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THE JOURNAL

of the

KANSAS MEDICAL SOCIETY

Owned and Published by The Kansas lAtedical Society

Volume XLIX

JANUARY, 1948

No. 1

PRESENT STATUS OF SURGICAL TREATMENT OF

DUODENAL ULCER*

Edward S. Judd, Jr., M.D.**

Rochester, Minnesota

Any discussion of surgical treatment of duodenal ulcer in modern times immediately brings to the fore the possibility of resection of the vagus nerve supply to the stomach. Dragstedt1 and his co- workers have now followed a large series of patients for a long enough time to draw certain definite conclusions and they feel that their hypothetical viewpoint is well justified. As is the case with many new, or at least reintroduced, procedures, perhaps uncritical use of vagotomy by scattered investigators who may or may not be completely qualified may cast some air of pessimism on the results, which tends to cloud the picture. It has been said that vagotomy for duodenal ulcer has reached its crossroads. In the relatively near future, it should be definitely decided whether the oper- ation will become recognized as the best of all possible procedures or will be relegated to treatment of only a small group of patients. In the Mayo Clinic such excellent results have been obtained by time-honored principles of surgical management that a majority of the surgeons prefer to treat complicated duodenal ulcers with means that have proved to be of lasting value. At the same time, close watch is being kept on results reported from other clinics in cases in which vagotomy has been performed and a modified series of vagotomies is being analyzed progressively. It would seem, there- fore, to be of the most practical value to consider first those measures which are known to be sound and to finish the discussion with a short appraisal of those factors which must be considered in va- gotomy.

PHYSIOLOGIC CONSIDERATIONS

Before going into even a brief discussion of va- gotomy, therefore, it seems appropriate to review

•Read at the meeting of the Kansas Medical Society, Topeka. Kansas, May 15, 1947.

* ‘Division of Surgery, Mayo Clinic.

quickly what has been learned concerning other procedures. The causation of duodenal ulcer for practical purposes appears quite definitely to be largely dependent on the hypersecretion of an ex- cessively acid gastric juice2. One difficulty in the treatment of the disease has been that therapy, whether medical or surgical, has concerned itself with attempting to counteract this hypersecretion. Thus far nothing has been developed to eliminate the original factor which produces this derangement; therefore, medical treatment has been directed toward neutralizing or at least diluting the secretion and surgical treatment originally did exactly the same.

More recently, surgical treatment has approached the problem in a more fundamental way by at least attempting to remove the source of the diffi- culty. It was early recognized that a good deal of protection to the duodenal mucosa came by way of the bile and pancreatic juices. Several different operations have been concerned with the attempt to take full cognizance of this fact and to attempt to maintain a regurgitation of this alkaline fluid over the vulnerable duodenal mucosa. More recently, greater attention has been paid to the neurogenic factor. It has been known for some time that the emotionally unstable, constantly agitated individual is much more likely to get into difficulty than the more stable, less excitable person. There appears to be a direct neurogenic effect on the gastric secre- tion and the secretory cells within the gastric mucosa.

An excellent means of laboratory reproduction of this situation was afforded some years ago in Wan- gensteen’s laboratory. It so happened that Code"* had been greatly interested in chronic histamine poisoning. In order to maintain a prolonged stimu- lus from histamine, he devised a histamine and beeswax mixture which he implanted in the mus- cles of laboratory animals. This mixture then slowly

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liberated a steady dose of histamine. It was dis- covered that typical duodenal ulcers developed in these animals in a variable period. Not all of these ulcers perforated but in at least 98 per cent of the animals the ulcers were of such severity that there could be no question what the lesion was. This result is more interesting in view of the fact that Ivy and his co-workers had previously injected laboratory animals for as long a time as 60 days, employing an aqueous solution of histamine and giving an injection every two hours. No peptic ulcers were found in their animals. In Wangen- steen’s laboratory, this by-product of Code’s experi- ment was immediately put to use to study means of protecting laboratory animals from the development of these ulcers. Wangensteen had long felt that the acid factor was by far the most important one and he now had material for a critical assay of the situation.

EXPERIMENTAL OBSERVATIONS

It was my privilege to spend some time in Wangensteen’s laboratory and, while I was there, we performed all of the commoner gastric operations on various series of dogs. Following a recovery period, the animals were injected daily with a standard dose of histamine and beeswax mixture. It was found that all the controls presented perfo- rated ulcers at the time of necropsy. In all of those animals which had been protected by resection of at least 75 per cent of the stomach, ulceration failed to develop. In 100 per cent of the gastro-enteros- tomized animals, an anastomotic ulcer was observed. In various other procedures, the incidence of ulcers was so high as almost to condemn any operation other than a wide resection. Hunt4 had just written an article favoring 50 per cent resection for duo- denal ulcers, stating that this would be adequate for most patients who had duodenal ulcer. Immedi- ately, we submitted a series of dogs to 50 per cent , resection and found that in some of these animals jejunal ulceration could be made to develop but the results were nowhere as consistent as with gastro- enterostomy and other types of procedures.

As a sidelight on this experiment, other stimu- lants for gastric secretion were imbedded in bees- wax and injected into laboratory animals. It was found5 that caffeine would produce ulceration in approximately 40 per cent of the subjects but the results were not consistent. Roth and Ivy6 later took up this branch of the problem and corrobo- rated our observations. In their opinion the ulcer- ation was once again due to the excessive secretion of a very high acid gastric juice.

Gastro-enterostomy had almost been condemned in Wangensteen’s clinic and, following this further laboratory evidence, he felt that the operation could now be discarded. Wangensteen and Lannin7, in

applying the evidence to a large series of patients and analyzing the operative results in these cases, admitted that the criticism they had directed toward gastro-enterostomy and toward other investigators’ series might some day be directed to their own gastric resection series. It was found that an inter- val of 15 years or more after gastro-enterostomy had elapsed in many cases before a gastrojejunal ulcer developed. It was admitted that only four or five years had elapsed since a large series of the high gastric resections had been performed and it was just possible that after 15 or 20 years there might be some further difficulty. I believe, how- ever, that all observers were convinced that the problem was being attacked in a vigorous manner.

