Anesthesia: The state of the art

ANESTHESIA: THE STATE OF THE ART LEROY D. VANDAM, M.D.

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TABLE OF CONTENTS SELF-ASSESSMENT QUESTIONS . INTRODUCTION

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REGIONAL ANESTHESIA .

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347

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349

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350

INHALATION ANESTHETICS .

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359

ANESTHETIC TOXICITY

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361

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COMPARISON OF THE EFFECTS OF HALOTHANE, ENFLURANE AND ISOFLURANE ON ORGAN SYSTEMS . HALOTttANE HEPATITIS .

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366

THE MALIGNANT HYPERTHERMIA SYNDROME

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371

ATTITUDES TOWARD ANESTHETIC MORTALITY

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375

ANESTHESIA AND THE CONTROL OF OPERATING ROOM INFECTIONS

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381

T I t E ANESTHETIZING MACHINE

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386

SELF-ASSESSMENT ANSWERS

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394

346

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SELF-ASSESSMENT QUESTIONS TRUE OR FALSE?

1. The nonionized form of a local anesthetic is necessary for penetration of the nerve fiber, while the ionized moiety is largely responsible for anesthesia. 2. The majority of systemic reactions to local anesthetics are responses to the epinephrine incorporated in the anesthetic solution. 3. Although the newer potent inhalation anesthetics are relatively inert, therefore nonflammable, a major problem has been their biotransformation to toxic compounds. 4. Without exception the potent inhalation anesthetics cause cerebral vasodilation, depress respiration centrally and the myocardium peripherally while producing antidiuresis. 5. The antidiuresis observed during general anesthesia is largely the result of stimulation of production of antidiuretic hormone. 6. Immunogenic phenomena are most likely responsible for development of hepatic necrosis after halothane anesthesia. 7. The National Halothane Study revealed that halothane hepatitis is a rare event and that halothane use results in a lesser mortality than that associated with cyclopropane. 8. Malignant hyperthermia in conjunction with anesthesia has probably existed from the beginning, but only in the 60s was it found to be a genetically transmitted syndrome. 9. The syndrome of malignant hyperthermia need not occur in conjunction with anesthesia and few anesthetic techniques are free of inducing the disease. 10. Perhaps the most accurate study of anesthetic mortality was performed by Beecher and Todd in the 50s, but their contention of a higher death rate in association with curare was baseless. 11. Considerable epidemiologic data exist to suggest t h a t anesthesiologists, the equipment used, and their techniques contribute to development of surgically acquired infections. 12. Malfunctioning of anesthesia machines is responsible for significant anesthetic morbidity and mortality because there are no safeguards and their safe use is dependent on the anesthesiologists' surveillance. 13. One way to avoid development of halothane hepatitis is to refrain from repeating its use within a 3-month interval. 14. As the ester-type local anesthetics are inactivated by pseudocholinesterase, cumulative toxic reactions are less likely t o 347

develop than with the amide variety, which are metabolized by hepatic microsomal enzymes. 15. The newest general anesthetics, ethrane and forane are distinguished by high potency, relative inertness, and little tendency to sensitize the myocardium to catecholamines. Answers are listed at the end of the article.

348

is Professor of Anesthesia at Howard University. He graduated from New York University College of Medicine and received his surgical training at Peter Bent Brigham Hospital in Boston. Besides his dedication to patient care and medical research, Dr. Vandam's major interests encompass teaching, writing, editing and watercolor painting.

INTRODUCTION WHILE THE WORK OF THE SURGEON is in full view, the anesthesiologist, unobserved behind the traditional ether screen, resorts to the use of m a n y drugs to m a k e operation feasible. Both the rationale for the use of these drugs and j u d g m e n t in giving them are a private m a t t e r rarely evident to the surgeon who proceeds with dissection, content to leave the patient's welfare in the hands of someone he trusts. A capable anesthesiologist can discreetly minimize blood loss by m a i n t a i n i n g an appropriate m e a n blood pressure level and body position'and controlling ventilation to prevent the accumulation of carbon dioxide and a high venous pressure. By observing the operative field and feeling the compliance of the anesthesia rebreathing bag, one can see to it t h a t muscle relaxation is good. The field is always observed in order to detect dark blood and possibly hypoxia. Rightfully, some m a t t e r s are brought up for m u t u a l discussion between anesthesiologist and surgeon. For example, should a transfusion be given? A drug injected to induce diuresis? W h a t m a y be done to improve operating conditions without jeopardizing the patient's well-being? If something puzzling or worrisome occurs, the surgeon should of course be notified and a s k e d f o r permission to take corrective measures and, if necessary, operative manipulations are adjusted accordingly. I have just described the relation between surgeon and anesthesiologist as might best prevail during operation. Unfortunately, such cooperation sometimes breaks down because of personalities, individual capabilities, knowledge and j u d g m e n t and other factors involved in h u m a n intercourse: (This happens less t h a n it used to:) In a controversy only the p a t i e n t suffers the real insult. To prevent this danger, an anesthesiologist should u n d e r s t a n d the n a t u r e of the operation beforehand and cultivate over time a 349

degree of surgical j u d g m e n t so t h a t he can be helpful in times of difficulty. Similarly, a surgeon should have more t h a n a general idea of anesthetic p r a c t i c e - b u t , as intimated above, this is a much more etusive goal. In this review, I shall, by m e a n s of a series of miniessays t h a t can be perused individually, present recent anesthetic information t h a t should be part of a surgeon's body of knowledge. A good deal of philosophy pervades this discoL~rse, with an eye to historical antecedents.

REGIONAL ANESTHESIA Properly used, there is• perhaps no more precise or safe - : [kind of \ . anesthesia t h a n the regional approach, a term corned by z , a r y e y Cushing around the t u r n of the century. Apart from ~he thorac.~c and abdominal c a v i t i e s - a n d perhaps the c r a n m m , where lengthy, complicated operations are p e r f o r m e d - i t makes good sense to confine anesthesia to the area under treatment• Often, as in the past, the surgeon himself can give the anesthetic, as is often done in oral, maxillofacial and plastic procedures, and for m a n y a superficial operation. As simple as local anesthesia m a y seem, it is often given poorly, for several reasons: failure to prepare the patient for the experience and to provide reassurance during anesthetic and surgical manipulations; lack of fine anatomical knowledge, with the result t h a t local anesthetics cannot be given sparingly; failure to use a m i n i m a l l y effective concentration and total volume of local anesthetic (anesthetic mass), and failure to add the relatively harmless concentrations o f epinephrine in the anesthetic mixture to produce vasoconstriction and a bloodless field. Improperly prepared emotionally and pharmacologically, a patient m a y require large amounts of sedatives and narcotic analgesics to make up for the deficiencies. As a result of disorientation and overreaction, large amounts of medication m a y lead to the "uncontrolled general anesthetic," where nobody is in control and the patient would appear to have been better off under the influence of light general anesthesia. For some patients, local anesthesia with its stresses, strains and the possible untoward circulatory response to it and epinephrine, m a y not be as safe as a carefully given general anesthetic. How LOCAL ANESTHETICS ACT Knowledge of w h a t happens at the t a r g e t site dictates choice of agent, concentration and volume and the appropriate use of epinephrine (still the vasoconstrictor of choice), all of which are based on the a n a t o m y of the area to be anesthetized. In the smallest u n i t of a peripheral nerve, an axon, the axop l a s m consists of a gel replete with potassium ions, separated 350

STIMULUS

l~i-

T

/" - --

;

,'

,, Y

....

,

B ~-YJ -

: _-.:~J~"_

:,;

.....

/.

Fig 1 . - A , upon stimulation,

FIRINGTHRESHOLD voltage across the membrane

:

-

reaches - 5 5 mv, the axon's firing threshold. B, depolarization now complete, J with the interior of the membrane 40 mv, positive in relation to the exterior. (From de Jong, R. H.: Physiology and Pharmacology of Local Anesthesia (Springfield, II1.: ,DEPOLARIZED Charles C Thomas, Publisher, 1977). Used by permission.)

ILA_/.7

..~_

:

)

i..- Y

from the extracellular fluid by a semipermeable lipoprotein membrane. A high external concentration of sodium makes for an electrical potential across the membrane in the resting or polarized state (Fig 1). The charge measured at - 9 0 / ~ V results from a differential permeability to the two chief ions, potassium more or Fig 2 . - T h e sodium channel illustrated here differs from the potassium channel in that it is a pore or hole in the cell membrane. At rest, the opening to the pore is covered by a gate that is held in place by calcium. Depolarization to threshold dislodges the calcium and causes the gate to withdraw. Diffusion of sodium ions through the open pore into the axon produces the depolarizing voltage, whictl} is electronically transmitted to the next sodium pore (not shown hereL The read~_r sl~r,u~d bear in mind that the illustration is imaginary and that no one hag ever seel, -~ sodium pore. (From Eger, E. I., I1: Anesthetic Uptake and Action {Baltimore: The Williams and Wilkins Co., 1974). Used by permission.) No + No.,I.

No + Na +

DEPOLARIZING

Ca ++

No +

Na +

/~.,

No +

35t

less free to come and go, while the sodium is exteriorized by an active process. When a stimulus is applied to a.receptor (paintouch-temperature) in a sensory nerve, or a motor fiber is activated, the physical event is transduced electrically so t h a t a wave of excitation occurs, depolarizing the resting m e m b r a n e (see Fig 1). Apparently the electrical event is accompanied by a change in configuration of the structure of the membrane, so t h a t sodium ions readily cross the b a r r i e r via a channeling mechanism, and potassium exits (Fig 2). The wave of depolarization is self-propagated, but only momentarily, for a metabolically activated pump mechanism extrudes the sodium, potassium reenters, and the polarized resting state is restored. In myelinated fibers, where the sheath is interrupted at the nodes of Ranvier, the electrical nerve impulse jumps from node to node wherever the sodium channels are highly concentrated. This is called saltatory conduction. The insulation provided by myelin between the nodes probably prevents dissipation of current and the stepwise process explains the more rapid passage of impulses in heavily myelinated fibers, such as motor fibers. This oversimplified description of nerve m e m b r a n e activity provides the background for a knowledge of local anesthetic action. After a local anesthetic has permeated the membrane, a physicochemical change takes place in the lipoprotein matrix, altering the available electrolyte channels so t h a t ion exchange no longer occurs in response to the impulse. Thus, conduction is blocked and the fiber r e m a i n s polarized without change in resting metabolism. STRUCTURE OF LOCAL ANESTHETICS

More t h a n a few new useful anesthetics have been introduced over the last 2 0 - 3 0 years. Their characteristics are quite different from those of the cocaine and Novocain of old. Further, a better u n d e r s t a n d i n g of their action m a k e s for rational usage inSofar as time of onset, duration and adverse reactions are concerned. These facets m u s t be known to the surgeon. All of the useful injectable local anesthetics are tertiary, aminocompounds, with either an ester or amide linking a lipophilic portion of the molecule on the one side to a hydrophilic compon e n t on the other. The alkaloid or basic form of the molecule is insoluble in a q u e o u s solutions, so t h a t the salt form is needed for solution in an injectable medium. Depending on the acid-base milieu in body tissues, the salt dissociates into anion and cation. However, it is the basic form, which is lipid soluble, t h a t a c c o u n t s for most of its capacity to penetrate a nerve fiber. One'the other hand, the cation form is believed to be the active moi~ty t h a t m a y physically chahge the m e m b r a n e and thereby block sodium chan352

nels, at either the external or internal mouth. Thus, by preventing sodium influx, local anesthetics m a i n t a i n the polarized state of fibers and both motor and sensory anesthesia result from blockage of the nerve impulse. This, again, is a highly -~implified explanation, not agreed upon by all, but it helps to have the picture in the mind's eye. It is apparent, then, t h a t the pH or hydrogen ion concentration of both the local anesthetic solution and the tissue fluids is a crucial d e t e r m i n a n t in anesthetic activity. The ratio between anion and cation determines both penetrability and blocking activity. In any case, however, a critical minimal concentration of anesthetic is needed for blockage. In fibers with a small diameter, the surface of the m e m b r a n e is large relative to their interior, and the n u m b e r of sodium channels is relatively small; therefore, those fibers are more readily affected by a m i n i m a l anesthetic concentration. Conversely, in larger myelinated fibers at least a minimal length of fiber must be exposed to the anesthetic in/order for it to reach the successive nodes of Ranvier. Here the sodium channels are concentrated and large in number, both factors requiring a higher concentration of anesthetic. These physical factors explain how it is possible to a t t a i n a differential nerve block in a mixed peripheral nerve. A lesser concentration of anesthetic affects fibers of smaller diameter, e.g., those subserving transmission of one kind of pain (pinprick), t e m p e r a t u r e and sense of position. On the other hand, complete anesthesia can result only when Jthe concentration of local anesthetic has reached the threshold for blockage of fibers with large diameters, i.e., deep pain, position, motor and touch fibers. These considerations are a necessary part of practical local anesthesia where the mass of local anesthetic injected, concentration times volume, m u s t sufrice for the task at hand. TISSUE DISTRIBUTION OF LOCAL ANESTHETICS

