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Nitrous Oxide in Small Animal Practice
Symposium on Controversial Problems in Clinical Practice
Nitrous Oxide in Small Animal Practice P. H. Cribb,B.Sc., M.R.C.V.S.*
HISTORY Nitrous oxide was discovered in 1776 by Priestley, who described loss of consciousness following administration of the gas. In 1799, Humphrey Davy described the analgesic effects of nitrous oxide and experimented with its use on several animals and on himself. His efforts to have it used in surgical operations were unsuccessful. The pleasurable and thrilling sensations that occur with the inhalation of nitrous oxide, as described by Priestley himself, give some idea why the gas is occasionally abused by some people today. Indeed the first major use of nitrous oxide was for "laughing gas" parties in the 1840s, and it was after one such demonstration that Horace Wells, a dentist in Hartford, Connecticut, realized the possibilities of nitrous oxide for analgesia and had one of his own teeth extracted under the influence of the gas. Nitrous oxide has been the subject of controversy since it was first introduced as an anesthetic agent in man. Horace Wells became insane and committed suicide as a result of the dispute and legal battles over who should be given credit for the discovery of anesthesia Wells with nitrous oxide or Morton, Jackson, or Long with ether. Wells attempted to give the first demonstration of inhalation anesthesia in Massachusetts General Hospital in Boston in January 1845, and although details of the event vary, the result was a failure. Either sufficiently deep anesthesia was not obtained and the patient woke too early and in pain, or (the other version) the patient, a medical student, howled as a practical joke. Nitrous oxide was discredited and, with ether coming on the scene in 1846, it did not come into general use until the late 1860s, when it became used mainly in dentistry *Associate Professor; Chairman, Anesthesiology and Radiology, Department of Clinical Studies, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada
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(although some major surgical operations had been performed in i848 under nitrous oxide anesthesia). Not until 1868 was it discovered that the administration of oxygen together with nitrous oxide permitted longer periods of narcosis without danger of asphyxiation (anoxia). It was apparent that true anesthesia could not be achieved in man, or in animals, using nitrous oxide alone at normal atmospheric pressures. In 1879 Paul Bert discovered that anesthesia could be achieved in man by the inhalation of 15 per cent oxygen and 85 per cent nitrous oxide at 1.2 atmospheres pressure. Nitrous oxide again became the center of controversy when in 1927 Brown, et a!., working with rabbits and cats, were unable to duplicate the experiments. What was not realized then, and is still not properly appreciated by many, is that there is a definite species difference in reaction to nitrous oxide. In fact, in 1973 and 1974 conflicting results were still being produced from different laboratories on the suitability of nitrous oxide anesthesia, either alone or following ultrashort-acting barbiturates (e.g., thiamylal, methohexital), for cats. In 1974 a controlled experiment was carried out by Steffey, et al., 4 which showed that 7 5 per cent nitrous oxide alone could not produce significant anesthesia in dogs and cats and that it only lowered the requirements of halothane by about 33 per cent, in contrast to man, in whom halothane and methoxyflurane requirements are lowered by 75 per cent.
EFFECTS ON CARDIOVASCULAR SYSTEM There has been much debate on the effects of nitrous oxide on the cardiovascular system, both in man and in animals, and, since conditions for different experiments vary so much, it is very difficult at times to make a true comparison of results. Anesthesia may have been induced with a barbiturate or an inhalant anesthetic or a neuroleptic agent; preanesthetic medication may or may not have been given; anesthesia may have been maintained with an inhalation or injectable agent, or the animal may have been restrained only with a muscle relaxant; measurements may have been made at varying periods of time after induction; total gas flows into the anesthetic system may have varied. The picture may be different in clinical practice, where parasympatholytic drugs (atropine), plus phenothiazine derivatives (tranquilizers) and/or narcotics (meperidine, morphine) or other agents, are commonly used prior to induction with a thiobarbiturate or other agent. It appears, however, that at light levels of anesthesia, nitrous oxide has minimal effects on the cardiovascular system when used in conjunction with other agents. At deep levels of anesthesia
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with spontaneous ventilation, there may be cardiovascular stimulation owing to hypoxemia, hypercapnia, acidosis, and sympathetic stimulation. It appears obvious that, as with any other agent, the lighter the anesthetic plane consistent with the surgical procedure, the better. Also, much less insult to the patient's normal physiological functions will occur if the lungs are expanded periodically, two to three times every three minutes, or more frequently ("sighing"), to assist in the elimination of carbon dioxide and the prevention of atelectasis. This, of course, suggests that the patient is better off with an anesthetist, rather than merely being attached to a machine.
EFFECTS ON RESPIRATORY SYSTEM Nitrous oxide has minimal effect on the respiratory system, although, as has been implied in the preceding paragraph, there may be some depression of the response of the respiratory center to carbon dioxide when nitrous oxide is combined with other agents, particularly at deeper planes of anesthesia. Again, the lighter the anesthetic, the better. One of the earlier theories concerning nitrous oxide was that the molecule could be split in the body into nitrogen and oxygen, and that the oxygen would be available for metabolism. Although at high temperatures (induced by a spark or naked flame) the molecule will split and thus support combustion, this does not occur at body temperature, and oxygen must be administered along with the nitrous oxide to avoid hypoxia. The difficulty that arises is that nitrous oxide is often administered in too high a concentration, in order to achieve maximum analgesia. It is unwise to administer nitrous oxide at more than 75 per cent concentration, with oxygen at 25 per cent. Indeed, even at this level, in dogs with spontaneous ventilation it has been shown that low arterial pressures of oxygen may occur, although with controlled ventilation high arterial oxygen levels are maintained. The use of 66.6 per cent nitrous oxide and 33.3 per cent oxygen in our clinic, with various complementary agents, has resulted in arterial blood levels of oxygen consistently over 100 mm of Hg in dogs. Similar results have been obtained using 67 per cent nitrous oxide together with fentanyl-droperidol in dogs by Krakwinkel, et al. 3
EFFECTS ON MUSCLES AND THE GASTROINTESTINAL TRACT Nitrous oxide does not produce muscle relaxation in man when used without other agents; however, in dogs under the influence of
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fentanyl-droperidol, the administration of nitrous oxide causes muscle relaxation (and reduces the response to auditory stimuli). There appears to be little, if any effect on the gastrointestinal tract.