It would be well at this time to mention in passing the work which is progressing in several laboratories in the attempt to suppress gastric secre- tion before it can produce duodenal ulceration. Ivy and his colleagues have discovered a substance present in the intestinal tract called "enterogastrone” and another substance in the urine called "uro- gastrone.” It is felt that these are represented in the third phase of gastric secretion, commonly known as the intestinal phase. This is the most prolonged of the three phases and it has been stated that it may last from three to nine hours. The clinical reports on this medical treatment of duo- denal ulcer are meager at present because this factor is still in the experimental stage. It is interesting to note the close correlation between this work and the interruption of the vagus nerve supply, as Dragstedt has pointed repeatedly to the fact that during the night the secretion of gastric juice by normal human beings is ordinarily small, whereas the ^nocturnal gastric secretion of patients suffering from, duodenal ulcer is much more voluminous and more acid.

INDICATIONS FOR SURGICAL TREATMENT

The indications for surgical treatment of duo- denal ulcer are now clear-cut. During the past 15 years the most gratifying progress has been made in the proper selection of patients for surgical treat- ment. The patients now fall into definite groups and can be tabulated as to primary and secondary factors to be considered as illustrated in Table 1.

Of the primary factors perhaps the most impor- tant is hemorrhage. This may present itself as an acute episode of massive hemorrhage or as a history of recurrent, rather massive hemorrhages in the past. There is still no great unanimity of opinion on the proper management of acute massive hemor- rhage. In the past many authorities used only medical treatment, and we are all familiar with Meulengracht’s method. A rather good working rule in our emergency service has been that those patients with duodenal ulcer who are less than 45 years of

JANUARY, 1948

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age frequently may be expected to respond satis- factorily to treatment for massive hemorrhage; however, those who are more than 45 years of age are observed very closely in this type of complication as the risk of medical management is greatly increased above that point. It is the practice at the clinic to institute medical treatment for at least 48 hours in all cases in which bleeding occurs. If there is still evidence of continued or recurrent bleeding, immediate surgical treatment is very seriously considered. If the patient presents him- self between hemorrhagic episodes and if there are other factors suggesting complication of the ulcer, one is much more inclined to suggest surgical inter- vention.

The second important primary complication is obstruction. The obstruction commonly falls into two different classifications: either the acute inflam- matory type or the chronic sclerotic type. We are all familiar with the acute type which comes on shortly after the flare-up in the patient’s ulcer symptoms. Most of these patients will respond in a short time to intensive medical treatment, which will include either frequent aspiration of the stom- ach or constant suction through a nasal tube, with either a retention type of liquid diet or a starvation program. Many of these patients will respond so remarkably in ten days or two weeks that they are not interested in any further treatment and they are dismissed to their homes, only to return later with the same problem all over again.

The patient who has the sclerotic type of ulcer presents a less dramatic episode when he is admitted but his history will reveal that the stomach cannot empty properly. There is a great deal of difference in the anatomic appearance of these ulcers, as the subacutely inflamed type is by far the more difficult to handle surgically. If a patient has a chronic obstructing type of duodenal ulcer, all are agreed that there is little to offer aside from surgical management.

Perforation of a duodenal ulcer is obviously an emergency when it is encountered as an acute phenomenon. There is agreement that the simplest most adequate closure of the perforation should be the method of choice. Further procedures during the emergency do not appear to be warranted. Roscoe Graham stated that the opening may be closed with a full omental patch rather than by suturing the defect shut. More extensive surgical procedures should be delayed until later. My col- leagues and I do not insist that all patients who have perforated ulcer should return at a later date for radical resection but repeated perforations are commonly seen. Wangensteen has emphasized the fact that the attempts at perforation are represented by many layers of tissue resembling lamellae and

actual tissue encountered may have no resemblance to the original duodenal serosa. The pancreas is commonly the site of a very deep crater. When such a pronounced defect is present it is not reasonable to expect that medical measures will be completely effective.

The fourth primary indication for surgical treat- ment is the intractability of the patient’s pain and other symptoms. This must be carefully evaluated because patients will frequently state that they "have taken good care” of themselves but when one analyzes the situation, the care that they have taken has been far from perfect. When a patient has actually tried for a period of several years to follow the diet and all other instructions outlined for him and still finds that he is unable to perform daily work or lesser tasks in a comfortable manner, most physicians will agree that surgical treatment is the best course for him.

Added to this last is a fifth factor, notably any doubt whether the lesion at the outlet of the stom- ach is benign or malignant. Frequently, an occasion will arise when there is an obstructing les on at the outlet with only a moderate degree of free acid present and other features which are not particularly helpful in establishing a proper diagnosis. In this type of case, my colleagues and I do not delay long in attempting to clear up the situation with medical means. All too often a small carcinoma just at the pylorus is known to present symptoms and signs strongly suggestive of duodenal ulcer. In this type of situation, surgical exploration is certainly justi- fied.

Besides these primary considerations, there are certain secondary factors which must be taken into account. Among these is the economic status of the patient. His primary concern is in making a living and providing for his family. It may be that he is an outstanding man in his own occupa- tion, but that occupation may make certain demands not allowed in a regimen for duodenal ulcer. In such cases, we are more inclined to advise early surgical treatment than when this factor is not present. In a small group of cases there is an inability to co-operate with the physician and, in spite of careful instruction in the dietary regimen, for one reason or another, the regimen cannot be followed so that surgical measures are the only recourse. Then, too, some patients will exhibit an excessive degree of free acid in spite of medical management and it appears that the only way to control this factor is to excise a large share of the acid-producing tissue. A prolonged history of symptoms of duo- denal ulcer experienced by a middle-aged patient, when taken into consideration with other factors, usually inclines one toward a decision to advise surgical treatment, as does marked severity of symp-

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toms which may persist in spite of a rather well- ordered life.