Regardless of theory, the surgeon m u s t s t a r t with a far higher concentration of local anesthetic t h a n the m i n i m a l l y effective dose in order to affect the target. I n t r a c u t a n e o u s and subcutaneous nerve fibers n g t only have small diameters but are easily bathed by the a n e s ~ e t i c solution without formidable tissue barriers. Thus, infiltration readily results in complete sensory block. However, with the deeper injection required for a n e s t h e s i a of a mixed peripheral nerve or one of the nerve plexuses, the anesthetic is dispersed in tissue planes, diluted by extracellular water and absorbed into capillaries, and the molecule is dissociated according to the H ÷ ion concentration t h a t prevails. Highly acidic conditions such as infection or edema have an impact; the former favors the cationic form with a lesser lipid solubility and the lat353

ter acts as a diluent. High vascularity, as in the head, neck and perivertebral regions, results in rapid absorption, hence lesser availability, and a tendency toward systemic reaction. Ultimately the injected solution must diffuse t h r o u g h the fibrous nerve sheath, epineurium, perineurium surrounding bundles of fibers and, finally, endoneurium before reaching~the nerve fiber per se. Anatomically, the outer (peripheral) fibers in a mixed peripheral n e r v e - t h e m a n t l e fibers, so to s p e a k - a r e first affected. Each nerve has a plexiform a r r a n g e m e n t of its own t h a t gives off fibers first to the proximal structures as the nerve courses peripherally. Thus, in a brachial plexus block, the shoulder and arm first!show the evidences of anesthesia, then the forearm and hand. Hence the onset of anesthesia does not progress from small- to !argediameter fibers as theory would hold, except in the distributional m a n n e r described above. Sensation and motor power recover in inverse fashion, the deep fibers first, then the mantle and ultimately the smallest fibers in each area. Sympathetic nerve fibers and a segment of the pain fiber spectrum are the last to recover. SYSTEMIC REACTIONS CENTRAL NERVOUS SYSTEM.-Local anesthetic is absorbed via lymphatics and capillaries, accounting for the dissipation of anesthesia. Absorption into the bloodstream u l t i m a t e l y results in metabolic conversion of the anesthetic to inactive compounds in liver and lung microenzymal systems, via pseudocholinesterase in plasma for the ester compounds, then excretion of the metabolites or unchanged compound in the urine. Rapid absorption of a large anesthetic mass, or intravascular injection, m a y result in a concentration sufficient to cause systemic effects. In the brain both inhibitory and excitatory centers are affected. If inhibitory action is blocked, stimulation ensues, v a r y i n g from garrulousness and excitement to muscle twitching and g r a n d mal seizure. In either instance, vasomotor and respiratory center depression may occur with respiratory and circulatory arrest. A local anesthetic absorbed into the bloodstream may cause, not a seizure, but somnolence and loss of consciousness. This indicates t h a t inhibitory neurons in the brain are activated or t h a t excitatory n e u r o n s are depressed. Subconvulsive doses of procaine or lidocaine t h a t have been given intravenously to supplement general anesthesia inhibit respiratory t r a c t reflexes and diminish the plane of general anesthesia required for surgery. Insofar as central stimulation is concerned, neuronal firing probably begins s u b c o r t i c a l l y / i n the limbic system, and amygdala, spreading Outward to progress from mere electroencephalographic activation to seizure. 354

Since cerebral metabolism is markedly increased during seizure (thus accounting for the postictal depression), ventilation o.f the lungs with oxygen to avert anoxic neuronal damage and shorten the duration of postconvulsive depression and retrograde amnesia is the first step in therapy. Paradoxically, although hyperventilation is often used to uncover seizure patterns in epilepsy, hyperventilation in the presence of local anesthetic stimulation raises the seizure threshold, perhaps by affecting ionization of the anesthetic. The convulsion should be terminated as~quickly as possible for obvious reasons. Although intravenous inj~;ction of a barbiturate, in narcotic rather than anesthetic dosage, has traditionally been a mode of therapy for this purpose, it a ~pears that diazepam (Valium) in a dose of 10 mg per kilogram f body weight may be more effective because it acts on the limbic area. This contention is based on animal experiments in which the prophylactic administration of diazepam permits the medianLconvulsive dose of a local anesthetic to be more than doubled. CIRCULATION.-- It is well known that procaine (Novocain), procainamide and lidocaine (Xylocaine), wl~ich are used to treat cardiac arrhythmias, diminish myocardial lirritability and slow the passage of impulses over the conductior~ system, probably by an action akin to the one that results in anesthesia in peripheral nerves. Smooth muscle relaxation occurs in,he peripheral vasculature. Thus, high levels of local anestheti~ in the bloodstream may cause, in addition to the central nervou~ system phenomena, a fall in blood pressure and cardiac arrest ibecause of combined central and peripheral effects. The treatment of such circulatory collapse is of course little different from o~dinary cardiopulmonary resuscitation. PREVENTION OF LOCAL ANESTHETIC REACTIONS

The avoidance of high circulatory levelspf local anesthetic depends on several measures. The first is to ~se the minimal anesthetic concentration necessary to get the jdb done (0.5% for infiltration as a rule, and from 1% to 2% for large nerve injection, depending on the potency of the local anesthetic) and then to restrict the total mass in terms of volume. These quantitative aspects should be figured out beforehand. The second is to avoid intravascular injection and retard absorption, particularly in highly vascular areas: head; neck, mouth, tracheobronchial tree and perivertebral areas. This is accomplished with the use of epinephrine, which not only delays absorption but produces an ischemic operating field and prolongs duration 6f\anesthesia. Epinephrine, however, a potent catecholamine alJsorbed into the 355

bloodstream, should be used only in minimally effective doses to avoid action on the heart..As a fl-sympathetic agonist, epinephrine leads to an increase in h e a r t rate and in myocardial contractility and enhanced myocardial irritability; the end result is vent r i c u l a r fibrillation. Epinephrine effects the central nervous syst e m and produces apprehension, agitation, headache, and tension. A reasonable compromise for epinephrine concentration in conjunction with the surgeon's needs is a 1:200,000 mixture, made by adding 0.5 ml of the standard 1"1,000 concentration (1 mg/ml) to 100 ml of the local anesthdtic solution. The amount added should be measured with a tuberculin syringe r a t h e r t h a n according to the number of drops, which vary g r e a t l y ' in size according to the dropper used. Perhaps a better ischemic, field is achieved by use of an 1 : 100,000 mixture, but systemic responses are more evident with the former mixture, especially when large volumes of local anesthetic are injected. After tachycardia and .\ blackout have occurred, the patient is often told t h a t this is an allergic reaction to the local anesthetic and t h a t he should 'not be given t h a t compound again. This is not the explanation. The pat i e n t has merely reacted to the epinephrine. THE LOCAL ANESTttETICS

In contrast to general anesthetics, which present a variety of molecular configurations, local anesthetics have a characteristic form: an aromatic lipophilic terminal g r o u p (Ar), an intermediate carbonyl linkage, either an ester or an amide, and a t e r m i n a l hydrophilic (HX) group. R

A r - - COO - - (CH2)n - - N /

\HX

\R / The local anesthetics are weak electrolytes, present in aqueous solution in ionized and nonionized forms, the proportions depending on the pH of the solution and the pKa of the drug. The relationship is defined by the Henderson-Hasselbach equation: salt acid

(1)

pH + pKa + log HA

(2)

pH = pKa + l o g Rewritten:

356

Thus, pH determines the dissociation of the local anesthetic: B pH = pKa + l O g B H +

(3)

Local anesthetic activity increases with electroactivity of the oxygen in the carbonyl group to form a dipole. The hydrophilic moiety is usually a tertiary aminoalcohol that combines with strong acids to form salts of weak acidic activity, it is ionizable, and in the cation form is largely responsible for specific anesthetic action. The lipophilic or hydrophobic moiety is usually an aromatic acid with substitution of radicals at various locations in the phenolic ring. The ester compounds are more or less hydrolyzed into inactive components (procaine-diethylaminoethanol and benzoic acid) by pseudocholinesterase circulating in plasma. This enzyme, synthesized in the liver, differs from true cholinesterase, which is responsible for the hydrolysis of acetylcholine at the neuromuscular junction. Thus pseudocholinesterase, which also Fi9 3.-Structure-activity relationship of local anesthetic agents. (From Covino, B. G.: Pharmacology of local anesthetic agents, Surg. Rounds: July, 1978, 48. Used by permission.) Chemical Structure

Relative Potency

Onset

(rain)

coocN~c.~x/ c~t,~c~sAmino---Ester

1

Slow

60.90

coocNp,' czNs

Amino--Ester

1

Fast

30.60

/..~-.~CH3 * ~CN3NNCO

Amino--Amide

2

Fast

120-240

~.,c~...-c~.7

Amino---Amide

2

Fast

120-240

~ N.coc.~ "c).s Amino---Amide ~ca 3 ""cz.s

2

Fast

90-200

Amino--Ester

8

Slow

180-600

Agent

Chemical Class

Duration

Low Potency--Short Duration Procaine

NT-~ CI

Chloroprocaine

u,. - ~

~ CtN$

Intermediate Potency and Duration Mepivacaine

Prilocaine

Cn3

¢H3 ___a CH3

Lidocaine

High Potency-Long Duration Tetracaine

,~c,s: , . ~ .

¢o0c,z, ,c,, '~.CH3

Bupivacaine

~L.)~ u~coT'"~

Amino---Amide

8

Intermediate

180-600

Etidocaine

~( )~-ms~,~a ~ , C;~s c,,7

Amino---Amide

6

Fast

180-600

357

T A B L E ].--SUGGESTED USES, CONCENTRATIONS, AND MAXIMAL DOSAGE OF THE LOCAL ANESTHETICS*

DRUGS

Esters Cocaine hydrochloride Procaine hydrochloride Novocain Ethocaine

TOPICAL

Respiratory tract 5 - 10% (4- 2 ml) Ineffective

DOSE (MG)

200

Chloroprocaine hydrochloride Nesacaine

Ineffective

Tetracaine hydrochloride Pontocaine Pantocaine

Respiratory tract 1-2% (8- 4 ml)

80

Infrequently used 0.2% (15 ml)

30

Respiratory tract 2 - 4% (10-5 ml)

200

Amides Dibucaine hydrochloride Nupercaine Percaine Cinchocaine Lidocaine hydrochloride Xylocaine lignocaine

Mepivacaine hydrochloride No data Carbocaine Bupivacaine hydrochloride No data Marcaine Etidocaine hydrochloride Duranest

No data

INJECTION

DOSE (MG)

Not used

200

Infiltration 0.5% 1,000 (200 ml) Peripheral nerves 1-2% (100-50 ml) Infiltration 0.5% 1,000 (200 ml) Peripheral nerves 2% (50 ml) Infrequently used for 100 infiltration and nerve injection, 0.1 to 0.25% Infrequently used

Infiltration 0.5% (100 ml) Peripheral nerves 1 - 2% (50- 25 ml) Infiltration 0.5- 1.0% (100- 50 ml) Peripheral nerves 1 - 2% Infiltration and peripheral nerves 0.25-0.75% Infiltration and peripheral nerves 0.25- 0.75%

500

500

500 500

*Use of local anesthetics for specialized techniques is not shown. (From Dripps, ~ . D., et al.: Introduction to Anesthesia (5th ed.; Philadelphia: W. B. Saunders Co., 1977~, p. 254. Used by permission.}

splits the neuromuscular blocker succinylcholine, offers a modi, cure of safety when the ester compounds reach the bloodstream. On the other hand, amide-linked compounds undergo the usual distribution in the body compartments and are then more or less metabolized in the hepatic microenzymal system; changed and unchanged compounds are thenexcreted in the urine. Hence this kind of local anesthetic m a y accumulate in plasma and reach toxic levels, as is well known in the use of lidocaine (Xylocaine) to treat ventricular a r r h y t h mias. The minimally effective concentration of local anesthetic 358

is inversely proportional to potency, the concentration decreasing in the following manner: dichloroprocaine (Nesacaine), procaine (Novocain), lidocaine (Xylocaine) and carbocaine (Mepivacaine), etidocaine (Duranest) and bupivacaine (Marcaine) and dibucaine (Nupercaine). Time of onset and duration of action also increase in the same order. Duration of action also correlates with the concentration used and physically, according to the degree of protein binding (albumin and erythrocytic protein) in plasma, therefore with firmer bonding to protein in neural tissues. These properties of local anesthetics are shown in the accompanying illustration of structure-activity relationships (Fig 3). Appropriate concentrations for various kinds of nerve block are given in Table 1.

INHALATION ANESTHETICS After 15 years of research a new inhalation anesthetic, isoflurane (Forane), was recently approved by the Food and Drug Administration for clinical use. By crude count, this is the fifth new anesthetic to appear in the past 20 years and several others are in the wings. Why this rapid turnover after 100 years of preoccupation with ether, chloroform and cyclopropane, once the major inhalation agents? And why is nitrous oxide the most widely used of the gases? After a bit of history I shall dwell upon the anesthetics currently in use, their advantages and disadvantages. With the exception of chloroform, all of the early vapors were flammable; chlorofor'm was a major circulatory depressant and hepatotoxin. Then came gaseous cyclopropane, a perpetrator of cardiac arrhythmias, most devastating when ignited because of the high oxygen concentration in which it was given. Only within the past few years have the diehards relinquished the use of ether and cyclopropane, because it cost so much to prevent an explosion and a n t i s t a t i c precautions may not be effective. Death due to anesthetic explosion is probably the only truly preventable mishap in anesthesia. Nonflammability was the major goal in the design of new agents. Because of their stable carbon bonding, the heavily fluorinated hydrocarbons Seemed to offer the necessary inertness. Robbins in 1946 reported preliminary studies on the anesthetic activlty of fluormate~ hydrocarbons. Then it was found t h a t the ether linkage (as in diethylether) provided more promising compounds that were far less hkely to senmtlze the myocardmm to the arrhythmogenic actions of epinephrine and norepinephrine (as with chloroform, ethylchloride and cyclopropane). J. F. Vitcha notes that as a result of the purification of uranium isotopes during the development of the atomic bond, a new fluorine chemical technology arose.This provided the background, first for the synthesis of fluroxene (Fluoromar), halothane (Fluothane), methoxyflurane 359 •

.

