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Volume 64 November 1971

1iBI

Section of Anesthetics
President Major General K F Stephens CB OBE FFA RCS

Meeting March 5 1971

Ketamine
Professor John B Dillon (Department of Anesthesiology, University ofCalifornia School ofMedicine, Los Angeles, California 90024) Rational Use of Ketamine as an Anaesthetic
A thorough study of the administration of many thousands of anesthetics with ketamine has proved it to be a safe and reliable antsthetic agent. Like all drugs it demonstrates occasional undesirable side-effects, some of which are remarkably similar to the undesirable actions of other more conventional antsthetics that have to a large extent been controlled by the use of adjuvant agents. Those phenomena mostly associated with the emergence from both conventional antsthesia and anaesthesia by ketamine are subject to the same management and control; it is compatible with all drugs used in anasthesia. Ketamine demonstrates several desirable sideeffects. Its action to support circulation and lack of respiratory depression make the agent unique among the antsthetics. These side-effects can be exploited in the management of numbers of patients to whom the administration of conventional anesthesia might pose serious hazards. When employed rationally, ketamine constitutes a valuable and significant contribution to the antsthetic management of the burned patient, the patient undergoing a variety of diagnostic procedures, as well as patients with circulatory and respiratory problems, both mechanical and functional, that would make anTsthesia with older agents a serious and perhaps life-threatening risk. There is no perfect antsthetic agent. Indeed, every drug used in medicine leaves something to be desired. It is doubtful if morphine, aspirin or digitalis would be considered acceptable drugs if they had been introduced under today's standards of pharmacological investigation. These drugs

were, and are, empirically effective and only after years of use are we aware of their deficiencies. Certainly no anesthetist has much regard for any anesthetic agent as an even moderately satisfactory drug for all purposes. Indeed, if diethyl ether or cyclopropane were to be introduced today with our present knowledge, the majority would be horrified, and the agents banned on the basis of their explosibility and possibly also because of their metabolic and cardiovascular effects. The use of chloroform, which is in some respects superior to ether, has been almost totally abolished because of its hepatic and cardiac effects; trichloroethylene has not been universally acclaimed; nitrous oxide has limitations that are well known. Many agents have been virtually abandoned, for example tribromoethanol (Avertin), ethyl chloride, divinyl ether and numerous derivatives of barbituric acid. Conversely, new agents have been introduced. The most widely used anesthetic today, halothane, was developed in England and is familiar to all. It has replaced ether and cyclopropane not only because of its effectiveness as an anesthetic, but also because it is nonexplosive. But halothane too has fundamental undesirable characteristics relating to the liver and heart. Methoxyflurane, also an effective nonexplosive anmsthetic, was introduced as a competitive agent; it also is less than perfect, being accused of nephrogenic diabetes insipidus. Other agents have come and gone, some because they were so little different from others that they possessed no advantages, some because they had gross disadvantages. The search for more effective and safer anesthetics, as for therapeutic agents, is a continuous process. Ketamine was introduced for clinical trial after investigation of a number of agents related to the basic phencyclidine nucleus. Phencyclidine was tried clinically a number of years ago. It was not only a relatively poor analgesic but a gross hallucinogenic agent (Greifenstein et al. 1958, Gool & Clarke 1964). It is effective as an ants-

