Inhalation anesthetics (Table 12.5)
Before discussing the agents one by one, we need to deal with the question of the uptake and distribution of inhaled drugs.
Behind this bland title lurks a concept that has baffled students for years, yet it is fairly straightforward. Here are the facts:
(i) Solubility of the anesthetic in blood has nothing to do with its potency. Indeed, anesthetic effectiveness has to do with the partial pressure of the drug and not with the amount of drug in solution.
(ii) Anesthetics taken up by the blood flowing through the lungs are distributed into different body compartments, depending on the blood flow these com-partments receive, the volume of the compartment, and the solubility of the anesthetic agent in that compartment.
(iii) The partial pressure exerted by a vapor in solution has nothing to do with the ambient pressure, but has much to do with the temperature of the solution.
Let us take these three items one by one:
(i) Solubility of the anesthetic in blood has nothing to do with its potency. Table 12.5tells the story. At equilibrium, you will find 12 times as much ether (when we say “ether” we refer to diethyl ether; some of the halogenated anesthetics are chemically also ethers, but we call them by their given name, e.g., sevoflurane and desflurane) in blood than in the overlying gas (blood/gas partition coefficient). The blood practically slurps up the ether. Every breath that brings in more ether dumps its load of the anesthetic into the blood perfusing the lungs. It takes breath after breath to deliver enough ether for the blood to come into equilibrium with the alveolar gas. At equilibrium, the partial pressure (but not the concentration per unit of volume) of the ether in the gas phase (alveolar gas) is the same as in the blood.
We have picked ether (no longer used in the Western world but widely used elsewhere) because of its extraordinary solubility in blood at body tempera-ture. In comparisson, look at sevoflurane. Ether is 20 times as soluble in blood as is sevoflurane. We can quickly bring enough sevoflurane into the alveoli to establish an equilibrium between alveolar gas and blood. For ether, it will take many, many breaths laden with ether to fill the blood compartment and to reach equilibrium between alveolar gas and blood. Yet, diethyl ether and sevoflurane have almost identical MAC values. MAC stands (neither for a computer nor for a truck) for minimal alveolar concentration, namely the concentration in alveolar gas at which 50% of patients no longer respond to a painful stimulus. Thus, when we have attained MAC values for ether and MAC values for sevoflurane, there will be much, much more ether dissolved in the patient than will be true for sevoflurane. It will be quicker to get the patient to sleep – and have him wake up again – with sevoflurane than with ether.
Observe in Table 12.5that, at equilibrium, you will find five times as much ether in fat than in blood and 45 times as much isoflurane in fat than in blood . . . which brings us to the next point.
(ii) Anesthetics taken up by the lungs are distributed into different body com-partments, depending on the blood flow these compartments receive, their volume, and the solubility of the anesthetic agent in that compartment.
Figure 12.3shows the relationships. Observe the low blood flow and large volume of the fat compartment (not even assuming an obese patient!) and the small volume but enormous blood flow to the vessel rich group.
These “compartments” are conceptual rather than anatomical; the vessel rich group contains heart and brain as well as kidney and liver.
You can easily imagine that during a long anesthetic, the fat compartment, despite its low perfusion, will accumulate much anesthetic agent because inhalation anesthetics are so very soluble in fat (they make excellent grease stain removers). At the end of the anesthetic, the poorly perfused fat compart-ment will slowly deliver anesthetic to the venous blood, causing the patient to have a protracted recovery from the anesthetic; the greater the solubility of the agent in fat, the more protracted.
(iii) The partial pressure exerted by a vapor in solution has nothing to do with the ambient pressure, but has much to do with the temperature of the solution.
Water vapor in the lungs at 37 °C has a vapor pressure of 47 mmHg. At that temperature, as many molecules of water leave the blood as enter it. The vapor pressure increases with rising temperatures. At the boiling point, the vapor pressure equals ambient pressure (at the top of the mountain you need to boil your egg a little longer because the water will boil at a lower temper-ature). At sea level (1 atmosphere or 760 mmHg ambient pressure), it takes 1.15% of isoflurane to render 50% of the population unresponsive to noxious (if the patient were awake the word would be “painful”) stimuli. At that baro-metric pressure, 1.15% equals about 9 mmHg. At altitude with a barometric pressure of 500 mmHg, these same 9 mmHg would be about 1.8% of vapor in the alveolar gas. Thus, the convention of reporting anesthetic concentrations in percent – as our vaporizers do – leaves something to be desired. In Table 12.6, we compare isoflurane MAC values in two cities of very different alti-tude that happen to have the same name. Remember that about half of our patients will be responsive, i.e., with a movement without being necessarily conscious, at 1 MAC. In order to have almost 100% of patients unrespon-sive to noxious (painful) stimuli, we need to expose them to 1.3 MAC. Also, remember that most patients have been given other CNS depressants; MAC values change with age (down they go); and distribution of the anesthetic agents also depends on the patient’s cardiac output, which, in shock with a very low cardiac output, may send a disproportionate percentage of the blood to brain and heart.