•

\

(Penthrane), enflurane (Ethrane) and then its isomer, isoflurane (Forane). Another factor in the development of new agents on the drawing boards was new knowledge about the uptake and distribution of inhaled gases and vapors based on such physical characteristics as vapor pressure and solubility in blood tissues. For example, it has been known since the 1920s t h a t prolonged induction and emergence with d i e t h y l e t h e r occurred because of its high solubility in blood. During induction, the high solubility in pulmonary capillary blood results in washout before the alveolar partial pressure can reach equilibrium with the inhaled, effective anesthetic tension. Since partial pressure r a t h e r t h a n concentration is the essential characteristic of the diffusion of gases across biologic membranes, constant lowering of the effective partial pressure in alveoli delayed induction and caused the classical excitement of the second stage of anesthesia, unless counteracted by high "overpressure" in the inhaled mixture. Conversely, because of its high solubility in blood, ether was not readily removed by alveolar ventilation during emergence, hence awakening was prolonged. Nitrous oxide, an inorganic gas with a very low blood-gas partition coefficient, quickly builds up its partial pressure in alveoli, hence both induction and emergence are rapid. Were it not for its low potency (a concentration of well over 80% is required fbr effective anesthesia, therefore diminishing the a m o u n t of oxygen available), nitrous oxide would be a superb anesthetic for m a n y reasons. Ideally, the higher the vapor pressure the easier the vaporizatiqn. This was dangerously the case with chloroform. The low vapor pressures of new halogenated compounds are balanced by their higher potency, so t h a t a change of 2 or 3 percentage points in a mixture can cause severe respiratory and circulatory depression. An essential requirement, then, was the availability of calibrated vaporizers for their administration, r a t h e r t h a n the handkerchief and cone of the chloroform and ether days. Furthermore, the development of the concept of m i n i m u m anesthetic concentration (MAC) allowed one to compare the physiologic effects of several anesthetics at equal potency. MAC can be determined experimentally in both a n i m a l s and m a n by the reaction to a painful stimulus during anesthesia. It is the minimal alveolar concentration at body equilibrium, at which 50% of the patients fail to respond. This corresponds nicely with the clinical situation, for the surgeon wishes to know if t h e patient will "lie still under t h e knife." Nonflammability, incorporation of the ether linkage (except for halothane), appropriate physical properties, and devices for more q u a n t i t a t i v e vaporization were all realized, but one characteristic of the inhalation anesthetics was not foreseen. For over a cent u r y it had been assumed that, except for trichloroethylene, the 360

gases and vapors were inert compounds t h a t obeyed the laws of ideal gases, and were therefore eliminated from the body without change in composition. But around 1965, VanDyke and then others, using carbon-labeled compounds, found t h a t the anesthetics were in fact metabolized to some degree. A few years later it was learned t h a t the metabolism was in some instances a toxification process. Now that fires and explosions during anesthesia are no longer a problem, the major concern with anesthetics old and new is the possible biotransformation of the compound t h a t can cause cell damage in either of two ways, i.e., the formation of biologically active metabolites in sufficient concentration to bind with cell constituents and cause destruction (discussed later in the section on hepatotoxicity), and the transformation of a compound into components that can act as haptens, binding with other molecules to induce hypersensitivity or an immune response. (The latter mechanism is less well established.)

ANESTHETIC TOXICITY Perhaps this heading is not quite correct, for the term toxicity implies a uniform dose-related toxic response. Chloroform approaches this definition in its hepatotoxicity and methoxyflurane more so with its nephrotoxicity, but the other inhalant agents are nontoxic according to this definition. Fluroxene (Fluoromar), recently withdrawn from the market, was an agent that under modern standards would never have been approved for clinical use. In several animal species, death was a uniform outcome, even with modera~:e exposure. Nevertheless, many anesthesiologists adopted this agent because, like ether and cyclopropane, it stimulated sympathetic activity which tended to maintain blood pressure at a satisfactory level. Currently, such stimulation is considered potentially hazardous because the extra myocardial work created by the tachycardia and increased contractility might not be met by a sufficient oxygen supply in the patient with coronary arteriosclerosis. However, the ether linkage in fluroxene did result i n less cathecholamineinduced myocardial irritability. But fluroxene was also flammable in the anesthetic concentration range; hence, it was not much of an advance over the older agents. Fortunately it was withdrawn from the m a r k e t befbre there was any anesthetic explosion. Fluroxene never achieved wide enough usage for hepatotoxicity to have proved a problem. There is one report of the development of massive hepatic necrosis over a period of 18 hours in a patient in status epilepticus who had been anesthetized with fluroxene while being treated with phenobarbital and phenytoin, which are hepatic microsomal enzyme inducers. 361

Toxic METABOLITES Several potentially toxic products have been isolated in animals following biotransformation of most of the newer anesthetics. However, it has not always been possible to link these metabolites with the events observed in man. For example, as suggested above, trifluoroethanol, a metabolite of fluroxene, is assumed to have caused death in the several species of animals studied, in which hepatic necrosis is one of several visceral lesions. In man, this metabolite is not a major offender. Death owing to hepatotoxicity is a rare event and is rapid, unlike the delayed chloroform poisoning of yore. Trifluoroacetic acid, one of the major metabolites of fluroxene, halothane and isoflurane, has no apparent toxic effects in man. The most striking example of toxic biotransformation of a compound was witnessed after methoxyflurane had achieved widespread clinical usage. Here the splitting off of inorganic fluoride resulted in a t u b u l a r lesion characterized by high renal output and vasopressin-resistant renal failure, once the plasma level of inorganic fluoride had risen to 5 0 - 6 0 mM/L. Inorganic fluoride poisoning was not unknown, and had been described by French authors as "diabetes insipidus fluorique." The tubules were not the only renal focus, for the clinical syndrome ranged from mild, completely reversible i m p a i r m e n t to anuria, in which vasoconstrictive nephropathy, a lesion common to all the toxic nephropathies, was usually found. Following exposure to methoxyflurane, several patients with irreversible renal failure eventually underwent renal transplantation. During microsomal enzyme induction in the laboratory animal, it is possible to transform methoxyflurane into oxalate; the crystals seem to form p a r t of the picture of renal failure. The fluoride lesion is a dose-response phenomenon. Enflurane (Ethrane) also releases free fluoride ion, but in the clinical setting the concentration hardly ever exceeds a level of 20 mM/L. Nevertheless, the plasma concentration of fluoride found after administration of enflurane can approach toxic levels in the presence of dehydration or prior renal insufficiency. At least one report has attested to this. This is one reason why isoflurane (Forane), a much more stable molecule, m a y supersede enflurane. Inorganic bromide is a product of halothane biotransformation, both serum and u r i n a r y concentrations being elevated after exposure. The plasma level is in the range of 3 mEq/L, not quite in the "bromism" range. Because the half-life o f bromine in m a n is about 10 days, some degree of bromide sedation is likely to persist after modest exposure to halothane, whereas a considerable degree of sedation might p r e v a i l after repeated, short-term exposures, as might occur in h a l o t h a n e administration for burn dressings. 362

Under the heading of toxicity one m i g h t also consider the effects of the halogenated anesthetics on the reproductive process in man, mutagenicity in the fetus, and carcinogenicity and mortality in personnel exposed to toxic vapors over prolonged periods of time. Several epidemiologic surveys, both here and abroad, have suggested t h a t an increased ratio and a higher inaidence of fetal abnormalities m a y occur in p r e g n a n t women exposed to trace a m o u n t s of anesthetic vapors in operating rooms. These reports have led to m a n d a t o r y regulations for scavenging of waste gases from anesthesia machines and a trend toward closedsystem rebreathing techniques. Nevertheless, an undisputed cause-and-effect relationship has not been proved for these occurrences. In the laboratory it has been impossible to demonstrate a mutagenic effect of the several anesthetics on a variety of cell populations. A carcinogenic influence has also been suggested as a result of several surveys, implicating a higher rate of d e a t h from neoplasia among anesthesiologists. Those who have criticized the methodology in these epidemiologic surveys contend t h a t the mere stress involved in working in operating rooms m a y be as much to blame in causing pathophysiologic alterations among personnel as is exposure to the trace gases.

COMPARISON OF THE EFFECTS OF HALOTHANE, ENFLURANE AND ISOFLURANE ON ORGAN SYSTEMS Central Nervous System All of these agents in clinical anesthetic concentrations lower the cerebral metabolic rate (CMRo2)and increase cerebral blood flow, particularly enflurane when given in equianesthetic dosage (MAC). Intracranial pressure m a y rise, especially in the presence of space-occupying lesions or cerebral edema. The rise in pressure is a u g m e n t e d by hypoxia but mitigated to some extent by alveolar hyperventilation, which lowers H ion concentration and causes cerebral vasoconstriction. Each of these anesthetics evokes its own peculiar p a t t e r n of electroencephalographic activity, but enflurane is unique in inducing an epileptiform pattern. In inspired concentrations greater t h a n 3%, and especially when alveolar hyperventilation lowers Paco2, seJ.zure patterns are seen on the EEG, accompanied by muscle movements t h a t s u g g e s t seizure. However, the latter occur only in about 1 - 2 % of anesthetized patients, and with no residual neurologic deficit. Nevertheless, the drug package insert suggests t h a t enflurane not be given to patients suffering from epilepsy. Intraocular Pressure The most common t r a n s i e n t rise in intraocular pressure during anesthesia results from the administration ofsuccinyldicholine, a 363

short-acting, neuromuscular depolarizing agent. This probably relates to the fasciculations occurring in the striated extraocular muscles before paralysis ensues. Other causes for more prolonged elevation of intraocular pressure during anesthesia a r e inadequate alveolar ventilation, with a rise in Paco2 and venous dilation, and a pattern of artificial pulmonary ventilation that results in a high, mean venous pressure. The inhalation agents halothane, enflurane and isoflurane tend to lower intraocular pressure.

Respiration At a central level, in the chemoreceptor and neural zones, each of the three anesthetics causes moderate-to-profound degrees of respiratory depression and blunts the peripheral chemoreceptor respiratory stimulation, which is the normal response to hypoxia and hypercarbia. There is thus a need for assisted or controlled respiration when these agents are used at depth. Enflurane is the more profound respiratory depressant at equal MAC, but the response seems to be partially reversible with duration of anesthesia. Peripherally, both halothane and ethrane cause bronchodilation, reducing airway resistance in experimental asthma as well as the bronchoconstriction caused by hypercapnia; halothane is perhaps more effective in this regard. Halothane inhibits mucociliary activity and there is little reason to suppose t h a t the other inhalants behave differently.

Circulation All three agents have been extensively studied in volunteers for their action on the heart and resulting hemodynamic effects. These agents cause a dose-related depression of myocardial performance, as shown by decreases in left ventricular function (dp/dt) and cardiac and stroke volume indices. Consequently, cardiac work is diminished and a lesser demand for oxygen permits a tolerance for the lessened mean arterial pressure and decreased coronary artery perfusion. There is also some degree of peripheral vasodilation. Apparently the myocardial depression produced in the absence of reflex sympathetic stimulation, such as occurs with diethlether, cyclopropane and fluroxene, results from interference with the source of energy needed for contraction, through inhibition of actomyosin ATPase. With the exception of halothane, the other inhalants, with their molecular ether linkage, hardly sensitize the myocardium to the arrhythmogenic properties of endogenous or exogenous catecolamines. Despite circulatory depression, in the lighter planes of anesthesia, manipulations such asiaryngoscopy and tracheal intubation or surgical stimulation elicit strong sympathetic nervous responses when these agents are used. The rise in circulating catecholamines along with the hemodynamic responses of tachycar364

dia and hypertension pose a threat to patients with coronary artery disease, where blood flow may not be equal to the increased demand for oxygen caused by the work created.

Muscle Relaxation All three inhalants exert a neuromuscular blocking effect centrally, internuncially in the spinal cord and at the neuromuscular junction, again in close-related manner. Blocking at the neuromuscular junction assumes importance when the nondepolarizing neuromuscular blockers are used in conjunction with these agents, because of the synergism and consequent lesser need for the larger doses of blocker than might be required when nitrous oxide is given in a balanced technique.

Liver In human beings all three anesthetics cause a decline in the estimated hepatic blood flow, without much change in splanchnic vascular resistance. Even though the decrease in hepatic perfusion exceeds the reduction in hepatic oxygen consumption, as evidenced by a reduction in hepatic venous oxygen tension, there is little evidence of any hypoxic effect in the way of excess lactate production. Nevertheless, the margin of safety is lowered, perhaps a factor in the rare case of hepatic necrosis. Moreover, certain events such as positive pressure breathing, accumulation of carbon dioxide, or hypocarbia, and the sympathetic response to surgical manipulation may increase vascular resistance and decrease ~.epatic blood flow. These events may account for the uniform appearance of mild forms of liver dysfunction following any kind of anesthesia and operation.

Kidneys As part of the splanchnic circulation, the kidneys also undergo marked changes in hemodynamics, water a n d electrolyte exchange and urinary output. With the three anesthetics, renal blood flow and glomerular filtration decrease as a result of renal cortical vasoconstriction; the t~ltration fraction rises, as does overall renal vascular resistance. Consequently, osmolar clearance falls, as does urinary output, with a rise in the urinary/plasma osmolar ratio. These hemodynamic alterations have been ascribed to a variety of influences: prerenal decrease in blood flow as a result of central cardiac depression and production of hypotension; liberation of antidiuretic hormone; the action of catecholamines on the renal vasculature: and, as recently suggested, an action of angiotensin resulting from activation of the renin-angiotensin system. On the whole, then, antidiuresis prevails no matter what agent is used during general anesthesia, which depending on dose is more or less profound, and more profound with associated endogenous catecholamine output. Evidence suggests that during light 365

planes of anesthesia changes i n renal function are both minimal and reversible if hydration is adequate. Where acute t u b u l a r necrosis (ATN) or renal cortical vasoconstrictive nephropathy m a y develop, as in aortic aneurysmectomy, antidiuresis should be countered with extrahydration and use of diuretics, both of the t u b u l a r acting and osmotic types.