TRENDS IN SURGICAL TREATMENT Having taken all of these indications into con- sideration, it is interesting to look back over the past 15 years of observation of a large number of patients on whom the diagnosis of duodenal ulcer was made. Figure 1 illustrates the trend of medical versus surgical handling. In 1931, more than 25

YEAR

Fig. 1. Incidence of surgical treatment for duodenal ulcer.

per cent of all the patients who had a definite diagnosis underwent surgical treatment. This inci- dence fell off rather rapidly and steadily with only occasional minor variations during the entire 15- year period. In 1944, it reached perhaps the irreduc- ible minimum of approximately 12 per cent being sent for surgical treatment. It is too early to be certain just which way the trend will be from that point forward because of the indeterminate status of vagotomy at the present time.

It is of interest to analyze this incidence of medical treatment further in order to see whether the type of operation being performed had any in- fluence on the decision in the minds of the surgeon and the internist alike. In 1931, as shown in Figure 2, gastro-enterostomy was the operation most fre- quently performed for duodenal ulcer. It maintained

DUODENAL ULCER

Fig. 2. Incidence of different surgical procedures for duodenal ulcer.

its favor for at least eight years, after which it rather rapidly dropped in incidence. During the same eight years, pyloroplasty was performed rather frequently but then rather suddenly it lost favor and has not been used at all in the past seven years.

On the other hand, gastric resection was in its in- fancy at the beginning of this same period. It had a rather slow start but after the first seven years it became much more frequently used and climbed steadily and rapidly to equal gastro-enterostomy in 1940. Since that time it has replaced that operation in many instances.

A report from the Massachusetts General Hospi- tal by Allen and Welch8 as recently as October, 1946, reveals that these authorities still find gastric resection to be the most satisfactory treatment to date. However, they also conclude that when the procedure is considered from every angle, it may not be quite as good as they had hoped it might be. They feel, as any conscientious surgeon does, that the wide resection of a large amount of gastric tissue still seems a bit radical for what sometimes appears to be a very small duodenal ulcer. They apparently feel, as my colleagues and I do, that the newer approach, transthoracic vagotomy, may well prove to be the answer to at least part of the problem.

In many clinics, as has been suggested previously, gastro-enterostomy has been all but condemned in the treatment of duodenal ulcer. As in any type of treatment or operation, one must hasten to state that an operation improperly performed might be ex- pected to give unsatisfactory results. Early investi- gators soon learned that complete diversion of the gastric contents away from the duodenum could produce a marked change in the acidity of the duo- denal contents. It was noticed that almost all of the duodenal ulcers were healed by this operation. It was felt that the constant supply of the alkaline duodenal contents at the direct point where the stomach joined the jejunum might protect that region from development of an anastomotic ulcer. However, for some reason, this turned out to be inadequate protection. Perhaps the greatest trauma produced by the emptying of the stomach is borne by this one point. Certainly the highest acid value would be at this point and it is common knowl- edge that the formation of a jejunal ulcer after gastro-enterostomy is not a rare phenomenon. In cases of obstructing duodenal ulcer, it was learned that a properly fashioned gastro-enterostomy pro- duced a proper emptying of the stomach. For this type of situation, immediate and permanent relief was obtained in many cases. It must always be borne in mind that gastrojejunal ulceration is ob- served from time to time after gastric resection also.

TECHNICAL CONSIDERATIONS

Some of the points usually stressed in the proper performance of gastro-enterostomy may be men- tioned briefly. My colleagues and I prefer to attach the jejunum to the posterior wall of the stomach, placing the afferent loop high on the lesser curva- ture side and directing the stoma obliquely down-

JANUARY, 1948

5

ward and to the left so that the efferent loop reaches from the lowest point just to the left of the angle of the stomach. We prefer posterior gastro-enteros- tomy because it appears to be much more dependent, a much shorter loop on the afferent side is possible and the postoperative gastric retention seems to be much less of a problem. In performing the anasto- mosis, the opening should be large enough for proper emptying, it should not be placed too high and the intestine should not be put straight across the stomach. Wangensteen always emphasizes that in any type of anastomosis, turning too much of a cuff, employing too many rows of sutures or too wide an application of sutures , can be expected to produce poor emptying. Two rows of sutures are ordinarily adequate but many surgeons prefer three, usually two rows of catgut sutures with an outer row of interrupted silk so that a stricture may not form, as might be the case if a running row of silk were used. It must be remembered that a dilated stomach will shrink to almost normal size and this will tend to make the stoma considerably smaller.

If posterior anastomosis is performed, my col- leagues and I are careful to suture the stomach below the incision in the mesocolon for a distance of at least three-fourths inch (2 cm.). Improper attention to this detail will result in angulation of the proxi- mal loop of the intestine, which may have a disastrous effect, or it may allow prolapse of another loop with obstruction. In certain cases it will be rather difficult to close the opening completely but it must be accomplished.

It has been acknowledged that anterior gastro- enterostomy is much easier to accomplish than pos- terior gastro-enterostomy with no danger to the blood vessels in the mesocolon, and, should gastro- jejunal ulceration develop later, it is considerably easier to approach the new ulcer to take down the anastomosis. We have not hesitated to employ an- terior gastro-enterostomy for markedly obese pa- tients with a high-riding, small stomach and a short thick mesocolon, but this situation does not occur very often.

Gastro-enterostomy at present has by no means been condemned at the clinic. In a very small group of cases it is the operation of choice. In an occa-

TABLE 1

Indications for Surgical Treatment of Duodenal Ulcer

Primary	Secondary
Obstruction	Economic or social status
Perforation	Repeated dietary and other
	indiscretions
Hemorrhage	Excessive gastric acidity
Failure of medical	Long duration of symptoms
management
Pyloric lesion with possible	Exceptionally severe
malignancy	symptoms

sional case, it is the operation of expediency; thus an older patient who is a poor surgical risk, who has a chronic, fibrotic, obstructing duodenal ulcer with a relatively low value for free hydrochloric acid, in whom we are certain there is not a carcinoma of the pylorus and who is not a high-strung, emotion- ally unstable individual may well benefit by gastro- enterostomy ( table 2 ) . Occasionally one encounters

TABLE 2

Choice of Operation for Duodenal Ulcer Factors Favoring

Gastric-enterostomy | Gastric resection

Advanced age Low acids No gastritis Chronic lesion Obstruction Poor surgical risk Minimal neurogenic factor Single ulcer

Middle age High acids Severe gastritis Subacute lesion Obstruction (optional) Good surgical risk Marked neurogenic factor Multiple ulcers

a situation in which a satisfactory closure of the duodenal stump would be very questionable because of the inflammation or would definitely be hazard- ous because of the proximity to the ampulla or common bile duct. Gastro-enterostomy is occasion- ally still done in this type of case.