OVEREXPOSURE Exposure to nitrous oxide for a period of over 24 hours may cause depression of bone marrow function. It has also been determined that such long exposures may be teratogenic. The length of exposure time required for such effects to develop makes this more of an academic problem than a practical problem for the patient and anesthetist. What may be of note is that the higher gas flows necessary with nitrous oxide will vaporize more of the potent inhalation agents and release them into the room if adequate exhaust facilities are not available. This again is unlikely to be of major importance in the average veterinary practice, since time exposures are generally short, but may be of consideration in the large practice, where operating room personnel such as anesthesia technicians are consistently exposed to anesthetic gases.*
OXYGEN AND NITROUS OXIDE DOSAGES High flows should be used during induction and the first 15 minutes of anesthesia to ensure rapid denitrogenation and to supply a constant concentration of nitrous oxide for the rapid uptake that occurs at the beginning of the period. In the absence of monitoring equipment to determine the concentration of oxygen in the circle system, or the partial pressure of oxygen in the blood of the patient, it is necessary to maintain fairly high flows into the circle to assure adequate oxygenation. A minimum volume of two to three times the metabolic demand of oxygen should flow into the circuit, and this means a flow of between 25 and 35 ml per kg per minute for a dog under anesthesia. Thus, an average 15 kg dog would require a total gas flow of between 1125 to 1575 ml per minute, 375 to 525 ml per minute of oxygen and 750 to 1050 ml per minute of nitrous oxide. These are much higher total flows than would be required in an almost totally closed circle system using oxygen alone as the carrier gas. With a nonrebreathing system used on a cat or small dog, the flows into the system are usually set between one and two times the respiratory minute volume to prevent rebreathing, depending on the system. Thus, a 5 kg animal would require a flow of about 1.5 L per minute of oxy*See Pollution Control in the Operating Room in this issue.
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gen, which is far above the animal's metabolic needs. A fresh gas flow of 1 L per minute of nitrous oxide plus 0.5 L per minute of oxygen could easily be substituted and still supply far above the metabolic requirements.
SOLUBILITY AND DIFFUSIBILITY Two of the most important properties of nitrous oxide are its low solubility combined with its high diffusibility. These properties are responsible for two of the major advantages of nitrous oxide, rapid induction and recovery, and two of its major disadvantages, postanesthesia diffusion hypoxia and an increase in volume or pressure of trapped air spaces in the body. Nitrous oxide is absorbed extremely rapidly from the alveoli during induction, so rapidly in fact that there has to be a net increase in tidal volume to replace the large volumes of gas absorbed. This rapid uptake of a relatively insoluble gas means that anesthetic induction is extremely rapid as the gas is transferred to the tissues (brain), and it also leads to the more rapid intake of any gases administered with it. A net increase of 10 per cent in the volume of halothane absorbed has been recorded in the first five minutes of induction of anesthesia in dogs when 75 per cent nitrous oxide is used as the carrier gas compared with 10 per cent nitrous oxide as the carrier gas. However, in the practical sense, this "concentration" or "second gas" effect is of minor importance. Nitrogen is less soluble than nitrous oxide and it also diffuses much more slowly through the cells. Thus, the volume of nitrogen excreted via the lungs is only about 3 per cent of the volume of nitrous oxide absorbed over a short period of time. This is of minor importance in most cases, but creates a potentially dangerous situation where there are closed pockets of gas in the body, such as in pneumothorax or torsion of the bowel. In dogs anesthetized with 75 per cent nitrous oxide, the volume of a closed intrapleural gas space doubled in 10 minutes and trebled in 45 minutes. The potential thus exists for severe effects on the ventilation and circulation. It must be realized that this potential only exists with a closed pneumothorax, and that once the thorax is open, the problem no longer exists. Administration of general anesthesia to patients with tension pneumothorax before the pressure has been relieved either by paracentesis or by insertion of a chest drain under local anesthesia is contraindicated. There is a reverse movement of gases at the termination of anesthesia, and it may be that the rapid excretion of nitrous oxide from the air spaces will reduce any pneumothorax remaining after closure of the chest more quickly than would occur if the animal were on another inhalant anesthetic with oxygen as the carrier gas.
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GASTROINTESTINAL TRACT GAS
It has been shown in dogs 2 that the volume of gastrointestinal gas doubles after two hours of nitrous oxide (70 to 80 per cent) anesthesia administration. These gases normally present in the bowel, such as hydrogen and methane, are even less soluble in blood than nitrogen. The increase in volume is relatively slow, and probably nitrous oxide could be used during induction and discontinued after the first 15 to 20 minutes. There seems little point in this, and it is recommended that in those cases in which potential problems exist, nitrous oxide not be used. In particular, nitrous oxide should not be used in cases of gastric dilatation, gastric torsion, or volvulus. In all cases in which distention of the bowel is observed during nitrous oxide anesthesia, the nitrous oxide should be discontinued.