1154 Proc. roy. Soc. Med. Volume 64 November 1971 thetic for small animals and we use it today for primate anasthesia. Ketamine is distinctly different from phencyclidine. The comment that because ketamine is derived from phencyclidine it too is hallucinogenic is both inaccurate and unscientific, and can be termed 'guilt by association'. The fact that some patients when given ketamine alone or with only belladonna derivatives may have dreams both pleasant and unpleasant, or may suffer from a sense of 'depersonalization' when inappropriately stimulated, is perfectly true. Dreaming phenomena are not unique to ketamine. The experiences of Sir Humphrey Davy with nitrous oxide as well as those of his associates were described by him (Davy 1800) and make very interesting reading. Ether dreams are well known (Lyman 1883, Coppolino 1963). Possibly they are known to many, as they are to me, as a result of an aneesthetic with open drop ether years ago. Simpson had much to say about the psychic effects of chloroform (Fulop-Miller 1938). Cyclopropane is associated with dreaming and occasionally almost maniacal emergence phenomena (Eckenhoff et al. 1961, McCuskey 1940). Barbiturates may produce misinterpretations and dreams in a number of patients (Lund 1950). Narcotics are associated with unpleasant psychic effects. We have learned to control most of the psychic side-effects of anmsthetics by proper premedication and supplementation and I cannot understand why many anmsthetists have been reluctant to do this-while administering ketamine. Properly administered there are no more dreams or recollections associated with the administration of ketamine than with conventional anesthesia. The safety of ketamine has been adequately demonstrated. In over 20,000 documented administrations no death as a direct result of the drug when properly used has been recorded. Ketamine has been given many times in as high as ten times the recommended dose without serious result, although respiratory depression was reported in a number of cases given gross overdose. I know of no anmsthetist who believes that there is one perfect anmsthetic agent. The administration of anmsthesia should be the thoughtful application of an agent or agents to produce the desired result with minimum physiological harm. Ketamine possesses characteristics which are distinctly different from other anmsthetic agents and which can be exploited for the benefit of patients for specific purposes. This may be termed the 'rational' use of ketamine as an antsthetic. It is reputed to possess undesirable characteristics which produce adverse reactions. Several of these may be considered adverse from one point of view, but some of these reactions are phenomena different from those seen with other agents, that is they do the patient no harm.

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Cardiovascular The administration of ketamine is usually associated with elevation of blood pressure and pulse rate which varies in magnitude but is usually most marked when the drug is injected rapidly by the intravenous route. The duration of this is variable but is usually 5-15 minutes. For this reason ketamine is generally contraindicated in patients with hypertension. What is considered hypertension is an individual decision, but we have not used it for patients with resting systolic blood pressures of over 160 mmHg. I am unaware of any reported cardiovascular catastrophe resulting from the administration of ketamine and I believe, like many other anwsthetists, that an increase of blood pressure and pulse rate may be a highly desirable reaction in many patients. There is growing evidence that the blood pressure rise may be partly controlled by means of prior administration of small intravenous doses of chlorpromazine (10-20 mg) or other blockers. Our experience with ketamine, particularly in ocular surgery, is that it is antiarrhythmic and that the oculocardiac reflex is depressed or abolished. On the basis of considerable experience, we believe ketamine to be the anesthetic ofchoice for cardiac catheterization in children. Arrhythmias which may be produced by the cardiac catheter appear to be less severe when ketamine is used than with other anaesthetics. We use it for inducing conventional antesthesia for cardiac operations. Corssen et al. (1970) have found it a satisfactory sole anesthetic for open heart procedures (Dowdy & Kaya 1968). Respiration The rapid injection of large doses of ketamine intravenously, usually in excess of 2 mg/kg, may result in a transient apneusis which usually follows a deep inspiration. This adverse reaction is almost uniformly the result of inappropriate administration. Laryngospasm may occur and be severe if the larynx is stimulated, because the laryngeal and pharyngeal reflexes are unobtunded by ketamine; many people consider this to be an advantage rather than an adverse reaction. In most cases, however, respiration is normal or mildly stimulated.

Ocular Slight elevation of intraocular pressure is commonly associated with the elevation of pulse and blood pressure. This is transient and probably of no significance. Ketamine is considered the anesthetic of choice byour ophthalmologists forroutine examination of padiatric patients with glaucoma who undergo repeated tonometry under anmesthesia. I would not recommend the administration of ketamine to a patient with an open globe, but see no contraindication to its administration for