Here it should be noted that many surgeons throughout the country today are performing gastro- enterostomy and adding a subdiaphragmatic vagot- omy at the same time. This is confusing the evalu- ation of the newer operation, for it has been proved that gastro-enterostomy will heal the ulcer. However, it is to be admitted that in a case of obstructing duodenal ulcer with highly acid secretion in which the patient is not a good candidate for extensive resection, the obstruction must be relieved by some sidetracking procedure and perhaps the great reduc- tion in volume and acidity of secretion afforded by vagotomy will protect against further development of an anastomotic ulcer.

The more or less standard procedure at present in many clinics is subtotal gastrectomy. The purpose of the operation is obviously, first of all, to remove a large share of the acid-producing tissue. Another reason for performing subtotal gastrectomy is to provide a new opening to restore gastro-intestinal function. It has been our experience that retention is less common and much less severe after gastric resection than might be the case if gastro-enteros-

TABLE 3

Some Factors Which Influence Choice of Operation for Duodenal Ulcer

Race	I Severity of symptoms
Sex	[ Gastric acidity
Age	| Roentgenologic evidence
Occupation	1 Gastritis
Economic status	| Local nature of lesion
Personal habits	Multiplicity of lesions
Type of symptoms	| Difficulty of operation

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tomy had been performed. There is a resultant reduction in the capacity of the stomach and ob- viously there will be a great change in the physio- logic aspects as well as the anatomic ones. Critics state that this small gastric pouch may produce un- toward symptoms after the operation. An occasional patient is observed who has what is known as the "dumping’' syndrome because the stomach empties so rapidly. I believe that this phenomenon is being observed less frequently than previously but it still should be kept in mind.

There are many modifications of gastric resection but the one most commonly performed is that known as the "posterior Polya” type. At least the lower two-thirds of the stomach and occasionally the lower three-fourths are resected. The danger point of the operation is in the inversion of the duodenal stump. In the highly inflamed duodenal tissue it is occasionally difficult to obtain a satis- factory closure. Frequently by doing the so-called open procedure in which no clamps are placed across the duodenum, a good inversion can first be obtained by the Connell suture without crushing any of the tissue. This can be reinforced by two rows of sutures, the last turning the stump to the pancreatic capsule, and then the stump can be covered with an omental pad. The surgeon is ever on the alert for the common bile duct, especially in cases in which there is much inflammation and considerable foreshortening of the first duodenal segment. In such cases the distance from the ampulla, which we have found normally to average 8 cm., may be shortened to 4 cm. or less. One other point of caution concerns the patient who has had pyloro- plasty in the past. The pyloroplasty will have re- moved the pylorus and a variable amount of duo- denal tissue. Cases are on record in which the common bile duct has been inverted or injured because this fact was not kept in mind.

The Polya procedure employs the entire width of the stomach in the anastomosis whereas the Hof- meister procedure closes the lesser curvature side, allows high resection on that side and permits a smaller anastomosis. The immediate result of this is that the anastomosis can be performed with better exposure, as one is working in the center of the surgical field, with the lesser curvature already secure. A word of caution here reminds one that the esophagus frequently comes in at what appears to be a low point because the fundus of the stom- ach extends so high above the esophageal junction. Cases are on record in which the esophagus has been sutured shut from below by high application of clamps in attempting to perform the Hofmeister procedure.

Recently it has been the conclusion among many

of our surgeons that the actual removal of the duodenal ulcer is not as important as was once thought. Many cases have been described in which the ulcer has perforated or penetrated into the pancreas and the duodenum has been closed just proximal to this point, the ulcer not being removed. Subsequent examination has revealed that the ulcer has completely healed. Scattered reports from other clinics indicating severe injury to the ampulla or the common bile duct produced by attempting to excise a duodenal ulcer have led many surgeons to the logical conclusion that the removal of the ulcer is not worth what little additional protection might be gained.

When I was working with Wangensteen, he pointed out frequently that a very inflammatory ulcer is the greatest problem the surgeon can encounter in the duodenum. He pointed out that Bancroft had suggested that in this type of case, one can transect the pyloric antrum at a safe distance above the pylorus. One can then open the remain- ing stump and dissect out all of the gastric mucosa down to the duodenum. This will remove the gastrin factor of hormonal stimulation for con- tinued gastric secretion. It still leaves the muscularis and serosa which can be well closed. Although this procedure produces an odd appearance in some cases, it usually is very satisfactory and certainly is far safer than radical excision of the duodenal ulcer itself. I have had occasion to employ this procedure in a few instances and have been much gratified with the results. Postoperatively, all of the patients have exhibited complete achlorhydria to the routine type of test meal. I believe this pro- cedure should not be forgotten in the occasional cases in which it is appropriate.

Lahey9 reminds us frequently that in cases of low- lying duodenal ulcer with considerable shortening of the first duodenal segment, it might be well to open the common duct and identify the ampulla by inserting a T tube having a long distal limb which will extend through the ampulla. However, if the principle holds true that the ulcer need not be excised in every case, it will probably not be necessary to identify the ampulla in this way in many instances.

At the Mayo Clinic, Priestley10 and Clagett11 have done several large series of gastric resection for duodenal ulcers, completing the operations as Bill- roth I procedures. They both feel that this is a highly satisfactory operation. It presupposes that the patient has an ulcer which can be removed and still leave enough normal duodenal tissue for a good anastomosis. The patient must have enough mobilizable duodenum so that adequate resection of gastric tissue can still be carried out without placing

JANUARY, 1948

7

tension on the anastomosis. Certainly far less surgi- cal manipulation is necessary than in performing a Polya or Hofmeister operation, there is no threat to the mesocolon and no decision needs to be made whether the anastomosis is to be posterior or an- terior. Priestley and Clagett point out also that there will be no anastomotic jejunal ulcer, that the duo- denum is more resistant than the jejunum to re- current ulceration and that should there be recur- rence, the patient is no worse off than prior to the Billroth I type of anastomosis.