ECONOMICS One of the major selling points made by supporters of nitrous oxide in the past has been that it is economical to use, since it results in a saving of more potent anesthetic agents, which are more costly than the nitrous oxide. This is much more applicable in human than in veterinary science. There are many variables to be taken into account when trying to make cost comparisons: the prices of various agents, the price of the additional fixtures for an anesthetic machine to allow nitrous oxide to be used, and the cost of installing pipelines if a central distribution facility is to be installed in the hospital. Whether the gases, nitrous oxide and oxygen, are bought in small or large cylinders has a great bearing on the cost. In a practice in which very low flows of oxygen are used in a circle system, the addition of nitrous oxide and the consequent increase in total gas flow will cause an increase in cost. If halothane or methoxyflurane are used as coagents, then the increased gas flow will vaporize, in total, more of the anesthetic agent, despite its being at a lesser concentration. The cost will thus be increased. However, in nonrebreathing systems in which total gas flows are already high in order to prevent rebreathing, the nitrous oxide may substitute for some of the oxygen and still supply sufficient oxygen for the animal's metabolic needs. In this case, much will depend on the cost of the nitrous oxide in comparison with the cost of oxygen and the cost of halothane and methoxyflurane. However, in general a saving will result. Our figures show that the use of high flows of nitrous oxide and oxygen into a circle system with halothane or methoxyflurane may increase running costs by as much as 200 per cent, but this cost is still less than two dollars per hour and it is relatively insignificant in comparison with other costs. Cohen 1 has pub-
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lished costs from the use of nitrous oxide. For anyone looking for savings on anesthetics, it is apparent that, provided use is fairly high, more can be saved by purchasing oxygen in large cylinders (H) than by adding nitrous oxide in small cylinders (E) to the system.
CLINICAL USE OF NITROUS OXIDE In many minor surgical procedures in man, such as dentistry, analgesia is all that is required because the patient is cooperative, and the use of nitrous oxide as the sole anesthetic agent is suitable. In animals, where restraint is required in addition to analgesia, nitrous oxide would probably not be suitable even if it were equipotent in man and animal. The use of nitrous oxide for the extremely ill and the shock patient is debatable. Such animals require little if any restraint, and the least insult to the body that it is possible to give in the way of anesthetic agents is advisable. In this case nitrous oxide is ideal, with its analgesic effects and its minimal effects on the cardiovascular system. However, shock patients also require high levels of oxygen, and it is possible that the administration of only 33.3 per cent oxygen may be detrimental to the patient if ventilation is spontaneous and there is no way in which it can be assisted or controlled. In such cases it is probably best to use at least 50 per cent oxygen, together with low concentrations of halothane if needed. Where facilities exist for assisted or controlled ventilation, they should be initiated, together with muscle relaxants if required, and in these cases it is still probably advantageous to increase the oxygen concentration to 40 per cent (nitrous oxide 60 per cent).
MASK INDUCTION IN THE CAT
Nitrous oxide is very useful as an aid to mask induction of anesthesia, particularly in the cat. Induct~on in the cat often takes place as a struggle, with high concentrations of halothane being administered, the philosophy being that with struggling there is an increase in ventilation, more halothane is inhaled, and induction is rapid. With this technique, respiratory arrest is not uncommon, and the combination of high concentrations of halothane and high levels of circulating epinephrine (part of the .fear response) can cause the production of cardiac arrhythmias and possibly cardiac arrest and death. To avoid this problem, induction should be smooth and gentle. Admittedly, some cats are difficult to handle, but with suitable premedication and a quiet approach, the animal can be quietly restrained, the mask applied gently to the face, and nitrous oxide and oxygen administered (3 L :
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1.5 L) using a nonrebreathing system. After two to three minutes the cat will be mildly sedated and the halothane vaporizer can be turned on at 0.5 per cent. The concentration should be gradually increased in incremental depths of 0.5 per cent every five to l 0 breaths, to a maximum of 3 per cent. It is rarely necessary to go to a higher concentration. In three or four minutes it is possible to spray the larynx with a local anesthetic and intubate the cat. A similar technique, without the local anesthetic spray, may be used in the dog.