We can anticipate that many CNS depressants will lower MAC. Intuitively not so obvious, however, are reports that hyponatremia, metabolic acidosis, alpha methyldopa, chronic dextroamphetamine usage, levodopa, and alpha-2 agonists can lower MAC, as does pregnancy. We find elevated MAC values in hyperna-tremia, hyperthermia, and in patients taking monoamine oxidase inhibitors, cocaine and ephedrine. The administration of a sympathomimetic can some-times lighten anesthesia. Because we always titrate anesthetics to a desired effect and because patients vary greatly in their response to drugs – anesthetics as well as others – these differences in MAC rarely influence our anesthetic practice.
Only two anesthetic gases (as opposed to vapors) deserve to be mentioned: nitrous oxide and xenon. Cyclopropane and ethylene are two explosive gases used in the past.
Nitrous oxide has been around for centuries and is still widely used. Yet you will often hear it said that, if nitrous oxide were to be introduced today, it would never pass the FDA’s muster. For this jaundiced view, we can cite several reasons.
· The gas is a weak anesthetic with a MAC of 105%. Thus, it would require a hyperbaric chamber to administer that concentration with enough oxygen to make it safe. In concentrations up to 70% in oxygen, it is an analgesic rather than a reliable anesthetic.
· Because it is such a weak drug, in the past people tended to give high concen-trations of it, which is another way of saying that it was given with marginal concentrations of oxygen. Modern anesthesia machines will not let you give less than 25% oxygen, but many patients with ventilation/perfusion abnor-malities require a higher FiO2.
· It does some peculiar things to some important enzymes. By oxidizing vitamin-B12-dependent enzymes (methionine and thymidylate synthetase), it inhibits formation of myelin and thymidine (important in DNA synthesis). Prolonged exposure to nitrous oxide has caused neuropathy and megaloblas-tic changes as well as leukopenia. A decreased white count was noticed in tetanus patients requiring prolonged mechanical ventilation during which nitrous oxide was used continuously as an analgesic sedative. Attempting to use this effect to advantage, subsequent experiments with nitrous oxide in leukemic patients confirmed the observation that the gas could reduce the white count. Unfortunately, the effect did not last and upon discontinu-ation of the gas, the cell counts rose back to their pathologic condition. The neuropathic effect of nitrous oxide was observed by a neurologist who saw dentists complaining of different degrees of apraxia, ataxia, and impotence. Exposure to nitrous oxide was the common denominator in these patients. These effects are not observed during the relatively brief use (minutes or hours instead of repeated use or days of exposure) of nitrous oxide in patients undergoing surgical anesthesia.
· Despite its low blood solubility (blood/gas partition coefficient of 0.47), the high concentration of N2O administered (50% to 70% in oxygen) causes many liters to dissolve in the body during a lengthy anesthetic. Because it diffuses readily into air-containing bubbles, nitrous oxide can increase the volume of air in the cuff of an endotracheal tube, the gas in the bowel, a bleb in the lung, or gas in the middle ear. The volume of a closed air space, e.g., pneumothorax, will double in just 10 minutes! The doubling time for bowel is much slower (hours).
· We might also mention that it supports combustion, almost as well as oxygen.
· For neurosurgical procedures, even low-dose and brief exposure to nitrous oxide affects evoked potentials – which we monitor to keep an eye on the integrity of the spinal cord, among other things.
· Based on questionable epidemiologic data and on animal experiments, nitrous oxide has been accused of causing spontaneous abortion in person-nel repeatedly exposed to trace concentrations of the gas. Consequently, maximal acceptable trace concentrations of nitrous oxide in the OR have been established by the government: OSHA calls for a time weighted aver-age concentration of less than 25 parts per million.