The Uterus Once again, the administration of these t h r e e general anesthetics results in a dose-related depression of uterine muscle tone and causes uterine vascular dilation. These effects are of course of concern in therapeutic abortion and ordinary vaginal delivery. Nevertheless, these agents are useful in p e r m i t t i n g necessary i n t r a u t e r i n e manipulation in pathologic states where uterine relaxation is needed.

Summary There has been a rapid turnover in the use of inhalation agents, because of concerns with flammability, autonomic nervous stimulation, production of cardiac a r r h y t h m i a s , biotransformation, toxicity and other, broader epidemiologic concerns. On the whole, the careful, informed use of the currently available agents appears to result in only minimal and reversible dose-related changes in physiologic function.

HALOTHANE HEPATITIS After 20 y e a r s of widespread usage, with some diminution in recent years, even the diehards among anesthesiologists will admit t h a t h a l o t h a n e will on rare occasion induce hepatic necrosis. Controversy once raged between a staunch group of anesthesiologists infatuated with the drug and a more m i l i t a n t group of hepatologists who saw in its use a major epidemiologic hazard to the livers of their p a t i e n t s . It will be recalled t h a t halothane was introduced in the U.S. ar.~und 1958, following w h a t by today's standards were r a t h e r limited studies on animals and similar circumscribed studies in mar, t h a t revealed no e v i d e n c e of hepatic derangement. Halot h a n e was the first genuine innovation in. anesthesia after more than a century's use of nitrous oxide, ether, chloroform and cyclopropane as m a j o r agents. No doubt existed t h a t "delayed chloroform poisoning" was an entity but nearly 80 y e a r s elapsed before t h a t knowledge resulted in a b a n d o n m e n t of chloroform. Another halogen, carbon tetrachloride, is a well-known hepatatoxin. The anesthetic h a l o g e n s - ethylchloride, tribromethanol (Avertin compound-tribromethanol dissolved in a m y l e n e hydrate) and divinylether (Vinethene), an u n s a t u r a t e d nonhalogenated hydroc a r b o n - a l l proved to be hepatotoxic. But h a l o t h a n e was pre366

sumed to be inert, nonflammable in ordinary anesthetic concentrations, a worthy substance from the standpoint of stress-free induction and emergence as well as maintenance. The circulatory depression resulting in hypotension was soon accepted as benign, in t h a t work of the h e a r t was reduced with a lesser demand for oxygen when coronary arterial disease was present. During the late fifties and early sixties a spate of case reports appeared in which halothane was linked to the development of varying degrees of hepatic damage. Some patients were anicteric, some had t r a n s i e n t jaundice, some fatal hepatic necrosis, and some after recovery m a y have had postnecrotic cirrhosis. For the most part, these anecdotal case reports of one or several patients in an institution had no acceptable explanation other than the association with halothane. Although viral hepatities were suspect, there was at the time no means to establish the diagnosis by serological testing. Some patients incurred hepatitis after one exposure; more developed symptoms only after multiple administrations or in a sequence of administration with other halogens, e.g. methoxylfurane. More t h a n a few of the patients were middle-aged women, a good m a n y of them obese, with a high incidence of atopy in their histories. Unexplained fever appeared early, as did skin rash and a r t h r a l g i a among these patients, some of whom had eosinophilia; all of their liver function tests indicated hepatic necrosis. At postmortem examination the livers were almost totally necrotic; lesions began in the central portion of the ]obule, and pathologists were hard put to distinguish between viral ar, d drug-induced lesions. For most of these reasons hepatitis was interpreted as a sensitivity reaction. However, despite~ m a n y experiments and tests for sensitivity in man, the concept of sensitivity has not been substantiated. Some of the Original clinical tests in support of this thesis were later proved inadequate or nonspecific for diagnosis, such as the incorporation of tritiated t h y m i d i n e into lymphocytes derived from affected persons and the lymphocytic transformation test. The National Halothane Study was instituted in response to the controversy. For both practical and ethical reasons, this had to be a retrospective project based on postmortem findings of hepatic necrosis, one t h a t looked into clinical records to discover if halot h a n e had been used. In only somewhat over 50% of the deaths attributed to hepatic necrosis had there been postmortem examinations. In more t h a n a few instances microscopic sections suggested postmortem antolysis; in others, poorly stained sections were unfit for diagnosis and the panel of expert pathologists found it hard to distinguish the lesion of viral hepatitis from drug-induced disease because necrosis was so extensive. Although the study was confined to some 34 university hospital departments of anesthesia where data for analysis were avail367

able, several participating departments were eliminated because they were unable to supply adequate records. In addition, several hospitals represented in the final analysis supplied case material that had already appeared in print, so that an element of bias may have intruded. After the study, whose findings some analysts found inconclusive, had been completed, an attempt was made to mount a multiinstitutional prospective study on a large scale, but this failed because of the ethical problems involved in securing patients' consent on an informed basis. The National Halothane Study, based on 856,500 anesthetics, showed that halothane-related hepatitis was a rare event indeed, occurring about once in every 10,000 inductions of anesthesia, but that repeated exposure to the agent could well be a factor in the development of the lesion. Compared to ether, cyclopropane and the balanced technique of giving anesthesia (there were hardly enough cases for analysis), however, halothane had the best overall safety record, based on mortality figures (Table 2). Cyclopropane had the poorest record even though traditionally it had largely been reserved for the poor risk patient, and correction for risk (physical status) by statistical means failed to exonerate cyclopropane. Regardless of the anesthetic, most of the massive hepatic necroses developed in high risk operations, cardiac and neurosurgical, or in procedures involving massive trauma and shock. As in the case of cyclopropane, a strong sympathetic stimulant, sympathetic hyperactivity, the use of vasopressor drugs, anoxia and low flow states probably conspired to induce necrosis. In 1965 an astonishing report appeared in which these substances were shown to be reactive compounds metabolized in the body in varying degree, which potentially could form toxic intermediates. Methoxyflurane, which readily gave up its fluoride ion and formed oxalate crystals in the renal parenchyma, caused a unique kind of renal failure so that it has now virtually been abandoned. Fluroxene, highly toxic in animals, less so in man, has also been withdrawn from the market. During and after haloTABLE 2 . - - D E A T H RATES STANDARDIZED FOR PHYSICAL STATUS, AGE, A N D SEX, PERCENTAGE DYING WITHIN 6 W E E K S MORTALITY LEVEL OF SURGICAL PROCEDURE

HALOTHANE

N-B*

CYCLOPROPANE

ETHER

OTHER

TOTAL

Low Middle High

0.23 1.92 8.54

0.16 1.97 9.23

0.26 2.77 12.58

0.18 1.85 8.30

0.34 2.58 10.84

0.22 2.21 9.33

*N-B = nitrous oxide-barbiturate. (From SummmT of the National Halothane study, J.A.M.A. 197:775, 1966. Used by permission.}

368

t h a n e anesthesia free bromide ion is found in both plasma and urine. Why not a toxification in the breakdown of halothane? H a l o t h a n e is metabolized to a considerable extent but the main metabolites have proven innocuous. Brown and V a n d a m speculated t h a t the answer might lie in an unique kind of biotransformation. Biotransformation of a n y drug is not a solitary, onestage, predictable kind of reaction but a complex one both qualit a t i v e l y and quantitatively. It is perhaps influenced by sex, age, a m o u n t of adipose tissue (leading to storage of this fat soluble agent and its slow release), hepatic blood flow, oxygenation, acid base balance, unknown genetic factors and hepatic microsomal enzyme induction. With the m a n y subtle contaminants in the atmosphere, there need be no prior exposure to other drugs to account for enzyme induction. In 1975, Cohen et al. performed a detailed analysis oft.he urin a r y metabolites of halothane and found t h a t two were possibly reactive enough to combine with liver macromolecules. But the amounts of these compounds were small. Brown has detailed several mechanisms by which an organic halogen, such as chloroform m i g h t destroy liver cells. Lipoperoxidation is one of these, for the endoplasmic reticulum of hepatocytes contains a v a r i e t y of fatty acids (e.g. arachidonic and linoleic acid) coupled as esters with phosphatidylcholine and phosphatidylethanolamine, m a n y of which are long-chain u n s a t u r a t e d molecules. The u n s a t u r a t e d carbon bond decreases the binding energy of hydrogen so t h a t only m i n i m a l energy is required to displace the hydrogen ion and replace it with oxygen in the form of a peroxidizing radical. The latter, being unstable, a t t r a c t s still another hydrogen ion from an adjacent fatty acid to form a carboxylic acid group. The r e s u l t a n t cleaving action leads to d e n a t u r a t i o n of the fatty acid and an autolytic chain reaction t h a t causes catastrophic destruction of cellular components, a phenomenon known as lipoperoxidation. This is accepted as the basic m e c h a n i s m of chloroform and carbon tetrachloride toxicity. But the triggering event is biotransformation to a free radical. W h e n biotransformation of chloroform is minimal, little lipoperoxidation occurs, as evidenced histologically; if biotransformation is inhibited cell necrosis does not occur. On the other hand, in hepatic microsomal enzyme induction more free radicals are formed and massive hepatic necrosis m a y develop. A second recently proposed mechanism by which halogens m a y induce hepatic necrosis is the reduction of the hepatic content of free radical quenchers (antioxidants). Several compounds found in the liver can act on the covalent electron of a free radical, thereby a v e r t i n g destruction. Reduced glutathione, a polypeptide, is the most important of these substances. Vitamin E or alphatocopherol and certain ions such as zinc and selenium also act as antioxidants. Experimentally, if the glutathione content of liver is 369

reduced to 25% of normal, a hitherto nontoxic dose of chloroform (1% CHCI.~ for an hour) results in massive centrolobular hepatic necrosis. The centrolobular locus is explained on the basis of a presumed higher content of microsomal enzymes in the central portion of the lobule, as evidenced by a high concentration ofcytochrome P-450, the t e r m i n a l oxidase of the system. A third mechanism whereby halogens m a y destroy liver macromolecules lies in the process of covalent bonding, by which reactive intermediates or metabolites can couple with free fatty acids, proteins; phospholipids and other macromolecules. Such coupling with free radicals alters both function and structure; necrosis is part of the cascading reaction. Covalent binding would seem to be dose dependent, for if binding is extensive obvious biological changes occur. Biochemists believe t h a t during anesthesia with halothane a degree of covalent binding takes place but centrolobular necrosis does not develop and plasma enzyme concentrations do not increase. In s u m m a r y , all three mechanisms m a y coexist and the primary event in any of these reactions would seem to be the formation of reactive, intermediate or free radicals via biotransformation. In the case of chloroform, reactive intermediates are formed within a short time with a r e s u l t a n t dose-related response. When biotransformation is inhibited, hepatic necrosis does not appear but when biotransformation is enhanced via enzyme induction (as with administration of phenobarbital or phenytoin) the possibility of toxic dosage is greatly augmented. How do these theories apply to the hepatic lesion in man? I have observed t h a t ordinarily the biotransformation of halothane would seem to be innocuous, for the most part an oxidative reaction leading to the formation of trifluoroacetic acid, bromide and chloride ions. Even if the enzymatic p a t h w a y is induced, few h a r m f u l effects are seen in animals, provided t h a t hypoxia is avoided. But if animals are treated with the compound Arochlor to change the process to a reductive, non-oxygen dependent pathway, t h e n hepatic necrosis ensues. Can such an alteration occur in man? Even though phenobarbital induces the oxidative pathway, the rate of biotransformation is innocuous. Genetically, however, there could be a predisposition toward a reductive pathway and environmentally encountered chemicals (e.g. ethanol, insecticides) m a y play an ancillary role. Chance exposure to such chemicals between successive h a l o t h a n e administrations might t h e n lead to a centrolobular necrosis on repeated exposure. Anesthesia always reduces splanchnic blood flow. It would seem, then, t h a t the development of hepatic necrosis after administration of chloroform, fluroxene, h a l o t h a n e and ethrane (in diminishing o r d e r of possibility) might depend on a chance combination of events: genetic background, exposure to other drugs, reduced hepatic blood flow or hypoxia, dose and mo370

lecular structure of agent and the physicochemical properties whereby it might be retained in tissues. Hence hepatitis is rare and sensitivity to it need not be invoked at all. One can understand why, in this highly profitable market of anesthetics, pharmaceutical companies continue to develop new. anesthetics for inertness and appropriate physical properties. There may, however, always be the unique patient whose body constitution and environment will upset the grand design.