VAGOTOMY

Anyone seriously interested in any of the aspects of treatment of duodenal ulcer today will be con- versant with the literature on vagotomy. It has been aptly stated that vagotomy today has arrived at the crossroads. In the relatively near future it is anticipated that the operation either will be extended to a large group of patients and will continue to be described in enthusiastic terms or will be relegated to a somewhat narrowed field. It is apparent that no two surgeons or investigators have arrived at exactly the same conclusions regarding this method of treatment. The thoracic surgeons will frequently favor transthoracic division of the nerves, whereas those primarily interested in abdominal surgery will feel that they have approximately the same chances with the subdiaphragmatic approach.

The medical profession is tremendously indebted to Dragstedt for his exhaustive research and evalu- ation of this field. Dragstedt has emphasized that the success of the operation is based on complete resection of the vagus nerves to abolish the psychic phase of gastric secretion and perhaps other neuro- genic influences on the gastric mucosa. He has pointed out the evidence accumulated by Cushing, who reported an increased occurrence of acute per- forating ulcer of the stomach and duodenum in certain patients suffering from lesions of the brain. Perhaps the most significant features stressed by Dragstedt are that gastric hypermotility has been a marked feature in most cases of ulcer and that there is an excessive secretion of gastric juice occurring in an empty stomach in the absence of the usual stimulus of food. Complete section of the vagus nerves will remove both of these factors. It is pointed out that after vagotomy, the same type of ulcer pain previously noted can be produced again by administering hydrochloric acid to the patient. In Dragstedt’s opinion this shows that the relief of the pain is not due to interruption of the sensory fibers. It is now widely corroborated that healing of a large ulcer crater will frequently be shown by microscopic and roentgenographic evidence after this type of operation. Dragstedt further has stated that excessive secretion of the gastric juices occur- ring in the empty stomach without a buffering

effect of food and the neutralizing elements from duodenal secretion will obviously have much higher chance of producing ulceration.

The excessive hyperacid secretion noted by many investigators in the fasting stomachs of patients suffering from ulcer most probably is under a direct psychogenic or neurogenic control and, therefore, interruption of the vagus nerves appears to be a highly satisfactory procedure. It is now commonly known that the nocturnal gastric secretion of the ulcer patient is apparently the most significant factor, as the secretion then is most voluminous and is most highly acid. The great majority of investi- gators have reported that there is reduction of the amount of gastric secretion and the degree of acidity in the patients who have complete interruption of the vagus nerves. Decrease of the motor function of the stomach has also been listed and this factor has led other surgeons to proceed cautiously with vagotomy. Gastric retention has been reported from many centers, especially when no further surgical procedure such as gastro-enterostomy has been per- formed. The enthusiasts feel that the retention frequently rights itself within six to nine months although it may cause considerable distress to the patient during that time.

The time-honored operations for duodenal ulcer have now had at least 15 years for evaluation but the ultimate conclusion concerning vagotomy rests now only with the test of time. One frequently reads, especially in the reports from older, more experienced surgeons, that new operations are to be considered in the light of many which have been discarded. A prime example of this is total thyroid- ectomy, formerly done in the treatment of certain types of heart disease.

An attempt to reach a uniform conclusion con- cerning vagotomy today that would apply to many different clinics and centers ends only in confusion. It is known that in a series of dogs that had under- gone bilateral complete interruption of the vagus nerves by the transthoracic approach, the initial achlorhydria later was replaced by a definite degree of free acid in the stomach. In some of these animals, the preoperative level has been reached five years after the operation, and even at the end of five years some of the stomachs still revealed a markedly dilated state suggesting definite atony. However, one cannot overlook the fact that the early results being reported by the best investigators and having included a follow-up period of more than three years indicate that many patients are still completely well. This emphasizes the fact that other effects of vagotomy need not be considered too important. Abdominal distention has been reported but its exact nature is not entirely understood. The

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importance of the interruption of the secretory stim- ulus to the accessory glands of digestion is also not completely understood, but, from reports at hand, it is not entirely essential.

From the foregoing discussion, it is obvious that at present the definite indications for vagotomy will vary with the surgeons who are performing the operation for duodenal ulcer. The large majority of surgeons who have mastered the technic and all of the factors in performing gastric resection are still somewhat reluctant to attempt vagotomy widely. They feel that they now have the means at their disposal for the control of a relatively large number of patients and they continue to perform wide resection. At the same time, they are carefully evaluating all reports from surgeons who are inter- ested in developing the field of vagotomy. The outstanding impression that is left with one after surveying the literature is that, before a definite conclusion is reached, this field should be evaluated further by men such as Dragstedt and others who have done such commendable work in it. The argu- ment about supradiaphragmatic versus infradia- phragmatic interruption of the vagus nerves probably will continue for the present.

An interesting position has been taken by Lahey,9 who has pointed out that the greatest single draw- back to wide gastric resection is the definite inci- dence of development of further ulcerative change. Although this incidence is extremely low, any measure which might further diminish it is, in Lahey ’s opinion, well worth while. The position taken at the Mayo Clinic now is that the abdomen should be explored first because of the possibility of carcinoma in a gastric ulcer. Because the morbid- ity and the mortality rates from gastric resection for these conditions have been reduced to such a low figure, we are now rather loath to change from a direct approach to a more indirect one. Lahey and his associates feel that the employment of vagotomy in duodenal ulcer is most strongly indicated in the prophylaxis against gastrojejunal ulceration. Since the Polya method of anastomosis leaves a wide stoma, there should be excellent possibility for drainage of food contents. The technical difficulty of secondary resection in cases of gastrojejunal ulcer can be extremely perplexing. For these reasons, Lahey and his associates have performed bilateral infradiaphragmatic vagotomy in all cases of gastric resection for duodenal ulcer. They remove a 3 cm. section of the vagus nerve on each side. They have pointed out again that the operation is not a time- tried one.