· Finally, thrill seekers have extensively abused nitrous oxide, obtaining it legally (and stupidly) in the small whippet cylinders. There, the gas exists in its pure form, that is without oxygen. The ill-informed who inhale it from such a source expose themselves to the double trouble of inhaling a hypoxic gas mixture while breathing a harmful gas.
In fairness, we have to say something positive about the gas. Because of its low solubility, it does not take much time to reach equilibrium between alveolar gas and blood, which translates into fairly rapid induction and emergence with min-imal cardiovascular side effects. Some pediatric dentists like its mild analgesic effect and the fact that it is tasteless and odorless (which is why industry uses it as a propellant for canned whipped cream). In the pediatric dental practice, nitrous oxide is usually administered in concentrations between 30% and 50% in oxygen. Higher concentrations of nitrous oxide given by itself often lead to excite-ment. In anesthetic practice, therefore, we administer the gas together with other CNS depressants, for example thiopental or propofol or a halogenated anesthetic vapor.
Even though it has nothing to do with the pharmacology of nitrous oxide, and everything to do with the fact that we give it in high concentrations (up to 70% – whereas the halogenated agents are given in less than 1/10th that concentration), we need to mention three concepts linked to nitrous oxide: the second gas effect; the augmented inflow effect (also called the concentration effect); and diffusion hypoxia.
If you administer a high concentration of nitrous oxide to the lungs during induc-tion of anesthesia, much of the gas will go into solution in the body, thereby reducing its partial pressure in the lungs. The sum of all partial pressures will equal barometric pressure. In other words, if a large volume of nitrous oxide van-ishes, any other (second) (anesthetic) gas present in the lung will experience an increase in its partial pressure, which will speed its uptake by the blood.
Because of the large uptake of nitrous oxide, the exhaled volume will be dimin-ished, enabling the next breath to have an increased tidal volume to re-establish normal lung volume.
After hours of anesthesia with nitrous oxide, many liters of the gas go into solution in the body. At the end of anesthesia, when the patient no longer inhales nitrous oxide, the liters of nitrous oxide in solution will follow their concentration gradient and be delivered to the lung where the gas will displace other gases – including oxygen. Thus, we give oxygen for a few breaths at the end of anesthesia and thus prevent diffusion hypoxia.
This noble gas is even less soluble than nitrous oxide (blood/gas partition coeffi-cient of 0.12) and about twice as potent (MAC = 56%). In addition, it appears to have no major depressant effects on the cardiovascular system. We do not know how it produces anesthesia, being a noble gas (we don’t really know how the other not so noble agents do it, either). Xenon would make a desirable anesthetic, were it not for its high cost (about $17/L). Xenon is currently not used in the USA and most studies of the gas come from abroad.
Anesthetic vapors exist as fluids at ambient conditions. They have low vapor pressures, and the vapors overlying the liquid phase have anesthetic properties. It all started with diethyl ether, the granddaddy of anesthetic vapors. Over the last 150 years, uncounted chemists have rearranged the structure of these substances and, by adding halogens, have developed a host of promising anesthetics. Each has distinctive vapor pressures, blood/gas partition coefficients, potencies (see Table 12.5), and side effects, e.g., upper airway irritation, bronchodilation, cardiac irritability.
With the arrival of the non-flammable agents, i.e., halothane (Fluothane®) and the halogenated ethers, we were able to retire from clinical use the highly flammable diethyl ether. Methoxyflurane (Metofane®) was abandoned because of its extensive biotransformation, which led to the liberation of enough fluoride ions to damage the kidneys, causing a vasopressin-resistant high output renal failure. The much less extensive biotransformation of enflurane (Ethrane®) and sevoflurane (Ultane®) also liberates fluoride ions but in such small concentra-tions that renal problems have not been a cause for concern. Initial worries over nephrotoxicity from sevoflurane’s degradation by CO2 absorbent in the anes-thesia circuit (forming the dreaded “Compound A,” also known as pentafluor-isoprenyl fluoromethyl) appears to lack clinical relevance (unless anesthetizing a rat).