THE MALIGNANT HYPERTHERMIA SYNDROME The malignant hyperthermia or hyperpyrexia syndrome (MHS) is very much in the news these days because of the promotion of dantrolene (Dantrium) for both prevention and treatment of the syndrome. Dantrolene, a congener of hydantoin, has for some time been available as a skeletal muscle relaxant in the treatment of spasticity in stroke, cerebral palsy and spinal cord injury. Lack of an aqueous soluble form of the drug delayed its trial in MHS but an intravenous preparation is now at hand. Dantrolene has been effective both prophylactically and therapeutically in aborting MHS in several porcine species with a hereditary disposition toward development of the syndrome. In these species, major stress or the use of anesthetics and adjuncts known to produce the phenomenon in man results in the classical picture of MHS. HISTORY

W h e n did the problem of M H S arise? Recently it has been cited as the most c o m m o n cause of anesthesia-induced death in the U.S.. There is about i death for every 20,000 anesthetics given. Some 20,000 to 50,000 incidents of M H S are said to occur annually with a fatalityrate of 60%. Nevertheless, few anesthesiologists have encountered this complication. In the past ten years two international congresses have been devoted to discussion of this disease. Denborough of Australia deserves credit for calling attention to the problem in the 1960s, when he encountered a 21-yearold student who went to a hospital for reduction of a leg fracture. The m a n was concerned not so m u c h about the fracture as by the knowledge that 10 relatives of his had died as a direct consequence of anesthesia. His mother claimed, that diethylether was given to each relative and that they all h a d h a d high fevers. Further, the first familial death had occurred in 1922. Immediately this brought to Denborough's attention the hereditary aspects of the syndrome and indicated that the disease had been with us for a long time and was not merely a complication of modern anestl~,esia.Thus, perhaps for at least a century, some of the sudden deaths that occurred during or immediately after anesthesia 371

might have been caused by MHS, and one must suspect its presence in those children of yore who developed high fevers and convulsions during ether anesthesia. Although the kind of general anesthetic given the student was not mentioned, his temperature began to rise ten minutes after induction, the operation was terminated and he survived. He later withstood the effects of spinal anesthesia for extraction of an ureteral calculus without event. Apart from his broken leg, his physical examination and all biochemical tests were normal. Denborough, a geneticist, also examined the young man. Study of the family pedigree revealed that he had probably inherited this previously unrecognized error of metabolism as a Mendelian dominant characteristic. During the 20 years since then, much has been written about the pathophysiology, predictive characteristics and diagnostic modalities. Despite definition of some aspects of these categories and various suggested forms of treatment, the mortality is still said to be about 60%. To this day hardly any aspect of MHS is fully settled. The MHS is defined as a potentially fatal hypermetabolic syndrome induced by practically all of the currently used inhalation agents and usually triggered by concurrent injection of succinyldicholine (Anectine, Scoline), a short-acting, depolarizing neuromuscular blocker. Although some forms of anesthesia have been called safe, some apparently are not. More Americans may have MHS than has hitherto been realized. It is perhaps induced by major stress, trauma and emotional upheaval or strenuous exercise. Hyperactivity of the sympathetic nervous system, including the release of catecholamines and thyroid hormone, has been implicated in the progression of MHS, through its effects on mitochondria. It is possible that more than a few fatal instances of }mat stroke and mysterious deaths in athletes during the last decade may have been the result of MHS. Likewise, candidates for operation with undue anxiety, fever, and acrocyanosis before anesthesia may have MHS. ETIOLOGY Everyone agrees that the basis for M H S is an underlying muscle disease, a pathophysiologic phenomenon that m a y affectbody membranes in general. T w o predisposing kinds of myopathy would seem to exist.In one, M H S is a dominantly inherited subclinicalvariety. The other is a disease of young males with any of a galaxy of possible physical deformities: short stature, cryptorchidism, pectus carinatum, ptosis, low-set ears, kyphosis, lordosis,weak serratimuscles and antimongoloid slant ofthe palpebral fissures.Thus anesthesiologistshave been warned to pause w h e n they notice any of these defects and to take a history of untoward familial reactions to anesthesia. 372

The development of MHS depends on a combination of myogenic and possibly neurologic and endocrinologic derangements as well as a generalized membrane dysfunction. The distinction between causative and secondary events is unclear. For example, some claim there exists a nonpyrexic variety of the disease that might explain an occasional enigmatic cardiac arrest during anesthesia. Many of the theoretical considerations are based on the results of experiments in MHS-susceptible species of pigs (Dutch Landrace, Poland China, and Pietrain) that may not quite apply to man. These species may succumb to stress alone; such a syndrome is well~known in veterinary medicine, in the dog, cat and horse. Despite the prevailing confusion, more than a few carefully derived observations support a myogenic etiology. 1 have already mentioned the presence of human musculoskeletal abnormalities in MHS. Further, the development of muscle rigidity after intravenous injection of succinyldicholine, although by no means universal, is considered a prime sign of onset. As a predictive finding in patients susceptible to MHS, an elevation of serum creatine phosphokinase (CPK) is sometimes found and, at the height of the syndrome, CPK rises markedly along with myoglobinuria. Muscle biopsies at the time have revealed depletion of adenosine triphosphate (ATP) and CPK. Although the concept is not accepted by all, a rise in skeletal muscle oxygen consumption is said to precede the generalized rise in somatic oxygen use with a subsequent elevation in body temperature. In patients who may be susceptible to MHS, muscle biopsies yield no specific structural abnormalities either by light or electron microscopy. A BIOCHEMICAL THEORY The most reliable diagnostic laboratory test is the development of contracture in isolated muscle exposed to both caffeine and halothane. Caffeine in a concentration of 2.5 m M induces influx of calcium into the myoplasm from the sarcoplasmic reticulum in response to muscle depolarization, while at higher caffeine concentrations re-uptake of calcium into the S R is blunted. Halothane augments the contracture produced by caffeine. Further understanding of the phenomenon comes from a consideration of neuromuscular transmission and muscle contraction. T w o processes are involved in excitation-contraction. First, depolarization of the motor end plates occurs in response to acetylcholine released from the nerve ending. A transient a]teration of m e m brane permeability occurs with influx of sodium and eiffluxof potassium, and as the electrical potential is propagated in muscle, calcium is released into the myoplasm of the muscle fiber. Calcium causes the actin or myosin filaments to slide past each other for the necessary contraction. The source of the bulk of the cai373

cium is thought to lie within the muscle fiber, probably the sarcoplasmic reticulum. Isolated muscle from patients susceptible to MHS displays more t h a n normal sensitivity to caffeine contracture when exposed to halothane. Some researchers believe t h a t a defect in the regulation of myoplasmic calcium exists, so t h a t on exposure to a triggering agent the MHS muscle is unable to control the level of intramyoplasmic calcium. As a result of the inability to strike a balance between the a m o u n t of calcium needed to sustain contraction and t h a t sequestered, hypermetabolism sets in. Dantrolene seems to act upon the excitation-contraction mechanism t h a t couples depolarization of the sarcolemma m e m b r a n e and release of calcium from the sarcoplasmic reticulum. However, the exact mode of action ofdantrolene is still not established. CLINICAL SYNDROME AND TREATMENT

The clinical state of MHS probably begins with a hypermetabolic state of muscle followed by generalized h y p e r t h e r m i a . Development of sustained contracture after succinyldicholine is a good warning sign. On rare occasions, some of the narcoAc analgesics will cause contracture a p a r t from the MHS syndrome. Few anesthesiologists routinely monitor body t e m p e r a t u r e except in major operations on the h e a r t a n d brain. Thus, the first sign of M H S is usually tachycardia, secondary to fever, metabolic and respiratory a c i d o s i s - a l l metabolically induced. T a c h y c a r d i a is, however, commonly seen in response to surgical stimulation during light planes of anesthesia, or merely as a result of the muscarinic blocking action of atropine, while both pancuronium (Pavulon) and gallamine (Flaxadil) can elevate pulse rate. Tachycardia also m a y be a sign ofthyrotoxicosis and thyroid storm, and fever as well. In MHS the skin feels hot and venous blood in the operative field m a y look d a r k as a result of excessive oxygen consumption in tissues. Tachypnea is observed in the spontaneously b r e a t h i n g patient, owing to.excess carbon dioxide production but obviously not in paralyzed patients whose lungs are being mechanically ventilated. If MHS is about to develop, anesthesia and surgery should be terminated as quickly as possible and cooling begun by one or a combination of measures: lavage of stomach and body cavities with iced saline; immersion in iced water; surface cooling with ice packs (the least effective step). In at least one reported instance, extracorporeal circulation was instituted to combat hyperthermia, a complex t h e r a p y indeed. With cooling it is i m p o r t a n t to avoid drift into a hypothermic range. P u l m o n a r y hyperventilation is instituted and sodium bicarbonate given intravenously to combat both respiratory and metabolic acidosis. Monitoring of 374

arterial blood gases and acid-base status is necessary to follow the course, and the bladder is catheterized to monitor fluid exchange. An osmotic diuretic should be given to a v e r t acute tubular necrosis or vasoconstrictive nephropathy. Cardiac arrhythmias or arrest m a y comprise the initial signs of MHS. In this case the choice in t r e a t m e n t of a r r h y t h m i a s is not lidocaine, which seems to aggravate the biochemical alteration in muscle, but procaine and preferably procainamide. H y p e r k a l e m i a should be treated by administration of insulin along with glucose infusion. Now t h a t dantrolene is available, some suggest t h a t 1 mg/kg body weight up to a dose of 10 mg/kg body weight be given as soon as possible. All of these measures are continued postoperatively in the intensive care setting, for relapse m a y occur, again suggesting a generalized metabolic abnormality. Commonly reported late complications include disseminated i n t r a v a s c u l a r coagulation (DIC) and acute t u b u l a r necrosis. Coma when present m a y be irreversible, a manifestation of ischemia secondary to overutilization of oxygen. Whatever the outcome, blood relatives of the victim should be examined for MHS potential and those susceptible to MHS might very well acquire Medic-Alert bracelets. Although CPK determinations are not reliable the in vitro caffeine-halothane contracture test is. A muscle biopsy is required; this laboratory procedure can be carried out at one of several c e n t e r s scattered throughout the U.S. When faced with the need for anesthesia and operation, patients susceptible to MHS should be given dantrolene prophylactically. Although no single anesthetic regimen can be considered statistically safe, the b a r b i t u r a t e s (pentobarbital and thiopental), neuroleptics (droperidol - Inapsine) and a nondepolarizing n e u r o m u s c u l a r blocker (e.g. tubocurarine and pancuronium) are judged to be least likely to induce MHS. Regional anesthesia is a good choice when possible, as is heavy sedation to avoid stress, and use of one of the ester local anesthetics (procaine or tetracaine), r a t h e r t h a n lidocaine. A carefully t a k e n history of family problems with anesthesia, attention to emotional states and certain physical defects, and concern for the heavily muscled male who has been injured are among the i m p o r t a n t m a t t e r s for the anesthesiologist to consider. Incidentally, in order to be prepared one must have on hand a sufficient stockpile of dantrolene (Dantrium), which costs about $800. The drug has a shelf life of about 2 y e a r s when refrigerated.

ATTITUDES TOWARD ANESTHETIC MORTALITY Not too long ago Keats, in a Crawford Long Memorial Lecture, asked, "What do we know about anesthetic mortality?," including 37~

in his r e m a r k s material from an earlier essay on the risk of anesthesia. Keats' comments are logical and at the same time deliberately contentious, for he claims t h a t there is really no accurate definition of anesthetic death, t h a t in the past we have focused on presumptive errors in anesthetic administration and have overlooked the risk-benefit aspects. At the same time, he repeats an observation made by several others, t h a t anesthesia is not an end in itself, t h a t it has no gain value and offers little therapeutic benefit other than in the t r e a t m e n t of pain. We have been guilty of bias in three ways: first, we do not categorize anesthetics in the same context as other pharmacologic agents where there are large variations in response to drugs, among which anesthetics are the most potent; second, untoward reactions m a y simply signify interaction with other drugs; and third, induction of hepatic microsomal enzymes m a y be a more important factor in adverse reactions t h a n we have hitherto realized. Years ago, the term anesthetic death was used simply out of ignorance. For example, in the burned p a t i e n t or in the neurologically ill with denervation of muscle or d e m y e l i n a t i n g disease, the administration of succinyldicholine for muscle relaxation led to excessive release of potassium and a high p l a s m a level, resulting in cardiac arrest. Such occurrences were mysterious, unexplained anesthetic deaths until the cause was established m a n y y e a r s later. Similarly, death on the operating table might have been a consequence of m a l i g n a n t hyperthermia. Prolonged respiratory depression after the use of succinylcholine was perhaps misunderstood or undetected because an abnormal kind of pseudocholinesterase or its absence led to failure of hydrolysis of the compound. Many surveys probably termed such incidents p~'eventable deaths. It is worth noting t h a t a certain n u m b e r of inhospital deaths fall into the obligatory category, including nosocomial infection, ventricular a r r h y t h m i a s consequent to the use of digitalis, and unrecognized respiratory depression following the use of narcotic analgesics. Since 250,000 sudden deaths occur every year in the U.S. (including death from acute a r r h y t h m i a , mitral valve prolapse, Prinzmetal's angina, and prolonged QT interval), why m i g h t not some deaths in the peri-operative period be of a coincidental nature, without postmortem evidence? ObviouslY there is much t r u t h in Keats' r e m a r k s but he overlooks error in anesthetic administration. Macintosh of Great Britain and Cole of N e b r a s k a have r e m a r k e d t h a t every anesthetic death is preventable. In the subsequent discussion on hazards of the anesthesia machine, I have referred to Cooper's study of preventable a n e s t h e s i a mishaps, a critica] analysis of the h u m a n factors involved, in which 82% of 359 critical incidents fell into the category of h u m a n error, while another 14% involved failure of equipment. Errors of this kind have certainly led to 376

death in the p a s t - a n e s t h e t i c deaths, surely, and preventable ones at that. In reality we are talking about the epidemiology of anesthetic accidents, just as others have viewed aircraft, automobile and recent nuclear catastrophes. Epidemiology is the study of events in a population large enough to provide meaningful data. One looks at the host, the agent and the environment in which the event occurs in relation to a disease, accident or epidemic or infectious disease. To be sure, in anesthesia the host is the patient with both medical and surgical ailments, and a certain socioeconomic status. Members of minority groups, children, and the aged have special problems, as do those afflicted with the ills of modern society: alcoholism, smoking, drug usage and lack of preventive dental care. The agent in anesthesia comprises the anesthetist, the drugs he gives, the apparatus employed and also the sufficiency of anesthesia training, plus continuing education and the environment in which he practices, whether he is isolated or exposed to new developments and concepts in the field. Finally, the environment of anesthesia is composed of the hospital, personalities and capabilities of people working in operating rooms and supportive units, and operating schedules which must allow for the overall case load, cancellations, changes in procedures and routine, and the intrusion of emergencies. Is the staff large enough to cope with exigencies in the schedule, such as the need for preoperative visits, recordkeeping, supervision of technicians and coverage of special units? Is supervision of the operating list adequate, does fatigue occur and is relief available? Bearing in mind both Keats' critique and the belief that all anesthetic deaths are preventable, it may be helpful to reexamine some surveys of anesthetic deaths conducted over the years. In 1848, months after chloroform was first administered, the first anesthetic-related death was reported. Hannah Greener, aged 15, collapsed while she was having an infected toenail removed and while she was probably still in the induction phase of anesthesia. Brandy poured into her throat for resuscitation proved to be of no avail. By 1858, John Snow in his text on chloroform and other anesthetics was able:to report on 50 chloroformrelated deaths in England and Wales, where reportage was voluntary. Lyman's work in 1882 listed 393 deaths resulting from the use of chloroform. In those days deaths were not uniformly reported and the source of the figures was limited geographically. Over subsequent decades, every anes~hetic death reported in those countries was related to chloroform usage and the rate rose as more and more operations were performed. Goaded by the journal Lancet, the medical and surgical profession appointed a succession of investigative committees, none of which could come to 377