NEUROLEPTANESTHESIA The phrasing used when discussing nitrous oxide often betrays a prejudice and also influences the way in which the listener or reader thinks about the gas. Many people talk about nitrous oxide being a good agent to supplement another anesthetic, thus automatically relegating it to a minor role, while others talk of the use of sedatives, narcotics, or inhalational anesthetics to supplement one or the other functions of nitrous oxide, assigning to nitrous oxide the role of the major agent. We should, rather, talk of coagents or of a technique rather than trying to assign a major or minor role to complementary agents. Thus, although the word is not the most elegant, to speak of "neuroleptanesthesia" is preferable to "neuroleptanalgesia supplemented with nitrous oxide," "nitrous oxide supplemented with neuroleptanalgesics", or "nitrous oxide supplemented with narcotics and tranquilizers." The properties of nitrous oxide in producing analgesia and mild sedation together with minimal effects on the cardiovascular and respiratory systems are employed most usefully in the technique of neuroleptanesthesia in dogs. This anesthetic procedure has proven particularly useful in dogs with cardiac disease, since it has minimal effects on the cardiovascular system. The drugs used are nitrous oxide and a neuroleptanalgesic, most commonly fentanyl-droperidol (Innovar-Vet), although morphine-promazine (l to 2 mg per kg of each) may be used. Fentanyl-droperidol anesthesia may be induced using either the intramuscular or intravenous routes or a combination of both, following premedication with atropine. Variable results are obtained by the use of the intramuscular route alone, and it is probably best to use light doses only as a premedicant except with very fractious dogs. The injection of fentanyl-droperidol as a bolus intravenously is suitable for reasonably healthy dogs, but here again some variability may be expected. For the dog with cardiovascular disease, the smoothest induction is obtained when the fentanyl-droperidol is injected slowly over a period of several minutes. A dilution of 3 ml fentanyl-droperidol in 100 ml of Ringers or saline solution is a very
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satisfactory solution administered via a microdrip administration set and an intravenous catheter. As the animal becomes sedated, oxygen may be administered by face mask, and this helps to avoid problems that may arise because of respiratory depression. Animals may be intubated at quite a light plane of anesthesia if the pharyngeal and laryngeal regions are sprayed by xylocaine endotracheal aerosol (or swabbed with a pledget of cotton soaked in plain xylocaine). If this procedure is not followed, then deeper anesthesia will be required prior to intubation, either by giving more fentanyl-droperidol or by substituting nitrous oxide-oxygen for the oxygen. Maximum effect of intravenous fentanyl-droperidol occurs about three minutes postinjection, and the maximum initial dose is 1 ml per 12 kg. After intubation the administered gas should be nitrous oxide and oxygen, 2:1. The lungs are inflated two or three times by pressure on the reservoir bag in order to obtain a swift turnover of gases in the lungs and to ensure a rapid build-up of nitrous oxide in the body. If a circle system is used, the circuit should be flushed two or three times in the first 15 minutes to maintain a level of 66 per cent nitrous oxide. It is advisable to expand the lungs (sighing) two or three times every two or three minutes. Using nitrous oxide (66 per cent) and oxygen, together with the fentanyl-droperidol, produces better muscle relaxation and decreases the response to auditory stimuli seen with fentanyl-droperidol alone. If anesthesia becomes light, further doses of fentanyl-droperidol may be given. Signs of lightening anesthesia include dilation of the pupils and rotation of the eyeball downward in the orbit. The usual regimen is to give approximately one-fourth of the initial induction dose intravenously. This will generally be effective for 10 to 20 minutes. One should generally not give more than a total equal to the original dose in prolonging the anesthetic period. The use of fentanyl alone (Sublimaze) has much to recommend it as the additional dose; however, it is a preparation for human use (0.05 mg per ml in 2 ml vials) and is comparatively more expensive than the fentanyl (0.4 mg per ml) in the fentanyl-droperidol mixture. The use of Sublimaze avoids the hypotensive effects of droperidol and leads to a faster recovery. Since the effects of intravenous fentanyl last for only about 20 minutes, it is rarely necessary with this technique to give an antagonist to reverse its action. Assisted or controlled ventilation prolongs the anesthetic period slightly and gives a smoother anesthetic.
SUMMARY Nitrous oxide has a definite role to play in veterinary anesthesia, but the limitations of its use must be understood, and it must be correctly administered, as must any other drug, if benefit is to be ob-
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tained from its use. It is just one more agent in the anesthetist's armamentarium, and it has advantages and disadvantages as does any other. Although there are dangers of low arterial oxygen levels using 75 per cent nitrous oxide and spontaneous ventilation, problems are unlikely to arise in the normal, relatively healthy animal anesthetized for routine elective surgery and for procedures such as orthopedic surgery on long bones, provided that the concentration of nitrous oxide is limited to 67 per cent with oxygen. In cases in which the respirations may be embarrassed owing to positioning, e.g., head down tilt for perineal surgery, nitrous oxide should not be used unless there is provision for assisting or controlling ventilation (i.e., an anesthetist is needed). Flows into circle systems must be high enough to ensure that there is sufficient oxygen supplied to the patient. Nitrous oxide should not be used in patients with bowel stasis or other closed gas spaces in the body, such as closed pneumothorax, pneumomediastinum, or pneumoperitoneum. It is safe to use in open pneumothorax. One other danger that does exist with the use of nitrous oxide is that if the flowmeter controls are accidentally moved, or if the oxygen supply runs out, there is still gas volume being supplied to the patient, so that signs of respiratory distress do not appear until the animal becomes cyanotic or has a cardiac arrest. Care must be taken to continuously monitor all aspects of the anesthetic, including the gas supply. In shock cases nitrous oxide should not be used in higher than 60 per cent concentration, and where spontaneous ventilation is employed consideration should be given to discontinuing its use entirely for such patients. Nitrous oxide allows smooth mask induction of small animal patients with rapid recovery from anesthesia. Combined with fentanyldroperidol in neuroleptanesthesia it is a good anesthetic with good cardiovascular stability for the canine patient with cardiac disease. Nitrous oxide appears compatible with all other anesthetic agents and may often be used to advantage when anesthesia is too light, a prolongation of the anesthetic period is required, and one does not wish to administer any more of the primary agent, e.g., with ketamine hydrochloride in the cat.
REFERENCES l. Cohen, C.A.: The economics of veterinary anesthesia. Vet. Economics, 16:22, 1975. 2. Eger, E.I., and Saidman, L.J.: Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology, 26:61, 1965. 3. Krakwinkel, D.J., Sawyer, D.C., Eyster, G.E., et al.: Cardiopulmonary effects of fentanyl-droperidol, nitrous oxide and atropine sulfate in dogs. Am. J. Vet. Res. 36:1211, 1975.