Along these same lines, Walters and his associ- ates12 felt that the most thorough knowledge of the anatomy of the vagus nerve just below the dia- phragm is indicated; therefore, they performed dis-

sections in more than 100 cases at necropsy. Their conclusion is that in more than 90 per cent of the cases, the infradiaphragmatic approach permits almost as perfect a division of all of the vagus nerve supply as does the transthoracic approach. In less than 10 per cent of the subjects, the exact anatomic distribution of the nerve fibers was inconstant and in a few of the subjects there was no one well- developed trunk on one or on both sides of the esophagus and the vagus nerve supply was distrib- uted through many small branches. It is in the latter type of case that the surgeon would probably realize a less perfect result in attempt'ng to interrupt the entire vagus nerve supply.

Taking the other viewpoint are Moore and his group13 in Boston. In their report, all of the patients who had duodenal ulcer had undergone transthoracic vagotomy. It was felt that a much more complete division of the nerves was possible in this way. Their results are carefully and critically classified. It was noted that even in the cases in which satisfactory results were obtained, there were occasional gastro-intestinal symptoms. Some of these were transient but the patients were concerned enough about them that from that standpoint the immediate postoperative results were a little short of what they had expected. Three of the patients complained of diarrhea which was still persisting three to five months after the operation with three to five daily stools. The diarrhea appeared to the surgeons to be a source of inconvenience but not of actual physical detriment. Two patients had some symptoms suggesting fullness and there was also a feeling of faintness in several instances. This obser- vation is interesting in that the so-called vagal syn- drome after gastric resection without vagotomy presented much the same picture.

Study of the literature reveals definite contra- indications to interruption of the vagus nerves. Earlier reports had sounded a word of caution about the operation in hypertensive patients, especially those who had previously undergone various types of operations for interruption of the sympathetic fibers. There are scattered reports in just such cases. Moore and his associates reported one death result- ing from a cerebrovascular accident nine months after vagotomy. This late death raises the question whether hypertension would be more rapidly pro- gressive in some of these patients. It also made Moore and his associates wonder whether any type of sympathetic resection should be performed cn patients who have active duodenal ulcers and on the other hand whether vagotomy should be offered to any patient who has severe hypertension. Moore and his associates felt that the vagotomy was of definitely more benefit to those patients who had previously undergone only gastro-enterostomy than

JANUARY, 1948

9

to those who had undergone an inadequate gastrec- tomy. This is at variance with reports of other surgeons who feel that the stomach perhaps will not empty as well after gastro-enterostomy as after partial gastrectomy. However, I believe the point which Moore wishes to make is that considerably more difficulty was experienced in those patients with inadequate gastrectomy in that a large share of the pyloric antrum was still present. He wishes to point out that perhaps many surgeons are too prone to seize on the reduced motility of the stomach as complete failure of the operation rather than as only a temporary result.

All of the investigators urge that anyone attempt- ing to do a series of these operations with whatever approach, should check the results by means of the insulin test. The response of the level of gastric acidity to hypoglycemia produced by intravenous injection of 20 to 25 units of insulin is definitely abnormal in cases of duodenal ulcer. This test is not without its own severe effects and actually can be dangerous if it is not completely controlled at all times. Studies of blood sugar levels must be made and all of the facilities for the immediate intra- venous injection of solution of glucose must be available.

The criterion for the proper performance of complete bilateral vagotomy is the abolition of the gastric acid response to the hypoglycemia produced by this intravenously administered dose of insulin. Any tendency toward abnormal response suggests that there are still some fibers of vagus nerves remaining intact. Studies of gastric motility have been made employing intragastric balloons and ky- mographic tracings. Moore and others feel that the gastric stasis is overcome within nine months although delay in the emptying of the stomach may persist. In addition to the test for suggestive pain which is demonstrated by the introduction of hydro- chloric acid into the vagotomized stomach, it is possible to produce gastric pain by overdistention of the balloon, which once again produces symptoms showing that the result of the operation is not contingent on relief of pain alone.

Further study of the literature will only present arguments either for or against situations which now appear to be quite well established and will report only the present preferences or prejudices of the various investigators. If one is deciding which pro- cedure to employ in the surgical management of duodenal ulcer, he still must keep in mind that his criterion is going to be the best surgical result which he personally can produce ( Table 3 ) . At present our choice of operation at the clinic still favors wide gastric resection in those cases in which there are definitely one or more clear-cut indications for sur- gical intervention.

Here it must be emphasized that in the past not enough practical psychologic analyses have been available to the surgeon at all times. As Dragstedt pointed out earlier and as other surgeons have re- emphasized, patients in the past have been con- sidered either candidates for the psychiatric service in the hospital or else strictly surgical problems. It becomes more and more apparent that in many of those cases in which the result after surgical treat- ment is considered a failure, one can look back with the wish that complete psychiatric investigation had been performed before surgical intervention. A very important point for the surgeon to establish in his own investigation is whether the so-called intractable pain with which the patient presents himself is actually pain produced by the ulcer itself. It has been our experience that ulcer pain, no matter how intense and no matter of how long duration, can usually be controlled, if only for a very short time, by extensive medical measures in the hospital. If the patient has some bizarre tendencies in his pain pattern or some slight suggestion of psychologic imbalance, it would be well worth while to defer any further thought of surgical intervention until all of these factors have been properly evaluated. All too often, one sees a patient who apparently has withstood a fairly large surgical procedure, and from all anatomic standpoints the operation has been successful, but the patient still has the same type of pain experienced for years. In any con- clusion concerning any type of surgical procedure, the results will be clouded if any of the unstable or psychologically unbalanced patients are included, no matter which way the results appear to point.