any firm conclusion. They deliberated over methods of giving chloroform and argued about respiratory versus circulatory causation. All the while, both ether and nitrous oxide were available and nitrous oxide had already begun to be given with oxygen. It is probable that some deaths had already occurred both with ether and nitrous oxide. Only at the end of the 19th century and during the first two decades of the 20th century did the use of chloroform decline. In fact, this was more a result of the introduction of regional anesthesia than it was of the availability of better general anesthetics. It was then shown experimentally that death associated with chloroform was usually the result of ventricular fibrillation. Introduction of the electrocardiograph and synthesis of epinephrine permitted A.G. Levy to observe the onset of ventricular fibrillation in the cat, which he declared to be the result of sensitization of the myocardium by chloroform to the endogenous release of epinephrine. Interestingly, cyclopropane, which has the same property, was used extensively in this country and abroad, in the 1940s through 1960s, and was responsible for many an episode of ventricular arrhythmia. At the time relatively little attention was paid to the not infrequent occurrence of delayed chloroform (hepatic) poisoning which surely resulted in many deaths. From the epidemiologm standpoint one must assess these chloroform deaths, both circulatory and hepatic, as purely ~'agent"-related problems, the anesthetic per se and the anesthesiologist's belief in its usefulness. This kind of mentality exists today where cyclopropane and other halogenated hydrocarbons that cause cardiac arrhythmias, renal failure and hepatic necrosis are still used. At the University of Wisconsin, which had one of the leading academic departments of anesthesia in this country, the decision was made in 1950 to reinvestigate the usefulness of chloroform according to the latest methods of administration. One thousand patients underwent routine electrocardiographic monitoring, liver function tests and urine analyses and were given chloroform for operation along with a control group given other anesthetics. In the CHCI~ group one patient had major a n d one had minor hepatic necrosis; ventricular tachycardia was observed in half of the patients. Electrocardiographic cardiac arrest appeared in one patient and incipient arrest in another. It was concluded that chloroform i s a powerful agent which produces both reflex and direct cardiac depression. :But, the researchers wrote, ¢~Fear and distrust of chloroform are out of all proportion to the facts. If chloroform were introduced today it would be used with great enthusiasm." The concept of preventable deaths in anesthesia was entrenched b y the establishment of an Anesthesia Study Commission in Philadelphia in the forties. Hospital departments were 378

encouraged to report operating room deaths anonymously. Fatalities were then discussed at monthly meetings of the Philadelphia Society of Anesthesiologists. It was assumed t h a t a~esthesiologists were responsible for all factors related to death, other t h a n surgical care. Deaths were classified by vote as preventable and non-preventable. In a published report in 1944 47% of 306 deaths were deemed preventable, 38% not, and the r e m a i n d e r indeterminate. The highest percentage of preventable deaths were found in the good risk category and ascribed to inadequate management, inadequate oxygenation, overdose, and error in judgment. Forty-three of 59 spinal anesthetic deaths were called preventable, a method of anesthesia which is easily examined for its faults. Except for inadequate oxygenation, the other judgm e n t s were probably subject to interpretation b u t one m u s t assume t h a t at t h a t time the judges were well informed and impartial. P a t t e r n s of mortality established then still exist today. The only prospective study of anesthetic deaths was reported by Beecher and Todd, who tried to establish exact operative death rates, why such deaths occurred and whether they were attributable to anesthesia. From 1948 to 1952, all operative deaths at 40 medical school-associated hospitals were subjected to immediate examination. Cause was determined by an independent committee of surgeons, anesthesiologists and internists. The statistical analysis was very good but there were shortcomings: (1) Not all deaths were assigned a cause; (2) the committees per se were not directly involved in the deaths and they had to rely upon records; (3) reporting to the central coordinating office was a voluntary matter; (4) decisions were made within the institution; (5) institutions were not compared; and (6) no details of the deaths were supplied in the final report. Deaths were ascribed to error in diagnosis and surgical j u d g m e n t and technique; deaths related to anesthesia were ascribed to choice of anesthetic, toxicity, abnormal sensitivity, error in administration, inadequate supervision, error in postoperative care and miscellaneous reasons. The death rates derived are shown in Table 3. While the report was accepted for most o f the data given, a major controversy erupted over the contention t h a t death rates were significantly higher when curare was a part of the anesthetic technique (Table 4). This was explained by Beecher and Todd as owing to an inherent toxicity. The body of anesthesiologists could not accept this contention. But one might recall t h a t the study was carried out at a time when techniques of administration of curare were in a state of flux, monitoring of neuromuscular transmission was u n h e a r d of and muscle paralysis was not routinely reversed with atropine and prostigmine. One might argue; then, t h a t if the statistics are correct, as I believe they were, the higher death rate resulted from undetected prolonged respiratory paralysis. Therefore the deaths occurred because of a combination of inadequate 379

"['ABLE 3.--ANESTIIESIA D E A T H

TOTAL CASES

1948 1949 1950 1951 1952 TOTALS

108,100 117,800 123,600 122,000 128,000 599,500

RATE

DEATHS

RATIO OF D E A T H S TO CASES

75 80 89 72 68 384'

1:1440 1:1470 1:1390 1:1690 1:1880 1:1560

(From Beecher, H. K., and Todd, D. P.: A Study of the Deaths Associated with Anesthesia and Surgery (Springfield: Charles C Thomas, Publisher, 1954). Used by permission.) a l v e o l a r v e n t i l a t i o n a n d loss of r e s p i r a t o r y drive, b o t h l e a d i n g to h y p o x e m i a . In addition, B e e c h e r a n d Todd concluded t h a t u n s u b s t a n t i a t e d c l i n i c a l i m p r e s s i o n s of t h e c a u s e s of a n e s t h e t i c d e a t h a b o u n d e d , a n e s t h e t i c p r a c t i c e s w e r e u n s e t t l e d a n d too often t h e r e w a s too m u c h h a s t e to b l a m e or praise. N e v e r t h e l e s s , t h e anest h e t i c d e a t h r a t e d e c r e a s e d from 1 : 1 4 4 0 to 1 : 1 8 8 0 a n e s t h e t i c s g i v e n (see T a b l e 3) d u r i n g t h e s t u d y . O v e r a l l s u r g i c a l d e a t h r a t e s w e r e a s c e r t a i n e d in t h e N a t i o n a l H a l o t h a n e S t u d y , cited e a r l i e r , as p a r t of a r e t r o s p e c t i v e a t t e m p t to discover t h e i n c i d e n c e of f a t a l h e p a t i c necrosis. T h e r a t e s were based on n e c r o p s y r e p o r t s of d e a t h s o c c u r r i n g w i t h i n six w e e k s of o p e r a t i o n in 34 h o s p i t a l s over t h e y e a r s 1 9 5 9 - 1 9 6 2 . O n l y 11,289 of 16,840 d e a t h s w e r e subject to n e c r o p s y a n d in 10,141 t h e abd o m i n a l c a v i t y w a s e x a m i n e d . We saw e a r l i e r t h a t t h e i n c i d e n c e of f a t a l h e p a t i c necrosis proved to be 1:10,000 a n d t h a t reexpoTABLE 4.--SURGERY AND ASSOCIATED ANESTHESIA DEATHS W I T H AND W I T H O U T C U R A R E PRESENCE OR ABSENCE OF MUSCLE RELAXANT

No Curare Curare Totals

STATUS OF

TOTAL NO. OF PATIENTS $ (LIVING AND

NO. OF ANESTHESIA

ANESTHESIA

ANESTHESIA DEATH

SURGERY

DEAD)

DEATHS

D E A T H S (~)

RATE

35 69 162 21 12 85 384

13 26 61 18 10 72

none minor major none minor major

349,939 205,519 27,777 16,313 599,548

1 : 5071 1 : 1270 1:2314 1 : 192

*Based on the assumption that the same percentages of major (37) and minor (63) surgery existed in the curare and no-curare group as was true for the overall data. (From Beecher, H. K., and Todd, D. P.: A Study of the Deaths Associated with Anesthesia and Surgery (Springfield: Charles C Thomas, Publisher, 1954). Used by permission.) 380

sure to halothane was a prominent thctor. But for death rates alone (see Table 2) halothane emerged as the anesthetic with the best overall death rate, 1.8%, other anesthetic choices with 1.93%, and cyclopropane with the poorest record. Perhaps the most provocative statistic was a tenfold difference in institutional death rates, a m a t t e r which has yet to be rationalized. In conclusion, one has the distinct impression from this discussion on anesthetic mortality t h a t in modern anesthetic practice m a n y errors related to h u m a n error, faulty design and use of a p p a r a t u s occur in administration. But the overall death rate seems (without supporting data) to be on the decline in spite of the increasing n u m b e r of complicated major operations on people of ever-increasing age and severity of disease. Improvement if any, m a y have come from a better understanding of preoperative factors in anesthetic deaths; the use of predictive indices in certain categories of illness such as arteriosclerotic h e a r t disease and myocardial infarction; more logical monitoring of physiological functions during anesthesia; an improved understanding of the pharmacokinetics and pharmacodynamics of anesthetics and other drugs; and a burgeoning knowledge of pharmacogenetics in relation to anesthesia. The newer general anesthetics and adjuncts such as the neuromuscular blockers and ketamine were introduced to practice after considerable preliminary study. Still the nagging questions remain. How do we prevent deaths? Are all anesthetic deaths preventable? Why do d e a t h rates differ from institution to institution? In this context two final recommendations of the National H a l o t h a n e S t u d y a r e worth repeating. Limited randomized studies of the various anesthetics, particularly the newer ones, ought to be begun; and a group of institutions t h a t cooperate in serving as a panel laboratory for the acquisition of t r u s t w o r t h y information on new drugs, not merely anesthetics, ought to be established.

ANESTHESIA AND THE CONTROL OF OPERATING ROOM INFECTIONS Most people u n d e r s t a n d t h a t after the introduction of anesthesia in 1846, surgery made little progress until two m a i n issues were resolved: revision of the traditional humoral theory of disease so t h a t surgery might be accepted as a mode of medical therapy, and the prevention of p o s ~ p e r a t i v e wound infection. Both m a t t e r s were for the most part solved toward the end of the century, in the former instance b y the revelations of pathological a n a t o m y and postmortem examination, and in the l a t t e r by the acceptance of aseptic technique. Today we look upon operation as merely a brief phase in the overall surgical experience, for m a n y other factors, pre-, intra- and postoperative, m a y lead to wound sepsis. Nobody is confident t h a t the problem of wound sepsis is 381

completely under control, while some declare that the incidence of postoperative infections of all kinds has hardly changed over the last 25 years, with an overall rate of 1 0 - 20%. In addition to the wound, the infections encountered involve the lungs, u r i n a r y tract and e n t r y sites for invasive diagnostic and therapeutic modalities. If these contentions are accepted as true, failure to effect an improvement in the sepsis rate probably relates to the increasing complexity and duration of operations, the worsening status of patients accepted for surgical p r o c e d u r e s - the aged and those with complicating pulmonary, circulatory, hepatic and renal d i s e a s e - and the fact that patients now survive long enough in intensive care units to contract bacterial and fungal infections. Perhaps just as important is the t u r n a b o u t in therapeutic philosophy: problems once strictly medical are now approached as almost purely surgical diseases. Despite their increasing involvement in all three phases of the surgical experience (pre-, intra-, and postsurgical), anesthesiologists have largely held themselves aloof and blameless in regard to the infection problem, for the most part focusing on methods of cleaning and sterilizing anesthetic r e b r e a t h i n g apparatus and eschewing either a strict, ongoing infection surveillance program or m epidemologic survey. Thus a possible role of anesthesia in the development of perioperative infection can hardly be defined. Although there are no hard data, C. W. Walter, a pioneer specialist in the surgical asepsis field, has cited several localized epidemics of sepsis clearly attributable to the activities of anesthesiologists. In 1848, the spread of cowpox in a group of children undergoing operation was easily traced to a commonly used ether inhaler. In 1968, at an obstetric hospital in Boston, the precepts of Semmelweiss and Holmes were recalled in relation to an outbreak of puerperal fever caused by Streptococcus pyogenes. Twenty three mothers and five newborns were affected, and one anesthesiologist who had given anesthesia to 16 of the parturients was found to have a t r a u m a t i c ulcer that he had incurred while gardening. He had an active lymphangitis and the offending bacterium was readily cultured. At another Boston hospital, 256 Staphylococcus aureus and Klebsiella pneumoniae infections were discovered in a consecutive series of 2,000 operations. These were traced to three individuals: a n u r s e / a n e s t h e t i s t with intractable onychomycosis and a shedding type of psoriasis t h a t did not respond bacteriologically to pHisoHex baths; a neurosurgeon whose child was suffering from chronic otitis media (one of the offending organisms was recovered); and to a surgical intern with furunculosis. Other reports of this n a t u r e are at hand, one by G r y s k a in 1970, in which !3 beta-hemolytic streptococcus infections were traced to an anesthesiologist with licheniform pruritus, and another in Great Britain by P a y n e in 1969, in which there were 23 infections in 217 382

patients; four deaths were attributed to a psoriatic anesthetist from whom Serratia marcescens was cultured. Anesthesiologists are not the only culprits. But such infections might be anticipated since anesthesiologists work not only in operating rooms but in respiratory and intensive care units, make hospital rounds and specialize in respiratory therapy and resuscitation. Thus the peripathetic anesthesiologist, like the surgeon, internist and nurse, can easily spread infection. In analyzing this problem and approaching a solution, which admittedly can hardly be perfect, it is convenient to follow Kaufman's classification of the control of operating room infectionsthe five D's: defense mechanisms, drugs, discipline, design and devices. I shall look at these topics through the eyes of an anesthesiologist. DEFENSE MECHANISMS AND DRUGS

