first compartment, and it's going out to C2, and you also define a C3, if the brain is in C1 and muscle is in C3 and fat is in C2 and they all have equal blood flows, but muscle and fat are larger, the effect of the infusion says that brain will equilibrate first, rapidly, because we're starting a constant infusion of the drug. so we had solubility, we had blood flow, and we had volume, but more important is relative volume in proportion to blood flow. if you change blood flow, you can redistribute drug from one compartment to another compartment. consider inhalational anesthetic as constant infusion of drug. you've eventually - you're at some steady state, and you're under anesthesia,a nd flow is going between all compartments in proportion to whatever the cardiac output is. you change CO and you change distribution. you can make it go up or down to any particular compartment, because you change the redistribution of blood in tissue (he's not making sense to me). suppose you have a hypovolemic animal. it has reduced plasma volume. you inject the same drug into central compartment.what happens to distribution? well, you have reduced blood volume, and increased concentration of drug in the blood - what happens? more blood shifts into central compartment from periphery due to vasoconstriction. so when you inject into central compartment, more drug is distributed to heart, lung,kidney, and less to muscle, fat. this doesn't mean you can't inject into that compartment, it just means you should be more judicious in the injection of stuff. solubility - defined as a drug that moves very rapidly from vascular compartment into other tissues,for now. blood flow to tissue relative to CO compartment volume solubility in tissue drug may take a long time to equilibrate in fat because it's taken up a lot in fat due to solubility - and fat has low blood flow. how quickly do you know when that tissue has been equilibrated? if you know the input into the organ, how do you know when it equilibrates? well, what goes in comes out. measure what comes out. if you know the arterial side and venous side... so when venous concentration is close to the arterial concentration, you know that the tissue is equilibrated with what's going in. what you are looking at is the arterial-venous difference across that tissue. when it approaches zero, you have equilibrium. therefore, if you know the flow to the tissue, know the volume of the tissue, have a drug moving across rapidly, measure venous concentration - you can tell quickly when equilibrium occurs. and theoretically, if your target concentration is x, and what's coming out is just a tad less than x, you know you have anesthesia, or that you've infused the concentration that should produce anesthesia, because you've equilibrated the target tissue with the concentration you're delivering. number two, if you have a drug which is very lipid soluble, moves across very rapidly, is soluble in the target tissue, what are the limitations of delivery of drug to the tissue? what determines how rapidly that organ becomes equilibrated with the concentration you're delivering? volume of tissue, perfusion of tissue. so for a very lipid soluble drug that moves rapidly the determinant of how quickly equilibrium is reached for a tissue is blood flow for the tissue - if you reduce it, you increase the time it takes to reach equilibrium. it takes longer to induce anesthesia. thiopental is flow limited -moves across tissue rapidly - flow to tissue determines how quickly tissue equilibrates. if you look at tissue drug concentrations vs time for a thiobarbiturate, the tissue that is most perfused equilibrates rapidly, and least perfused tissue never really equilibrates. kidney and brain equilibrate first, then heart,lung, etc, and fat is at the bottom of the pile. those are drugs in which you have high solubility and ability to move across tissues from plasma into tissues very rapidly. it's the perfusion that limits the time in which they equilibrate. there are drug limitations as well. all else being equal, characteristics of drug will limit time to equilibrium. questions on solubility, perfusion, size/flow relationship? guessnot. we've gone over the three compartment model. there's other stuff there on volume of distribution. you could take the three compartment model and divide it - C1 is brain, heart, kidney, liver, lung; C2 is muscle, skin - large mass, less blood, fairly labile; C3 is fat, tendon, ligaments - large mass, low perfusion. rapid distribution elimination slow/very slow elimination are the phases in a three compartment model as with thiopental or flunixin rapidly produce anesthesia (equilibrate through C1 - concentration in brain parallels concentration in plasma), then distribute to muscle and you see a rise in concentration in muscle and then a drop in concentration in muscle, over time. animal will start waking up as drug is redistributed into fat - at 36 hrs out, there's no more drug in plasma that you can detect but you can find it in fat. classic rapid entrance into CNS, slower secondary distribution into muscle, then a slow uptake by fatty tissues - thiopental. if you were to model this you would probably define a three compartment model. rapid uptake by highly perfused tissue, slower uptake by muscle, and third compartment of slowly perfused deeper types of tissue. slope of first part is steep,then flatter for second part, and really flat for third part. ok? that's simple stuff. now. because you can give the drug in mg/kg, and you can give it IV, IM, orally, it's easier. now, trying to give it by inhalation - normally, you define this as some percent of total gas flow. -inhaled -exhaled -end tidal (approximation of alveolar concentration) -alveolar partial pressure PP = % HAL * (BP-SWVP) = 0.03 *760 mmHg = 21.4 LD50 is X effective dose is Y what does this tell you? you know when 50% of the animals will croak and when 50% of animals will be affected. how do you define an anesthetic agent? same way. MAC: end tidal concentration at which 50% of theaniamls will respond to a noxious stimulus. equivalent to ED50 in that it defines potency adequate anesthesia is produced at 1.25 to 1.5 mac end tidal concentration mac is used to compare anesthetic agents because they are varied in their potency. if mac is .9 for halothane, and .2 for sevoflurane, and .3 for something else, then you have a measure of comparative potency. for surgical level you multiply mac by about 1.3 to get the end tidal concentration sufficient to produce a level of anesthesia. mac is not a surgical level of anesthesia! so if you've defined that drug x has a mac of 1%, that means that if you stimulate the next 50 animals 25 will respond and 25 won't, and to produce anesthesia you want 1.25 to 1.5 MAC. MACs to know: halothane .8 iso 1.5 enflurane 2.2 methoxygglurane 0.23 nitrous 188 sevoflurane 2.0 mac does NOT define how rapidly you will induce anesthesia, it just tells you the potency. just because methoxyflurane is more potent than isoflurane, doens't mean induction is faster (it isn't). it just says that when you get there, the end tidal concentration is lower. says nothing about speed of induction. induction is related to drug solubility we talked about thiobarbiturates - comparing those to oxybarbiturate, what did we say? we induce more quickly with thiobarbiturate b/c it is very soluble. with inhalational agent, higher solubility causes slower induction. factors altering anesthetic requirements: circadian rhythms (obviously, he says) - changes in metabolism over time body temperature age - young children take less anesthesia other drugs - CNS stimulants increase requirement for anesthesia. tranquilizers/sedatives reduce the requirement. species variability ---end----