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4. Steffey, E.P., Gillespie, J.R., Berry, J.D., et al.: Anesthetic potency (MAC) of nitrous oxide in the dog, cat and stump-tail monkey.]. Appl. Physiol. 36:530, 1974. Department of Veterinary Clinical Studies Western College of Veterinary Medicine University of Saskatchewan Saskatoon, Saskatchewan Canada S7N OWO
Nitrous Oxide in Small Animal Practice P. H. Cribb,B.Sc., M.R.C.V.S.*
HISTORY Nitrous oxide was discovered in 1776 by Priestley, who described loss of consciousness following administration of the gas. In 1799, Humphrey Davy described the analgesic effects of nitrous oxide and experimented with its use on several animals and on himself. His efforts to have it used in surgical operations were unsuccessful. The pleasurable and thrilling sensations that occur with the inhalation of nitrous oxide, as described by Priestley himself, give some idea why the gas is occasionally abused by some people today. Indeed the first major use of nitrous oxide was for "laughing gas" parties in the 1840s, and it was after one such demonstration that Horace Wells, a dentist in Hartford, Connecticut, realized the possibilities of nitrous oxide for analgesia and had one of his own teeth extracted under the influence of the gas. Nitrous oxide has been the subject of controversy since it was first introduced as an anesthetic agent in man. Horace Wells became insane and committed suicide as a result of the dispute and legal battles over who should be given credit for the discovery of anesthesia Wells with nitrous oxide or Morton, Jackson, or Long with ether. Wells attempted to give the first demonstration of inhalation anesthesia in Massachusetts General Hospital in Boston in January 1845, and although details of the event vary, the result was a failure. Either sufficiently deep anesthesia was not obtained and the patient woke too early and in pain, or (the other version) the patient, a medical student, howled as a practical joke. Nitrous oxide was discredited and, with ether coming on the scene in 1846, it did not come into general use until the late 1860s, when it became used mainly in dentistry *Associate Professor; Chairman, Anesthesiology and Radiology, Department of Clinical Studies, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada
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(although some major surgical operations had been performed in i848 under nitrous oxide anesthesia). Not until 1868 was it discovered that the administration of oxygen together with nitrous oxide permitted longer periods of narcosis without danger of asphyxiation (anoxia). It was apparent that true anesthesia could not be achieved in man, or in animals, using nitrous oxide alone at normal atmospheric pressures. In 1879 Paul Bert discovered that anesthesia could be achieved in man by the inhalation of 15 per cent oxygen and 85 per cent nitrous oxide at 1.2 atmospheres pressure. Nitrous oxide again became the center of controversy when in 1927 Brown, et a!., working with rabbits and cats, were unable to duplicate the experiments. What was not realized then, and is still not properly appreciated by many, is that there is a definite species difference in reaction to nitrous oxide. In fact, in 1973 and 1974 conflicting results were still being produced from different laboratories on the suitability of nitrous oxide anesthesia, either alone or following ultrashort-acting barbiturates (e.g., thiamylal, methohexital), for cats. In 1974 a controlled experiment was carried out by Steffey, et al., 4 which showed that 7 5 per cent nitrous oxide alone could not produce significant anesthesia in dogs and cats and that it only lowered the requirements of halothane by about 33 per cent, in contrast to man, in whom halothane and methoxyflurane requirements are lowered by 75 per cent.
EFFECTS ON CARDIOVASCULAR SYSTEM There has been much debate on the effects of nitrous oxide on the cardiovascular system, both in man and in animals, and, since conditions for different experiments vary so much, it is very difficult at times to make a true comparison of results. Anesthesia may have been induced with a barbiturate or an inhalant anesthetic or a neuroleptic agent; preanesthetic medication may or may not have been given; anesthesia may have been maintained with an inhalation or injectable agent, or the animal may have been restrained only with a muscle relaxant; measurements may have been made at varying periods of time after induction; total gas flows into the anesthetic system may have varied. The picture may be different in clinical practice, where parasympatholytic drugs (atropine), plus phenothiazine derivatives (tranquilizers) and/or narcotics (meperidine, morphine) or other agents, are commonly used prior to induction with a thiobarbiturate or other agent. It appears, however, that at light levels of anesthesia, nitrous oxide has minimal effects on the cardiovascular system when used in conjunction with other agents. At deep levels of anesthesia
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with spontaneous ventilation, there may be cardiovascular stimulation owing to hypoxemia, hypercapnia, acidosis, and sympathetic stimulation. It appears obvious that, as with any other agent, the lighter the anesthetic plane consistent with the surgical procedure, the better. Also, much less insult to the patient's normal physiological functions will occur if the lungs are expanded periodically, two to three times every three minutes, or more frequently ("sighing"), to assist in the elimination of carbon dioxide and the prevention of atelectasis. This, of course, suggests that the patient is better off with an anesthetist, rather than merely being attached to a machine.
EFFECTS ON RESPIRATORY SYSTEM Nitrous oxide has minimal effect on the respiratory system, although, as has been implied in the preceding paragraph, there may be some depression of the response of the respiratory center to carbon dioxide when nitrous oxide is combined with other agents, particularly at deeper planes of anesthesia. Again, the lighter the anesthetic, the better. One of the earlier theories concerning nitrous oxide was that the molecule could be split in the body into nitrogen and oxygen, and that the oxygen would be available for metabolism. Although at high temperatures (induced by a spark or naked flame) the molecule will split and thus support combustion, this does not occur at body temperature, and oxygen must be administered along with the nitrous oxide to avoid hypoxia. The difficulty that arises is that nitrous oxide is often administered in too high a concentration, in order to achieve maximum analgesia. It is unwise to administer nitrous oxide at more than 75 per cent concentration, with oxygen at 25 per cent. Indeed, even at this level, in dogs with spontaneous ventilation it has been shown that low arterial pressures of oxygen may occur, although with controlled ventilation high arterial oxygen levels are maintained. The use of 66.6 per cent nitrous oxide and 33.3 per cent oxygen in our clinic, with various complementary agents, has resulted in arterial blood levels of oxygen consistently over 100 mm of Hg in dogs. Similar results have been obtained using 67 per cent nitrous oxide together with fentanyl-droperidol in dogs by Krakwinkel, et al. 3
EFFECTS ON MUSCLES AND THE GASTROINTESTINAL TRACT Nitrous oxide does not produce muscle relaxation in man when used without other agents; however, in dogs under the influence of
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fentanyl-droperidol, the administration of nitrous oxide causes muscle relaxation (and reduces the response to auditory stimuli). There appears to be little, if any effect on the gastrointestinal tract.