Patients at High Risk

In operating rooms and special care units these days one encounters a spectrum of patients rendered immunologically incompetent by inheritance, disease, or immunosuppressive drugs used in therapy and the transplantation of organs and tissues: patients with burns, leukemia, or uremia, the aged or nutritionally impaired, those undergoing chemotherapy and recipients of bone marrow, kidneys, hearts, etc. A recent report by Tilney amply documents the improvement in morbidity and mortality rates of renal transplantation, due largely to infection control. Mortality, at one time in the 25% range in the first year, has declined to 2% in living donor transplant recipients and 5% with the use of cadaver donors. Routine perioperative therapy with ampicillin, oxacillin and gentamicin is now the mode in many a transplant procedure. Similarly, the prophylactic use of antibiotics in other surgical procedures, though frequently abused or carried out for unnecessarily long periods and often challenged, has reduced infection rate, particularly in some surgical specialties. Unfortunately, drug-resistant bacterial strains arise, and in the most seriously ill, nosocomial, fungal and opportunistic-pathogen bacterial infections prove to be the ultimate cause of death. The general anesthetic agents temporarily suppress the immune response as determined thus far, only by superficial tests of host response: the lymphocytic transformation test (LTT) and the lymphocytic migratory inhibition test (LMIT). Inhalation anesthetics inhibit bacterial growth through a membrane action similar to the manner in which local anesthetics interfere with nerve conduction. Experimentally, however, chronic exposure to the anesthetic inhalants does not improve the survival of skin allografts. 383

Anesthetic Maniptdations It is well known that transient bacteremia follows dental extractions, bladder catheterization and even sigmoidoscopy. There is sufficient reason to expect that endotracheal intubation might be equally hazardous. The pharynx, an area rich in bacteria, is necessarily traversed. One seldom fails to recover bloodstained secretions upon suctioning the pharynx and trachea after intubation, and vigorous suctioning is quite traumatic, so that the mucous barrier is generally breached. Patients with dental and gingival infection are at high risk for bacteremia. In an ideal health care system, such patients might well undergo thorough routine dental prophylaxis before elective operation, or at least receive an antibiotic during invasive maneuvers, as do patients with heart disease during dental extractions. Experiments suggest that spinal or epidural anesthesia in the presence of bacteremia or septicemia may result in meningitis or the formation of an epidural abscess. Lewis Weed, pioneer neurophysiologist in the early twenties, could produce experimental meningitis following foramen magnum puncture in conjunction with intravenous injection of pathogenic bacteria. However, this can hardly be a common outcome in man, for spinal anesthesia has been the common choice for operation on the diabetic with sepsis, and resultant meningitis has not been recognized. Anesthesiologists do tend to favor regional anesthesia in the febrile patient whenever feasible. General anesthesia given in the incubating or active phase of viral hepatitis may exacerbate the disease, according to those who wish to exculpate halothane in connection with the development of acute hepatic necrosis.

Contraction of Infection by Operating Room Personnel While considering the patient foremost, one should not overlook the medical people- surgeons, nurses, anesthesiologists and a t t e n d a n t s - w h o risk contracting disease from patients. Tuberculosis is an old offender, although these days readily treated by drugs and more easily discoverable by skin test rather than chest x-ray study. Contraction of viral hepatitis by personnel in dialysis units, occasionally fatal, is a well-known phenomenon. The disease is still endemic in such units but an entire team of gloved surgeons reportedly contracted hepatitis during operation on one patient. What with promiscuity rife today, gonococcal pharyngitis, proctitis and atypical kinds of urethritis are not uncommon in the patient population and represent a threat of transmission. Finally, the most alarming instance of patient-to-patient and patient-to-physician transmission of disease has been the contraction of Creutzfeldt-Jakob disease, rare but increasingly reported. At least one neurosurgeon, an anesthesiologist, the brother of an anesthesiologist, two patients receiving cadaver corneal transplants, and several neurological patients undergoing stereotactic 384

brain studies have all succumbed to this ailment, one of the slowly fatal, central nervous system viral diseases. Gajdusek's discovery of the viral n a t u r e of Kuru in the cannibalistic natives of Papua, New Guinea, led to eradication of the disease by prohibiting them from eating their victims' brains. Slow viral disease is also the cause of scrapie in sheep and mink encephalopathy, a scourge for m i n k farmers. According to Gajdusek, the virus m a y be killed by boiling in water or exposure to 10% formalin, phenol or i o d i n e - i m p r a c t i c a l means of preventing t h e disease in surgical patients. Thus, neurosurgeons have become increasingly concerned over the performance of brain biopsy in individuals with puzzling neurological symptoms.

Operating Room Design and Housekeeping Anesthesiologists should perhaps be as much concerned about operating room housekeeping as ave the nursing and surgical staffs, or at least be cognizant of these matters, for most of their professional lives are spent in this environment. Air conditioning, ultraviblet lights and laminar flow techniques affect the welfare both of patients and personnel. A similar concern should prevail in regard to classification of clean versus "dirty" operations, maintenance cleaning techniques and traffic patterns. Perhaps the problem of sepsis has been overshadowed by current concern over contamination of the operating room environment with v~aste anesthetic gases. This is alleged to have caused menstrual and reproductive problems in women and a putative higher incidence of malignancy in anesthesiologists. On the surgical side, unduly prolonged operations favor the development of endogenous infection, a statistic found in the multiinstitutional trial of the efficacy of operating room ultraviolet light sterilization.

Discipline and Devices in Anesthesia Remarks made here a p p l y to all personnel in the operating theater though few individuals are conscientious in all respects. It would be well (but not always practical) if individuals would absent themselves from the operating room when they have an acute respiratory infection or a skin lesion such as poison ivy, until evidence of nontransmissability of infection has been established. The appropriate use of operating room clothing, head coverings, masks a n d shoes requires emphasis again and again. Controversy exists o v e r the use of disposable versus resterilized anesthetic breathing systems, on an efficacy versus cost basis. One thing is certain: whatever method of s t e r i l i z a t i o n - e t h y l e n e oxide or o t h e r w i s e - i s used the m a n n e r in which equipment is handled is the most i m p o r t a n t element. In addition to the rebreathing apparatus, the anesthesia machine and sodalime m u s t be suspected, as these items are seldom thoroughly cleaned with 335

antiseptics, except after use in patients with virulent infectionstuberculosis, gas bacillus and other pathogenic bacteria. Bacterial filters in breathing systems may to some degree prevent transmission of infectious air droplets and particulate matter from one patient to another. Many other circumstances in anesthetic care court infection: insertion of oropharyngeal and nasopharyngeal airways, institution of gastric drainage and suctioning and irrigation of the airway. Excessive gadgetry and unnecessary forms of invasive monitoring of vital signs have been implicated in many cases ofbacteremia and septicemia. These include the several kinds of intravenous lines and intraarterial catheters. Proctor has described several ways in which anesthesia and its manipulations may impinge upon airway defense mechanisms. Endotracheal anesthesia, in bypassing the protective, humidifying functions of the nose, oral cavity, pharynx and upper trachea, while using dry gases in open or semiopen breathing systems, causes mechanical injury to cilia and reduces the effectiveness of the mucous blanket and cilia in ridding the respiratory tract of particulate matter and bacteria. Cough and the functional residual capacity of the lungs are diminished by narcotics, both effects conducive to development of atelectasis. In addition to ciliary inhibition, mucus formation is decreased by action of the general anesthetics and the methods by which they are given. Conclusion Although this section focuses on the anesthetist, the message is a general one for all operating room personnel and emphasizes the need for asepsis in giving anesthetics. A careless anesthetist with poor technique does not provide good anesthetic care regardless of his knowledge of physiology and pharmacology.

THE ANESTHETIZING MACHINE This section is concerned with problems t h a t led to the design of a revolutionary new piece of apparatus. Ever since the late 19th century, the function of the anesthesia machine has been to vaporize liquid anesthetics and to deliver them and gaseous anesthetics with oxygen. The aim is to control the depth of anesthesia for operation, with an anesthesiologist at the helm. The original open techniques of giving ether or chloroform were inaccurate. These drugs were given according to traditional signs and stages of anesthesia and the patient was suspended in a plane of anesthesia neither too light nor too deep. But a t least the anesthetist had to watch both the condition of the patient and the progress of operation from minute t o minute. Complicated devices weaken links in the chain of control. The anesthesia machine created problems in the handling of compressed gases, use of individual386

ized vaporizers and flow meters to comply with the physical characteristics of the anesthetics employed, and delivery systems that incorporated directional valves, escape vents and sodalime cannisters for absorption of carbon dioxide. When one considers how much patients' lives depend on this apparatus, it is astonishing to observe how primitive and unsafe it is. The role of the anesthesia machine in anesthetic morbidity and mortality has recently been highlighted by a study of h u m a n factors in preventable anesthetic mishaps. (See the section ~'Attitudes toward Anesthetic Mortality.) The aim of this investigation was to discover patterns of frequently occurring incidents t h a t would engender prospective studies and therefore offer remedies. Through interviews with staff and resident anesthesiologists in one large university teaching hospital, complete descriptions of 359 preventable incidents were obtained over a two-year period. As anticipated, most of these incidents involved h u m a n error (82%), breathing circuit elements became disconnected, unintentional changes in gas flows occurred and drug-syringe misidentifications took place. Although equipment "errors" comprised only 14% of the total number, basic equipment design was frequently at fault in m a n y categories of h u m a n error, as were inadequate experience and insufficient familiarity with equipment plus lack of sufficient knowledge of the surgical operation. Of the 50 incidents involving equipment failure, 10 related to b r e a t h i n g circuits, 9 to airway components, 12 to monitoring devices, 6 to the laryngoscope and 6 to the anesthesia machine. These figures m a y seem low, but when they are extrapolated to the n u m b e r of anesthetics given annually in this country, they are impressive and sobering indeed. Most equipment has been designed to solve troublesome problems as they arise or to enable new anesthetics to be given; an "add on" m e n t a l i t y results. This kind of uncontrolled, retrospective approach, originating from m a n y professional and commercial sources and without effort at standardization, .has led to m a n y alterations in the basic anesthesia "car~." The result is a complexity of devices, inability to detect errors, and the need for additional alarm systems or safeguards, f~w of which are truly failsafe. In newly built facilities, the two m a i n gases used in anesthesia, oxygen and nitrous oxide, are coupled to the anesthesia machine from a central supply source. Because of a n a t u r a l h u m a n tendency to rely on built-in devices, several near-epidemics of cardiac arrest have occurred because the oxygen and nitrous oxide pipelines were crossed during installation. One might ask how this could occur, questioning not the construction error so much but the failure of more t h a n one d e a t h to arouse suspicion. The reason is of course t h a t nitrous oxide is always given with oxygen, so that, when the "nitrous oxide" (oxygen) was turned off, the "oxygen" 387