Being confronted then by a patient who definitely presents several of the primary indications for some type of surgical intervention, one will constantly be questioned concerning the new "nerve operation.’ Several of the surgeons in the clinic at present feel that the indications for vagotomy become more definite when there is nothing else which will assure a good result in the patient. An example of this type of condition is a young person, especially a male patient less than 30 years of age, who is obviously a high-strung type of individual, working at all times under a great degree of tension; analysis of whose gastric contents reveals high acidity, and whose pain is so intractable that he cannot perform his usual work properly and perhaps is comfortable only when he is under medical supervision in a hospital. Added to this, he will probably have a long history of ulcer distress in spite of his relative youth. This narrows the field down at present to a relatively small group of patients. In the hypo- thetical case just cited, obviously that type of man represents a group who may have further difficulty even after a rather wide gastric resection and who

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most certainly would have difficulty after gastro- enterostomy alone.

From my own standpoint, the indications for vagot- omy appear at the moment to be rather limited. At present, transthoracic vagotomy is being performed occasionally at the clinic for those patients who have undergone adequate gastric resection previously and who have had further ulceration in the jejunum. Walters has been vitally interested in this topic and his indications will necessarily be different from those that others might have. His approach has been mentioned as the subdiaphragmatic, and vagotomy is frequently combined with some other type of procedure. However, Walters re-emphasizes that the exact nature of the lesion must be determined in any case and that an obstructive type of lesion at the outlet of the stomach most certainly will require some type of further surgical intervention even though this lesion is proved to be benign. The surgeons at the clinic feel that evidence of pyloric obstruction, whether clinical or roentgenologic, con- traindicates the performance of vagotomy alone. Those patients who have come to the clinic after the performance of vagotomy and have presented further symptoms are occasionally found to give positive response to the insulin test; in other words, in a few cases it has been felt that an incomplete vagotomy has been performed. Obviously, these patients will not be criteria for any conclusions concerning vagotomy.

CONCLUSIONS

From my own present standpoint, therefore, my conclusions at the moment must be that a duodenal ulcer is strictly a medical problem until proved otherwise but that, in perhaps 12 per cent of the cases in which the diagnosis of duodenal ulcer has been accomplished, medical measures will not be completely satisfactory. One or more of the now well-established primary and secondary indications will be adequate reason for surgical intervention. When confronted with a complicated duodenal ulcer

which requires surgical management, I have felt that, for young, active ulcer patients who have a high degree of free acid, the operation of choice is an adequate gastric resection, usually completed as a Polya anastomosis or a Hofmeister modification of it. All of these patients are tested by analysis of gastric contents after operation and the degree of immediate anacidity has been most encouraging. The anacidity persists for at least four years in more than 80 per cent of the cases. A low concentration of free hydrochloric acid has been noticed in perhaps 20 per cent of the cases.

In dealing with the duodenal stump, the Bancroft modification need be employed only rarely but at present it appears to be a good alternative, to be kept in mind.

The final thought that I have is that a more nearly complete and a more practical psychologic approach to the patient who has complicated duo- denal ulcer will probably insure a higher percentage of cures.

REFERENCES

1. Dragstedt, L. R.: Section of the vagus nerves to the stomach in the treatment of peptic ulcer. (Editorial.) Surg., Gynec. & Obst. 83:547, Oct., 1946.

2. Priestley, J. T. : The choice of treatment for duodenal ulcer. J. Iowa M. Soc. 32:401, Sept., 1942.

3. Hay, L. J., Varco, R. L., Code, C. F. and Wangensteen, O. H.: The experimental product'on of gastric and duodenal ulcers in laboratory animals by the intramuscular injection of histamine in beeswax. Surg., Gynec. & Obst. 73:170, Aug., 1942.

4. Hunt, V. C. : Di’M^nal ulcer: Ind'^a-ons for and extent of partial gastrectomy. California & West. Med. 36:6, Jan., 1942.

5. Judd, E. S., Jr.: Experimental product'on of peptic ulcers with caffein. Bull. Am. Coll. Surgeons. 28:46, Feb., 1943.

6. Roth, J. A. and Ivy, A. C. : The pathogenesis of caffeine- induced ulcers. Surgery. 17:644, May, 1945.

7. Wangensteen, O. H. and Lannin, B. : Criteria of acceptable operation for ulcer; imoortance of acid factor. Arch. Surg. 44: 489, Mar., 1942.

8. Allen, A. W. and Welch, C. E. : Subtotal gastrectomy for duodenal ulcer. Ann. Surg. 124:688, Oct., 1946.

9. Lahey, F. H.: A position on the employment of vagotomy in the surg'cal treatment of peptic ulcer. Lahey Clin. Bull. 3:66, Jan.. 1947.

10. Pr'estley, J. T. : Personal communication to the author.

11. Clagett, O. T.: Personal communication to the author.

12. Bradley, W. F., Small. J. T.. Wilson. J. W. and Walters, Waltman: Anatomic considerations of gastric neurectomy. J.A.M.A. 133: 459, Feb. 15, 1947.

13. Moore, F. D., Chapman, W. P., Schulz, M. D. and Jones, C. M.: Resection of the vagus nerves in peptic ulcer; physiologic effects and clinical results, with a report of two years’ experience. J.A.M.A. 733:741, Mar. 15, 1947.

STILBESTROL MEDICATION

R. L. Newman, M.D.*

Kansas City, Kansas

Dodds, in a series of investigations starting in 1932, found a whole series of phenanthrene com- pounds which were estrogenically active. The in- teresting feature was that the only common point in their chemical structure and that of estrone and estradiol was the phenanthrene nucleus. Further work by Dodds, Robinson, and others in England

* University of Kansas Medical Center.

obtained a whole series of estrogenically active synthetic substances, the most potent of which is the substance we know as diethyl-stilbestrol, obtained in 1938. The great clinical importance was that estrogenic substances became available in large quantities, cheap in price and potent by mouth. Since that time, diethyl-stilbestrol, which we com- monly call stilbestrol, has been proven to be more

JANUARY, 1948

11

potent than the natural estrogens. Due, perhaps, to differences in metabolism, the synthetic drug is more resistant to deactivation, thus having a cumulative effect and being potent by mouth. The early reports of toxicity of the drug have been disproved to a large extent, and are rarely encountered with small dosage. These were gastro-intestinal disturbances, liver damage, and depression of the bone marrow. As far as is known, the latter two have never been encountered in the human subject. Diethyl-stilbes- trol can be used in any clinical situation where estrogenic substance is indicated, and the largest field for its use, naturally, is the menopause.