OVEREXPOSURE Exposure to nitrous oxide for a period of over 24 hours may cause depression of bone marrow function. It has also been determined that such long exposures may be teratogenic. The length of exposure time required for such effects to develop makes this more of an academic problem than a practical problem for the patient and anesthetist. What may be of note is that the higher gas flows necessary with nitrous oxide will vaporize more of the potent inhalation agents and release them into the room if adequate exhaust facilities are not available. This again is unlikely to be of major importance in the average veterinary practice, since time exposures are generally short, but may be of consideration in the large practice, where operating room personnel such as anesthesia technicians are consistently exposed to anesthetic gases.*
OXYGEN AND NITROUS OXIDE DOSAGES High flows should be used during induction and the first 15 minutes of anesthesia to ensure rapid denitrogenation and to supply a constant concentration of nitrous oxide for the rapid uptake that occurs at the beginning of the period. In the absence of monitoring equipment to determine the concentration of oxygen in the circle system, or the partial pressure of oxygen in the blood of the patient, it is necessary to maintain fairly high flows into the circle to assure adequate oxygenation. A minimum volume of two to three times the metabolic demand of oxygen should flow into the circuit, and this means a flow of between 25 and 35 ml per kg per minute for a dog under anesthesia. Thus, an average 15 kg dog would require a total gas flow of between 1125 to 1575 ml per minute, 375 to 525 ml per minute of oxygen and 750 to 1050 ml per minute of nitrous oxide. These are much higher total flows than would be required in an almost totally closed circle system using oxygen alone as the carrier gas. With a nonrebreathing system used on a cat or small dog, the flows into the system are usually set between one and two times the respiratory minute volume to prevent rebreathing, depending on the system. Thus, a 5 kg animal would require a flow of about 1.5 L per minute of oxy*See Pollution Control in the Operating Room in this issue.
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gen, which is far above the animal's metabolic needs. A fresh gas flow of 1 L per minute of nitrous oxide plus 0.5 L per minute of oxygen could easily be substituted and still supply far above the metabolic requirements.
SOLUBILITY AND DIFFUSIBILITY Two of the most important properties of nitrous oxide are its low solubility combined with its high diffusibility. These properties are responsible for two of the major advantages of nitrous oxide, rapid induction and recovery, and two of its major disadvantages, postanesthesia diffusion hypoxia and an increase in volume or pressure of trapped air spaces in the body. Nitrous oxide is absorbed extremely rapidly from the alveoli during induction, so rapidly in fact that there has to be a net increase in tidal volume to replace the large volumes of gas absorbed. This rapid uptake of a relatively insoluble gas means that anesthetic induction is extremely rapid as the gas is transferred to the tissues (brain), and it also leads to the more rapid intake of any gases administered with it. A net increase of 10 per cent in the volume of halothane absorbed has been recorded in the first five minutes of induction of anesthesia in dogs when 75 per cent nitrous oxide is used as the carrier gas compared with 10 per cent nitrous oxide as the carrier gas. However, in the practical sense, this "concentration" or "second gas" effect is of minor importance. Nitrogen is less soluble than nitrous oxide and it also diffuses much more slowly through the cells. Thus, the volume of nitrogen excreted via the lungs is only about 3 per cent of the volume of nitrous oxide absorbed over a short period of time. This is of minor importance in most cases, but creates a potentially dangerous situation where there are closed pockets of gas in the body, such as in pneumothorax or torsion of the bowel. In dogs anesthetized with 75 per cent nitrous oxide, the volume of a closed intrapleural gas space doubled in 10 minutes and trebled in 45 minutes. The potential thus exists for severe effects on the ventilation and circulation. It must be realized that this potential only exists with a closed pneumothorax, and that once the thorax is open, the problem no longer exists. Administration of general anesthesia to patients with tension pneumothorax before the pressure has been relieved either by paracentesis or by insertion of a chest drain under local anesthesia is contraindicated. There is a reverse movement of gases at the termination of anesthesia, and it may be that the rapid excretion of nitrous oxide from the air spaces will reduce any pneumothorax remaining after closure of the chest more quickly than would occur if the animal were on another inhalant anesthetic with oxygen as the carrier gas.
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GASTROINTESTINAL TRACT GAS
It has been shown in dogs 2 that the volume of gastrointestinal gas doubles after two hours of nitrous oxide (70 to 80 per cent) anesthesia administration. These gases normally present in the bowel, such as hydrogen and methane, are even less soluble in blood than nitrogen. The increase in volume is relatively slow, and probably nitrous oxide could be used during induction and discontinued after the first 15 to 20 minutes. There seems little point in this, and it is recommended that in those cases in which potential problems exist, nitrous oxide not be used. In particular, nitrous oxide should not be used in cases of gastric dilatation, gastric torsion, or volvulus. In all cases in which distention of the bowel is observed during nitrous oxide anesthesia, the nitrous oxide should be discontinued.