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Section ofAncsthetics

1155

extraction of a cataract if for other reasons this radiologist (Wilson et al. 1969, Wilson 1971) in agent is indicated. Eye movement may be aboli- over 400 cases ofketamine anesthesia for pneumoished by an appropriate small dose of curare encephalograms and arteriograms in patients with without depression of respiration. Nystagmus is suspected space-occupying lesions, there have transient during the induction following admini- been no adverse reactions attributable to anwsstration of ketamine, and both nystagmus and thesia. These patients were children suffering from diplopia are uniform on emergence from this a wide spectrum of intracranial pathology. For agent. These phenomena, which are also seen in patients over 14-15 years of age, unless they are patients emerging from conventional anesthesia, completely unmanageable, we do not use ketaresult in nausea and emesis, but they are avoidable mine for diagnostic purposes, depending rather if a patient is not stimulated early or asked to upon agents such as droperidol or diazepam since open his eyes before he has gained full cortical true anesthesia in the co-operative patient is not needed. control.
Gastrointestinal Psychological: Adverse Reactions Dreams have been discussed previously. They are Nausea and vomiting are common if the patient avoidable with a proper combination of ketamine is stimulated during emergence and is usually analgesia and a tranquillizer or sedative hypnotic associated with nystagmus and diplopia. There is such as droperidol, diazepam or a phenothiazine remarkably little anorexia, however, even in as premedicant, and perhaps with the use of small patients who are vomiting. They are perfectly doses of ultra-short-acting barbiturate or tran- willing to eat or drink following emesis. Emesis quillizer on emergence. They may also be avoided is very common during and following pneumoby the proper management of the patient in the encephalograms regardless of the anwsthetic immediate post-anvsthetic period. We do not agent used. I know of no case of aspiration of consider ketamine to be a short-acting anesthetic emesis being reported. agent and it must be used with understanding in the outpatient department. We do, however, use Skin this agent for many outpatients. It has been given Erythema may be seen in about 15% of the to pediatric patients daily on an outpatient basis patients and may be quite extensive or isolated and it has been acceptable to the parents as well as into islands. This is a transient phenomenon lasting 10-15 minutes and is of no consequence. being tolerated satisfactorily by the patient. Repeated intramuscular injections, i.e. daily for five days a week over a period of nine weeks, have Neurological Some patients demonstrate bizarre neuromuscular produced no signs of tissue injury in a series of reactions following ketamine administration. We more than 70 patients. Pain on injection of the have noticed that these patients are usually either drug is more related to the piercing of the deep those of less than 6 months of age or patients fascia with the needle than to the drug, since the with some pre-existing neurological deficiency, crying usually ceases promptly after the needle is usually cortical agenesis. We have also noticed withdrawn and the area lightly massaged. that patients who have been taking oral analgesics or have been receiving therapy with chlor- Clinical Uses ofKetamine promazine over a long period of time tend to When equating ketamine anesthesia with anmsreact to ketamine in a rather unusual fashion so thesia produced by vapours of volatile anesfar as the muscular system is concerned and are thetics, with balanced aneesthesia such as that difficult to manage. A recent case of unsatisfactory produced by barbiturates, narcotics, nitrous anaesthesia has been reported in a patient with oxide-oxygen and possibly muscle relaxants, or severe head injury involving the cerebral cortex with Innovar, nitrous oxide-oxygen or propanidid, (Drury & Clark 1970). The alcoholic may react one is perhaps confused because anmsthesia with adversely to ketamine as he does to many ants- ketamine is unique (Pender 1971). Ketamine aneesthesia requires understanding of its strengths thetics. Salivation is quite common if some belladonna as well as of its limitations. In children and in the agent is not administered prior to ketamine. aged it is completely satisfactory without suppleAtropine may be given shortly beforehand, i.e. mentation for well over 95 % of patients for a 5 or 10 minutes, with satisfactory suppression of large variety of procedures neither requiring salivation; belladonna or hyoscine may be used as muscular relaxation nor producing laryngeal stimulation. Many of these procedures could not well. Spinal fluid pressure may be elevated (Evans be done safely with conventional anaesthesia such et al. 1971). This is also seen with other agents, as some plastic procedures for correction of burn including halothane (Jennett et al. 1967, Jennett scars (Patterson & Belton 1971, Corssen & Oget et al. 1969). In the experience of our neuro- 1971, Wilson et al. 1967, Wilson et al. 1970).