So much for the halogenated ethers. Now to a different class, the halogenated aliphatic compounds, the ancestor of which, chloroform (HCCl3), dates back to 1847 when it was first shown to be an anesthetic. While neither irritating nor combustible (a big problem for diethyl ether), it eventually fell out of favor because of its propensity to cause arrhythmias and hepatic damage. A number of other halogenated aliphatic compounds came and went, until finally in the mid 1960s, halothane appeared and was soon widely used. It is still around, even though it had its lumps and bumps. It sensitizes the heart to arrhythmias triggered by catecholamines.
Soon after the introduction of halothane worrisome reports of “halothane hepati-tis” appeared. Fever, malaise, and evidence of liver damage as seen in the elevation of serum aminotransferases pointed to liver damage. Not the halothane molecule itself but the products of its biotransformation cause the trouble. Halothane falls prey to a reductive and an oxidative breakup, the former exaggerated in the pres-ence of hypoxemia, the latter in some patients causing an immune response that can set the stage for severe halothane hepatitis at a future exposure to halothane. Hepatitis after halothane anesthesia is rare (perhaps 1 in 30 000) and much rarer after the other halogenated anesthetics. The extent of biotransformation of the drug might play a role: halothane stands out with 20% to 46% of the agent under-going biotransformation as compared to isoflurane (0.2% to 2%) and desflurane (0.02%). The products of biotransformation of sevoflurane (2% to 5% metabo-lized) appear to cause no harm to the liver.
All anesthetic vapors affect consciousness and have analgesic effects. They depress ventilation, as judged by decreasing minute ventilation and increasing levels of arterial carbon dioxide, with increasing depth of anesthesia. A few words about generally subtle differences between these drugs:
The older halothane and the newer sevoflurane have established for themselves a special niche because they are less irritating to the upper airway than the others. Particularly in children, who abhor needle sticks (and whose veins are more easily cannulated when the child is asleep), anesthesia can be induced quite gently by inhalation of nitrous oxide/oxygen together with either one of these two drugs.
All volatile agents depress myocardial contractility and cause peripheral vasodi-latation. As long as baroreceptors function normally, heart rate will increase in response to hypotension. In deep anesthesia, this compensation will not suffice to prevent a drop in cardiac output. Here, halothane occupies an unusual position. It inhibits the baroreceptor; consequently, we see less tachycardia (even bradycar-dia in deeply anesthetized children) during halothane-induced hypotension and a greater drop in cardiac output than is true for the other agents at comparable levels of anesthesia. Another oddity regarding halothane anesthesia: otherwise well-tolerated levels of circulating catecholamines, whether injected or liberated by the body, trigger arrhythmias in the presence of halothane.
Under very deep anesthesia, ventilation stops, usually before the heart arrests. Thus, a respiratory arrest from an overdose with an inhalation anesthetic need not be fatal if discovered in time, and if ventilation of the (still perfused) lungs with oxygen can remove the volatile anesthetic.
In surgical anesthesia, spontaneous ventilation will still be maintained IF the patient was not given other drugs that depress ventilation – such as opiates – and IF the patient is not paralyzed by neuromuscular blocking drugs, so commonly used in order to relax striated muscles and thus ease the surgeon’s job.
In general, all halogenated inhalation anesthetics decrease minute ventilation by decreasing tidal volume. The compensatory increase in respiratory rate cannot prevent a respiratory acidosis (and hypoxemia when breathing room air) because any increase in respiratory rate increases the ventilation of dead space. Respir-atory depression and tachypnea are less pronounced with desflurane (Suprane®) and sevoflurane than with halothane, with isoflurane (Forane®) lying somewhere in between.
Under inhalation anesthesia, patients respond only sluggishly to rising arterial carbon dioxide levels (= respiratory depression). Even low concentrations of the inhalation agents also depress the chemoreceptor response to hypoxemia.
The inhalation anesthetics depress, in a dose-dependent manner, CNS function – as shown by clinical findings starting with a state of somnolence, during which the patient can still respond – to coma, in which external noxious (we do not call it “painful” as you have to be conscious to find something painful!) stimulation elicits no visible response. This sentence was carefully chosen, because invisible CNS responses are detectable by electroencephalography and evoked potentials; these persist long after motor responses have been abolished. Eventually, they too vanish in deep anesthesia. Halogenated inhalation agents tend to increase cerebral blood flow, which is not a desirable effect in patients at risk of brain swelling. In neurosurgical anesthesia, we rely greatly on intravenous techniques using the inhalation agents only in low doses and as adjuncts.
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