ECONOMICS One of the major selling points made by supporters of nitrous oxide in the past has been that it is economical to use, since it results in a saving of more potent anesthetic agents, which are more costly than the nitrous oxide. This is much more applicable in human than in veterinary science. There are many variables to be taken into account when trying to make cost comparisons: the prices of various agents, the price of the additional fixtures for an anesthetic machine to allow nitrous oxide to be used, and the cost of installing pipelines if a central distribution facility is to be installed in the hospital. Whether the gases, nitrous oxide and oxygen, are bought in small or large cylinders has a great bearing on the cost. In a practice in which very low flows of oxygen are used in a circle system, the addition of nitrous oxide and the consequent increase in total gas flow will cause an increase in cost. If halothane or methoxyflurane are used as coagents, then the increased gas flow will vaporize, in total, more of the anesthetic agent, despite its being at a lesser concentration. The cost will thus be increased. However, in nonrebreathing systems in which total gas flows are already high in order to prevent rebreathing, the nitrous oxide may substitute for some of the oxygen and still supply sufficient oxygen for the animal's metabolic needs. In this case, much will depend on the cost of the nitrous oxide in comparison with the cost of oxygen and the cost of halothane and methoxyflurane. However, in general a saving will result. Our figures show that the use of high flows of nitrous oxide and oxygen into a circle system with halothane or methoxyflurane may increase running costs by as much as 200 per cent, but this cost is still less than two dollars per hour and it is relatively insignificant in comparison with other costs. Cohen 1 has pub-
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lished costs from the use of nitrous oxide. For anyone looking for savings on anesthetics, it is apparent that, provided use is fairly high, more can be saved by purchasing oxygen in large cylinders (H) than by adding nitrous oxide in small cylinders (E) to the system.
CLINICAL USE OF NITROUS OXIDE In many minor surgical procedures in man, such as dentistry, analgesia is all that is required because the patient is cooperative, and the use of nitrous oxide as the sole anesthetic agent is suitable. In animals, where restraint is required in addition to analgesia, nitrous oxide would probably not be suitable even if it were equipotent in man and animal. The use of nitrous oxide for the extremely ill and the shock patient is debatable. Such animals require little if any restraint, and the least insult to the body that it is possible to give in the way of anesthetic agents is advisable. In this case nitrous oxide is ideal, with its analgesic effects and its minimal effects on the cardiovascular system. However, shock patients also require high levels of oxygen, and it is possible that the administration of only 33.3 per cent oxygen may be detrimental to the patient if ventilation is spontaneous and there is no way in which it can be assisted or controlled. In such cases it is probably best to use at least 50 per cent oxygen, together with low concentrations of halothane if needed. Where facilities exist for assisted or controlled ventilation, they should be initiated, together with muscle relaxants if required, and in these cases it is still probably advantageous to increase the oxygen concentration to 40 per cent (nitrous oxide 60 per cent).
MASK INDUCTION IN THE CAT
Nitrous oxide is very useful as an aid to mask induction of anesthesia, particularly in the cat. Induct~on in the cat often takes place as a struggle, with high concentrations of halothane being administered, the philosophy being that with struggling there is an increase in ventilation, more halothane is inhaled, and induction is rapid. With this technique, respiratory arrest is not uncommon, and the combination of high concentrations of halothane and high levels of circulating epinephrine (part of the .fear response) can cause the production of cardiac arrhythmias and possibly cardiac arrest and death. To avoid this problem, induction should be smooth and gentle. Admittedly, some cats are difficult to handle, but with suitable premedication and a quiet approach, the animal can be quietly restrained, the mask applied gently to the face, and nitrous oxide and oxygen administered (3 L :
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1.5 L) using a nonrebreathing system. After two to three minutes the cat will be mildly sedated and the halothane vaporizer can be turned on at 0.5 per cent. The concentration should be gradually increased in incremental depths of 0.5 per cent every five to l 0 breaths, to a maximum of 3 per cent. It is rarely necessary to go to a higher concentration. In three or four minutes it is possible to spray the larynx with a local anesthetic and intubate the cat. A similar technique, without the local anesthetic spray, may be used in the dog.