156 Proc. roy. Soc. Med. Volume 64 November 1971 Ketamine is ideal for procedures where support or control of respiration as a result of depression caused by conventional anesthesia is either undesirable, unnecessary or impossible. Its value in neuroradiological diagnostic procedures in children is unequalled. In the aged the support of circulation that ketamine affords is a very desirable attribute which may be exploitcd not only in noncardiac cases but particularly in patients in whom any type of depression is undesirable (Lorhan 1970). Ketamine is particularly useful in patients who are in shock or have severe restrictive cardiac disease in which maintenance of blood pressure is highly desirable. Ketamine can be combined with any drug used in anesthesia and this characteristic makes it in many ways an ideal agent for induction of many types of anesthesia because of its speed, smoothness and lack of depressive effect on respiration and circulation. Neither ketamine nor any volatile anesthetic should be employed alone for anesthesia in patients between 15 and 65 years of age because these patients tend to have a higher incidence (about 12 %) of psychological disturbances not only with ketamine but with all volatile antsthetics. It is not necessary to employ ketamine by itself and the wilful exposure of patients to an undesirable experience, even if it does no harm, is both unnecessary and unkind. Premedication of patients with a tranquillizer such as droperidol is, in my experience, quite satisfactory. There are other agents which can be used such as diazepam or a phenothiazine, as well as morphine or other narcotics. It is also my experience that a small dose of droperidol or a small dose of thiopentone at the termination of a procedure will permit recovery without memory. In a limited number of patients in severe shock due to blood loss and trauma ketamine anesthesia was not only satisfactory but, in my opinion, lifesaving as an induction agent which, supported by oxygen and a muscle relaxant, permitted repair and restitution of vascular integrity. Ketamine has been used particularly by Corssen et al. (1970) as a sole anesthetic agent with oxygen for open heart operations. We have used it successfully for the induction of many patients for open heart surgery, usually for coronary artery repair, but also as the induction agent for patients suffering from severe aortic stenosis where a fall in blood pressure during induction might well have been life-threatening. Ketamine's value lies in its ability to provide safe induction and maintenance of anesthesia in a variety of patients with unusual or life-threatening conditions. It is no substitute for conventional anesthesia in the vast majority of situations, nor was it intended to be, but is a valuable addition to our armamentarium of useful drugs.

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REFERENCES Coppolino C A (1963) Milit. Med. 128,238 Corssen G et al. (1970) Anesth. Analg. Curr. Res. 49, 1025 Corssen G & Oget S (1971) Anesth. Analg. Curr. Res. 50,95 Davy H (1800) Researches, Chemical and Philosophical: Chiefly Concerning Nitrous Oxide, or Dephlogisticated Nitrous Air, and its Respiration. London Dowdy E G & Kaya K (1968) Anesthesiology 29, 859 Drury W L & Clark L C (1970) Anesth. Anaig. Curr. Res. 49, 859 Eckenhoff J E et al. (1961) Anasthesiology 22, 667 Evans J, Rosen M, Weeks R D & Wise C (1971) Lancet i, 40 Fulop-Miller R (1938) Triumph over Pain. London Gool R Y & Clarke H L (1964) Anasthesia 19,265 Greifenstein F E et a1. (1958) Anesth. Anaig. Curr. Res. 37, 283 Jennett W B et al. (1967) J. Neurosurg. 26, 270 Jennett W B et al. (1969) Lancet i, 61 Lorhan P H (1970) Dissociative Anesthesia, Ketalar. In: Parke-Davis Handbook. Ann Arbor, Mich. Lund P C (1950) Amer. J. Surg. 81, 638 Lyman H M (1883) Artificial Anmsthesia and Anwsthetics. London McCuskey C F (1940) Anesthesiology 1, 26 Patterson J F & Belton M K (1971) J. Amer. med. Ass. 215, 777 PenderJW(1971)J. Amer. med.Ass. 215,1126 Wilson G H (1971) Lancet i, 243 Wilson G H, Fotias N A & Dillon J B (1969) Amer. J. Roentgenol. 106, 434 Wilson R D, Nichols R J & McCoy N R (1967) Anesth. Analg. Curr. Res. 46,719 Wilson R D, Knapp C, Traber D L, & Evans B (1970) Sth. med. J. (Bgham, Ala.) 63, 1420

Dr G Szappanyos, Dr M Gemperle and Dr K Rifat

(Department ofAna!sthesiology, School ofMedicine, University of Geneva, Switzerland)

Selective Indications for Ketamine Anaesthesia

The traditional anesthetic methods and agents permit us to obtain effective pain control by progressively depressing the central nervous system. However, this gives rise to undesirable secondary effects on the cardiovascular and respiratory systems. Recently, research has been orientated toward the selective inhibition of the conduction and perception of pain. The first step in that direction was the acceptance of the theory of H Laborit (1950, Anesth. et Analg. 7, 289; 1954, Presse med. 62, 359), followed by the introduction of neuroleptanalgesia. This technique with its remarkably potent analgesia and protection of the neurovegetative system made it possible to expand the indications and to avoid unnecessary deep anesthesia with its inherent dangers. But the problem of the respiratory depression was not solved and intubation with controlled respiration remained the rule with
neuroleptanalgesia. The development of ketamine hydrochloride (Ketalar), a phencyclidine derivative, represents a major advance in anesthesia since it does not normally depress respiration or blood pressure, and intubation is not usually required. However, its successful use requires a radical change in the conservative mental attitude of the aneesthetist.