(nitrous oxide) was administered alone. When a patient is in distress with evident cyanosis (a very poor, late sign of hypoxia) it takes a lot of wisdom and courage not to rely on an anesthesia machine for resuscitate'ion. The mask is a necessa~y part of the act and one forgets that air contains a life-sustainin-g-~20 o~oxygen concentration. Thus the "mixups" were discovered only ~fter a number of cardiac arrests had occurred. Furthermore, central lines have been disconnected quite a few times. Renovation of older facilities, use of outmoded apparatus for backup and failure to m a i n t a i n anesthesia machines all make harm more likely. There is no universally accepted color scheme for identification of nitrous oxide and oxygen in gas cylinders. Occasionally, cylinders used in laboratory work, for example mixtures of oxygen and carbon dioxide, find their way onto the anesthesia machine. Although the pin index system was devised to prevent attachment of the wrong gas cylinder to the manifold, the pins are sometimes broken or dislodged. Furthermore, attachment of an oxygen cylinder to a machine with ignitable materials, dust or oil can cause an anesthetic explosion when the cylinder is opened and the friction of high gas flow generates enough heat for combustion. AIthough the incorporation of reducing valves in-line reduces the high gas pressures in cylinders to 50 PSI, failure of pressure regulation is still possible because of distortion of internal linkage or wearing of valve parts. Inadvertent admission of high cylinder gas pressures to glass flowmeter tubes may rupture the conduits, while unrecognized low pressures may provide inadequate gas flows if gas flows are not observed and maintained on a frequent, recurring basis. "Failsafe" devices are incorporated in all machines these days in order to avert administration ofa hypoxic gas mixture. But the typical device serves only to monitor relative gas pressure~ delivered to the machine from central supplies or cylinders, so that nitrous oxide will not flow if there is no coincident pressure from the oxygen source. However, this system does not avoid deliverance of hypoxic mixtures to a patient when the operator sets the flow meters improperly. Since hypoxia, more hazardous t h a n overdosage, is by far the major hazard in anesthetic administration, it has seemed best to sense the partial pressure of oxygen in the anesthetic mixture as it is delivered to the patient, incorporating an alarm system to alert the anesthetist to a fault. Because of calibration errors, moisture condensation and battery failure, none of the devices so far adopted has reached the state of perfection at which they can t r u l y b e trusted. Further, a major hazard of alarm systems is the false sense of security they give. Now we progress to flow meters, tapered glass tubes in which gas flow is measured against a scale by means of a bobbin or rotameter, the flows being hand-set via knobs which control a needle valve opening. The beginner is n o t certain whether to read gas 388

flows at the top or bottom of the bobbin, and control valves though color coded offer no identifiable touch characteristics. When the knobs were squared r a t h e r than rounded for identification, a greater hazard arose: the undetected movement of an anesthetist, circulating nurse, visitor, etc. could change gas flows without recognition. Because gas flow through an orifice (the space between bobbin and glass wall) is influenced by density rather than viscosity, each tube is hand-calibrated and so guaranteed by the manufacturer. No gas should be allowed to flow through the tube other than the one for which it has been calibrated. Naturally, errors in installation can occur at the assembly plant or in replacement later on. Cracks in the glass tubing cause oxygen to leak, resulting in hypoxia or poor control of gas mixtures. For this reason, in a manifold of flowmeters it is essential to have the oxygen meter downstream from the other gases so that oxygen is entrained rather than forced out by the pressure of other gases on either side. More than a few varieties of machine provide separate meters for high and low gas flows (oxygen, nitrous oxide) so that it is possible to deliver a milliliter gas flow of oxygen in conjunction with several liters of nitrous oxide. The anesthesiologist should continually review gas flow settings and record them and observe the patient for signs of hypoxia. Anoxic pupillary dilation may not be evident if the miosis associated with the use of narcotic analgesics is present. One must always view the operating field and look for dark blood, even if the preoccupied surgeon fails to make the observation. It is remarkable how easily one's senses become so fatigued or distracted that an alarm is not heard or color changes go unnoted. The original vaporizers were of the draw-over kind, like Morton's inhaler, where the air breathed by or the gas supplied to the patient was wafted over the surface of the anesthetic liquid for vaporization. As cooling readily occurs upon vaporization and vapor pressure depends upon temperature, it was rarely possible to deliver a quantifiable mixture to the patient. Furthermore, the incorporation of a vaporizer in line with the main gas flow from a machine led to the possibility of injecting liquid ether into the circuit and into the patient's l~ngs when the emergency oxygen flush valve was turned on. As more potent anesthetics were introduced, vaporizers were made more accurate in terms of delivering concentrations within the necessary low percentages. These w e r e temperature controlled in copper containers of high specific heat so that vapor pressure would not alter with changing gas flows. Some were mounted in line so t h a t some of the gas flow could be sidetracked into the vaporizer and the delivered concentrations read on a dial. Out-of-circuit vaporizers require a separate oxygen flow meter for vaporization of the liquid, but the anesthetist must calculate the percentage in a gas mixture or use a chart. Few of the newer va389

porizers provide a way readily to identify the a g e n t within them or prevent i n a d v e r t e n t mixture with other liquids. Some of the liquid containers provide a lock-and-key a r r a n g e m e n t so t h a t only the specific anesthetic can be added to the vaporizer. Other vaporizers are not p e r m a n e n t l y mounted on the anesthesia machine and m a y be transported i~om one machine to another. Thus they can be dropped, their connections reversed or left unconnected. A n y of these circumstances m a y permit delivery of vapor concentrations m a r k e d l y different from those indicated on the calibration scale. An additional source of inaccuracy lies in the possible application of back pressure as the anesthesia reservoir bag is compressed. Reversal of gas flows and the pumping action thereby increase the concentration of vapor delivered. This hazard has been partially eliminated by the incorporation of one-way valves in line. The breathing circuits of anesthesia machines incorporating a CO,., absorber and the associated mechanical respiratory ventilators are the least standardized elements among anesthesia apparatus. Consequently, the possibilities for error are legion. Leaks m a y develop at gaskets and seals. Directional flow valves used to a v e r t rebreathing of carbon dioxide v a r y from site to site, according to manufacturer. The only way t h a t one can be certain of the competence of these systems is to b r e a t h e t h r o u g h them before the s t a r t of anesthesia (use tubing not intended for the pat i e n t in order to prevent transmission of disease). Leaks are sought by applying pressure tb t h e reservoir bag with exit valves tightly closed. In order to make u s e of carbon dioxide as a respiratory s t i m u l a n t (the older machines incorporated cylinders of carbon dioxide for the purpose), a bypass valve on the absorber m a y be present. Its presence m u s t be known to the anesthesiologist and its 'ton" or "off" position recognized. B r e a t h i n g circuits and their components m a y t r a n s m i t disease if they are not routinely Sterilized after use or if disposable circuits are not used (see Anesthesia and the Control of Operating Room Infections). Even so, an anesthesiologist m a y t r a n s m i t or contract disease depending upon the care with which circuits are handled. In addition, the highly lipid soluble i n h a l a n t s are quite soluble in plastics a n d rubber; thus, if a b r e a t h i n g circuit is reused the second p a t i e n t m a y be exposed to an anesthetic not intended, or the first m a y continue to b r e a t h e considerable amounts of anesthetic even though the vaporizer source has been t u r n e d off, and emerge more slowly from anesthesia. When outdated or subject to undue mechanical agitation, granules of carbon dioxide absorbent (sodalime or baralime) m a y form a caustic dust highly i r r i t a n t to the lungs. No longer used in this country, trichloroethylene (Trilene) when e~:posed to the heat generated by carbon dioxide absorption is broken down into phosgene and several other neurologically toxic products. This is the 390

reason why trichloroethylene was once used as an i n h a l a n t to t r e a t the facial pain of tic douloureux; numbness in the trigeminal nerve distribution often resulted. With the widespread use of n e u r o m u s c u l a r blockers for paralysis and the increasing complexity and duration of operations, mechanical p u l m o n a r y ventilators are now routinely used to assure satisfactory alveolar ventilation, prevent fatigue in the anesthesiologist (who at one time would have squeezed the reservoir bag) and free his hands for a m u l t i t u d e of other tasks t h a t are part of modern anesthesia. Often, however, mechanical ventilators are used merely for convenience. The m a i n danger lies in isolation of the anesthesiologist from the patient so t h a t he no longer feels the chest compliance. Palpation is valuable m e a n s of judging depth of anesthesia and the need for more muscle relaxation. In spite of a l a r m devices and the anesthesiologist's supervision, the ventilator m a y become detached from its connection to the patient and still sound as if it were functioning properly. One proceeds logically to the endotracheal tube. Connections between tube and breathing circuits were recently standardized. Even with uniformity, however, metal or plastic slip joints m a y not fit well, allowing for disconnection when out of sight of the anesthetist. In a spontaneously b r e a t h i n g patient, disconnection simply results in lightening of the plane of anesthesia. This is embarrassing, to say the least, but in the paralyzed patient this courts disaster. Again it is essential t h a t the anesthetist observe the operative field and chest m o v e m e n t or use an esophageal or precordial stethoscope in order to observe respiratory exchange. From this sampling of technical mishaps it should be a p p a r e n t t h a t a revolutionary new design of the anesthesia machine is necessary to provide the devices and a l a r m systems t h a t would eliminate the majority of mechanical failure and h u m a n errors in operation. One can be sure t h a t if as m a n y deaths as occur in airplane and t r a i n accidents were to occur whenever the anesthesia machine was at fault, stringent safety measures woald have been legislated long ago. Some time m u s t elapse before m a n u f a c t u r e r s can adopt some of the features of the new Boston Anesthesia Machine, a product of the bioengineering division of the H a r v a r d Anaesthesia Department's Center for Teaching and Research in Anaesthesia. The desirable features and the role of an anesthesia machine are diag r a m m e d in Figure 4. The anesthesiologist's sensing of the patient's condition is merely extended technologically by this machine. Decisions are made and appropriate actions are carried out by employing the anesthesia delivery s y s t e m - t h e machine, intravenous apparatus, ventilator and so on. The system m u s t be as closely monitored as the patient's status. It became apparent t h a t electronic technology had to be incorporated in any a p p a r a t u s designed to meet the constraints out391

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lined. Thus the machine centers around a minicomputer the function of which is not only to regulate but to check on the operation of the system and provide a warning as soon as there is a departure from the norm. G a s pressures are constantly monitored, so that a warning is sounded before a change in concentration occurs as a result of supply failure. The exact sequencing of o n and off valves to meter oxygen and nitrous oxide flows is carried out by the computer; their positions are checked every second. Instead of the time-honored vaporizer prototypes, volatile anesthetics are injected into a moving gas stream, a fuel injector system like that in the automobile engine, proven to work without failure over m i l l i o n s of hours. The computer detects any change in volatile anesthetic concentration, not only for the agent in use but to prevent cross-contamination. Instead of the customary flow meters, easily read bar graphs are generated by the computer; scale markings change with the agent used. Only ~temporary a d m i n i s t r a t i o n of a hypoxic mixture can occur because an alarm sounds when the oxygen concentration falls below 21%. If the alarm is ignored, an automatic return to a safe concentration takes place and the operator is so informed. The o x y g e n analyzer, a u t o m a t i c a l l y calibrated at the start, measures oxygen concentration in the patient's circuit. An alarm sounds if a disconnection is indicated by failure of airway 392

pressure to vary. If more than one system malfunctions, the computer sounds alarms in an order that calls attention to the most serious failure at the outset. As promising as this new technology might seem, it is still apparent that the machine is only o~e part of the total delivery system. One cannot eliminate the decision m a k i n g process entailed in giving either an inhalation or intravenous anesthetic agent. The aim is to assist the anesthesiologist in doing his work more reliably but this does not eliminate the need for a watchful, informed physician. In order to enhance this watchfulness, a checklist appears on the front of the anesthesia machine. It is an adaptation from the aviation industry, which has a remarkable safety record. Thus the plan for anesthesia m u s t be established in advance and reinforced by subsequent periodic scrutiny of the patient, monitors, intravenous lines and anesthetic machine. BIBLIOGRAPHY Aldrete, J. A. and Britt, B. A. (eds.): Malignant Hyperthermia: The Second International Symposium (1977) (New York: Grune & Stratton, 1978). Beecher, H. K., and Todd, D. P.: A Stucly of the Deaths Associated with Anesthesia and Surgery (Springfield: Charles C Thomas, 1954). Britt, B. A.: Etiology and pathophysiology of malignant hypez~hermia, Fed. Proc. 38:44, 1979. Brown, B. R., Jr., and Vandam, L. D.: A review of current advances in metabolism of inhalation anesthetics, Ann. N.Y. Acad. Sci. 179:235, 1971. Cohen, E. N., and Van Dyke, R. A.: Metabolism of Volatile Anesthetics: Implications for Toxicity (Reading, Mass.: Addison-Wesley, 1977). Cooper, J. B., Newbower, R. S., Long, C. D., and ,McPeek, B.: Preventable anesthesia mishaps: A study of h u m a n factors, Anesthesiology 49:399, 1978. Cooper, J. B., Newbower, R. S., Moore, J. W., et al: A new anesthesia delivery system, Anesthesiology 49:310, 1978. Covino, B. G.: Pharmacology of local anesthetic agents, Surg. Rounds, July, 1978, p. 44. Covino, B. G., and Vassallo, H. G.: Local Anesthetics, Mechanisms of Action and Clinical Use (New York: Grune & Stratton, 1976). de Jong, R. H.:Local Anesthetics (Springfield, Charles C Thomas, 1977). de Jong, R. H., and Heavner, J. E.: Diazepam prevents local anesthetic seizures, Anesthesiology 34:523, 1971. Eger, E. I., II: Anesthetic Uptake and Action (Baltimore: The Williams and Wilkins Co., 1974). Eger, E. I., II, and Epstein, R. M.: Hazards of anesthetic equipment, Anesthesiology 25:490, 1964. Gajdusek, D. C., Gibbs, C. J., Jr., Asher, D. M., et al.: Precautions in medical care of, and h a n d l i n g materials from, patients with transmissible virus dementia (Creutzfeldt-Jakob Disease), N. Engl. J. Med. 297:1253, 1977. Goldstein, A., Jr., and Keats, A. S.: The risk of anesthesia, Anesthesiology 33:130, 1970. Keats, A. S.: What do we know about anesthetic mortality?, Anesthesiology 50: 387, 1979. Laufman, H.: The control of operating room infection: discipline, defense mechanisms, drugs, design, devices, Bull. N.Y. Acad: Med. 54:465, 1978. Morgan, K. G., and Bryant, S. H.: The mechanism of action of dantrolene sodium, J. Pharmacol. Exp. Ther. 201:138, 1977. Moulds, R. F. W., and Denborough, M. A.: Biochemical basis of malignant hyperpyrexia, Br. Med. J. 4:241, 1974. 393

Nelson, T. E., and Flewellen, E. H.: Rationale for dantrolene vs. procainamide for treatment of malignant hyperthermia, Anesthesiology 50:.118, 1979. Ngai, S. H.: Current concepts in anesthesiology: Effects of anesthetics on various organs, N. Engl. J. Med. 302:564, 1980. Ruth, H. S.: Anesthesia study commissions, J.A.M.A. 127:514, 1945. Snow, J.: On Chloroform and Other Anaesthetics (London: John Churchill, 1858). Summary of the National Halothane Study: Possible association between halothane anesthesia and postoperative hepatic necrosis, J.A.M.A. 197:775, 1966. Tilney, N. L., Strom, T. B., Vineyard, G. C., et al.: Factors contributing to the declining mortality rate in renal transplantation, N. Engl. J. Med. 299:1321, 1978. Walter, C. W.: Cross infection and the anesthesiologist, Anesth. Analg. 53:63i, 1974.

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