NEUROLEPTANESTHESIA The phrasing used when discussing nitrous oxide often betrays a prejudice and also influences the way in which the listener or reader thinks about the gas. Many people talk about nitrous oxide being a good agent to supplement another anesthetic, thus automatically relegating it to a minor role, while others talk of the use of sedatives, narcotics, or inhalational anesthetics to supplement one or the other functions of nitrous oxide, assigning to nitrous oxide the role of the major agent. We should, rather, talk of coagents or of a technique rather than trying to assign a major or minor role to complementary agents. Thus, although the word is not the most elegant, to speak of "neuroleptanesthesia" is preferable to "neuroleptanalgesia supplemented with nitrous oxide," "nitrous oxide supplemented with neuroleptanalgesics", or "nitrous oxide supplemented with narcotics and tranquilizers." The properties of nitrous oxide in producing analgesia and mild sedation together with minimal effects on the cardiovascular and respiratory systems are employed most usefully in the technique of neuroleptanesthesia in dogs. This anesthetic procedure has proven particularly useful in dogs with cardiac disease, since it has minimal effects on the cardiovascular system. The drugs used are nitrous oxide and a neuroleptanalgesic, most commonly fentanyl-droperidol (Innovar-Vet), although morphine-promazine (l to 2 mg per kg of each) may be used. Fentanyl-droperidol anesthesia may be induced using either the intramuscular or intravenous routes or a combination of both, following premedication with atropine. Variable results are obtained by the use of the intramuscular route alone, and it is probably best to use light doses only as a premedicant except with very fractious dogs. The injection of fentanyl-droperidol as a bolus intravenously is suitable for reasonably healthy dogs, but here again some variability may be expected. For the dog with cardiovascular disease, the smoothest induction is obtained when the fentanyl-droperidol is injected slowly over a period of several minutes. A dilution of 3 ml fentanyl-droperidol in 100 ml of Ringers or saline solution is a very
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satisfactory solution administered via a microdrip administration set and an intravenous catheter. As the animal becomes sedated, oxygen may be administered by face mask, and this helps to avoid problems that may arise because of respiratory depression. Animals may be intubated at quite a light plane of anesthesia if the pharyngeal and laryngeal regions are sprayed by xylocaine endotracheal aerosol (or swabbed with a pledget of cotton soaked in plain xylocaine). If this procedure is not followed, then deeper anesthesia will be required prior to intubation, either by giving more fentanyl-droperidol or by substituting nitrous oxide-oxygen for the oxygen. Maximum effect of intravenous fentanyl-droperidol occurs about three minutes postinjection, and the maximum initial dose is 1 ml per 12 kg. After intubation the administered gas should be nitrous oxide and oxygen, 2:1. The lungs are inflated two or three times by pressure on the reservoir bag in order to obtain a swift turnover of gases in the lungs and to ensure a rapid build-up of nitrous oxide in the body. If a circle system is used, the circuit should be flushed two or three times in the first 15 minutes to maintain a level of 66 per cent nitrous oxide. It is advisable to expand the lungs (sighing) two or three times every two or three minutes. Using nitrous oxide (66 per cent) and oxygen, together with the fentanyl-droperidol, produces better muscle relaxation and decreases the response to auditory stimuli seen with fentanyl-droperidol alone. If anesthesia becomes light, further doses of fentanyl-droperidol may be given. Signs of lightening anesthesia include dilation of the pupils and rotation of the eyeball downward in the orbit. The usual regimen is to give approximately one-fourth of the initial induction dose intravenously. This will generally be effective for 10 to 20 minutes. One should generally not give more than a total equal to the original dose in prolonging the anesthetic period. The use of fentanyl alone (Sublimaze) has much to recommend it as the additional dose; however, it is a preparation for human use (0.05 mg per ml in 2 ml vials) and is comparatively more expensive than the fentanyl (0.4 mg per ml) in the fentanyl-droperidol mixture. The use of Sublimaze avoids the hypotensive effects of droperidol and leads to a faster recovery. Since the effects of intravenous fentanyl last for only about 20 minutes, it is rarely necessary with this technique to give an antagonist to reverse its action. Assisted or controlled ventilation prolongs the anesthetic period slightly and gives a smoother anesthetic.
SUMMARY Nitrous oxide has a definite role to play in veterinary anesthesia, but the limitations of its use must be understood, and it must be correctly administered, as must any other drug, if benefit is to be ob-
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tained from its use. It is just one more agent in the anesthetist's armamentarium, and it has advantages and disadvantages as does any other. Although there are dangers of low arterial oxygen levels using 75 per cent nitrous oxide and spontaneous ventilation, problems are unlikely to arise in the normal, relatively healthy animal anesthetized for routine elective surgery and for procedures such as orthopedic surgery on long bones, provided that the concentration of nitrous oxide is limited to 67 per cent with oxygen. In cases in which the respirations may be embarrassed owing to positioning, e.g., head down tilt for perineal surgery, nitrous oxide should not be used unless there is provision for assisting or controlling ventilation (i.e., an anesthetist is needed). Flows into circle systems must be high enough to ensure that there is sufficient oxygen supplied to the patient. Nitrous oxide should not be used in patients with bowel stasis or other closed gas spaces in the body, such as closed pneumothorax, pneumomediastinum, or pneumoperitoneum. It is safe to use in open pneumothorax. One other danger that does exist with the use of nitrous oxide is that if the flowmeter controls are accidentally moved, or if the oxygen supply runs out, there is still gas volume being supplied to the patient, so that signs of respiratory distress do not appear until the animal becomes cyanotic or has a cardiac arrest. Care must be taken to continuously monitor all aspects of the anesthetic, including the gas supply. In shock cases nitrous oxide should not be used in higher than 60 per cent concentration, and where spontaneous ventilation is employed consideration should be given to discontinuing its use entirely for such patients. Nitrous oxide allows smooth mask induction of small animal patients with rapid recovery from anesthesia. Combined with fentanyldroperidol in neuroleptanesthesia it is a good anesthetic with good cardiovascular stability for the canine patient with cardiac disease. Nitrous oxide appears compatible with all other anesthetic agents and may often be used to advantage when anesthesia is too light, a prolongation of the anesthetic period is required, and one does not wish to administer any more of the primary agent, e.g., with ketamine hydrochloride in the cat.
REFERENCES l. Cohen, C.A.: The economics of veterinary anesthesia. Vet. Economics, 16:22, 1975. 2. Eger, E.I., and Saidman, L.J.: Hazards of nitrous oxide anesthesia in bowel obstruction and pneumothorax. Anesthesiology, 26:61, 1965. 3. Krakwinkel, D.J., Sawyer, D.C., Eyster, G.E., et al.: Cardiopulmonary effects of fentanyl-droperidol, nitrous oxide and atropine sulfate in dogs. Am. J. Vet. Res. 36:1211, 1975.
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4. Steffey, E.P., Gillespie, J.R., Berry, J.D., et al.: Anesthetic potency (MAC) of nitrous oxide in the dog, cat and stump-tail monkey.]. Appl. Physiol. 36:530, 1974. Department of Veterinary Clinical Studies Western College of Veterinary Medicine University of Saskatchewan Saskatoon, Saskatchewan Canada S7N OWO