However, there are many women to whom the menopause comes as a boon, with striking improve- ment in general health and well-being. Only in a small minority of women are the characteristic menopausal symptoms sufficiently severe to interfere materially with health and happiness as measured roughly by the necessity for medical attention. Many of the symptoms complained of by women in the fifth decade of life are wrongly attributed to the menopause. The characteristic symptoms of the menopause are the well known vascular phenomena, the periodic flushes and sweats and, less frequently, the flashes of heat which may involve the whole body. The vasomotor phenomena may be much in- fluenced by the patient’s state of mind. Thus, endo- crine therapy is only a part of the management of the menopause. We do not know the mechanism of the vascular phenomena; perhaps there are points of contact between the hormone and cerebral path- ways, thus producing a psychoneurohormonal basis for the disturbances. At any rate, the withdrawal or lessening of the ovarian secretion produces a disturb- ance in the pituitary-ovarian relationship producing the menopausal upset. Thus, the administration of estrogens to women suffering with undoubted meno- pausal symptoms is strictly in accord with our present day knowledge of physiology. However, it is necessary to evaluate carefully the patient’s symp- toms. Headaches, dizziness, and irritability might perhaps be secondary to vascular upsets but they are also frequently associated with functional neu- roses. Hence, in determining the effectiveness of treatment, only the relief of vasomotor phenomena should be used. One needs to be something of a gynecologist, an endocrinologist, and a psychiatrist as well as using common sense in treating the meno- pausal patient. In using estrogenic substances, it is important to remember that they are growth stim- ulating in their action. All parts of the genital system are stimulated by them.

Atypical cellular proliferation with metaplasia or production of new growth has been elicited with estrogens in numerous instances. Loeb and Lacas- sagne and others have produced mammary adeno-

carcinoma in certain strains of mice. Certainly, there is enough evidence in the literature on the subject that abnormal estrogenic therapy can be classified conditionally as one of the factors respon- sible for breast cancer. It is also interesting that since 1939 Allaben and Owen, Auchincloss and Haagenson, Parsons and McCall have all reported cases in the human of carcinoma of the breast following estrogenic therapy. It was impossible to state specifically that the estrogen produced the. cancer since too many other factors are involved, such as local trauma, heredity, and the like. It has been pointed out many times that castration will reduce the incidence of cancer of the breast or reduce its rapid spread.

In regard to the uterus and cervix, several investi- gators have done a large amount of work on the subject. Adenomatous polyps of the uterus descend- ing into the vagina have been produced in mice by Lipschutz, Vargas and others. Pre-cancerous form- ations have been produced in the portio by Loeb, Suntzeff, Burns and others. Allen and Gardner have produced a definite carcinoma of the cervix. Many observers have reported the growth of uterine fibroids — and this is easily recognized clinically in the human subject. Gremmell and Jeffcoate in 1939 reported three cases of carcinoma of the cervix in women following estrogenic therapy. They could not prove a direct relationship but pointed out the importance of caution. The possibility of estrogens playing a role in the development of endometriosis has also been pointed out. Bradford in 1944 reported a case of endometriosis in a post-menopausal woman following estrogenic therapy. Meigs and associates in 1946 reported a case of adenocarcinoma following extensive estrogenic therapy.

Certainly hyperplasia of the endometrium is ac- knowledged as evidence of overactivity of estrogenic hormone. Nevertheless, such hyperplasia is merely an exaggerated and persistent proliferative phase of the endometrium, and it disappears when the effect of estrogens is withdrawn. It is, therefore, not a true neoplasm, since the process is reversible. How- ever, carcinoma not infrequently develops in an endometrium previously in a state of innocent hyper- plasia. All grades of epithelial activity from innocent hyperplasia to virulent carcinoma can be demon- strated in the same uterus.

Tumor growth may be defined according to Lipshutz as a localized cellular proliferation which is atypical in intensity of growth and is metaplastic. It must also persist even though the extracellular stimulus which may have been responsible for its proliferation is no longer active. Thus, the uterine fibroid and endometrial hyperplasia are not true tumor growths, since they regress when estrogenic

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stimulation is removed. The carcinogenic action of estrogens is comparable to that of the carcinogenic hydrocarbons, since here, also, the action is reversible under certain timing conditions, but no one doubts their true carcinogenic qualities.

From a clinical standpoint, it is noteworthy that carcinoma of the endometrium has a slight tendency to favor nulliparous women and it has also been reported to have a special predilection for women with a delayed menopause. Both of these trends suggest an endocrine factor. The exact relationship between hyperplasia and carcinoma is a disputed point. There is another group of cases which may constitute the most important evidence for an estro- genic factor in endometrial cancer. This is the steadily increasing list of patients who have been observed with an association of a granulosa or thecal cell tumor of the ovary with an adenocarci- noma of the endometrium. Attempts to demonstrate excessive estrogenic substance in the body fluids of patients with endometrial hyperplasia have not met with invariable success — although, here again, it is frequently found associated with granulosa cell tumors. The explanation of endometrial hyperplasia in post-menopausal women is not clear. There are two possibilities, a small unrecognized granulosa cell tumor, or an extra-ovarian source of estrogen. The possibility of endometrial hyperplasia preceding actual adenocarcinoma has not proved to be true clinically since a follow-up of women showing hyperplasia has not demonstrated an abnormally high incidence of cancer. Since adenocarcinoma most commonly occurs in the post-menopausal wo- men, the endocrinological connection seems compli- acted. The association of a late menopause or per- sistent follicular ovarian cysts has been suggested as possible factors.

In all fairness, it must be mentioned that certain investigators, Emge, Salmon, Geist, Walter and others have produced careful work casting doubt upon any carcinogenic action of estrogens, partic- ularly in humans. However, the great volume of work that has been done on the subject would certainly indicate that estrogenic stimulation in association with other specific factors is carcino- genic. Since diethyl-stilbestrol is a potent, synthetic, estrogenic substance, these conclusions have proved to be applicable to it. If there is danger, and there would seem to be, the potency of this drug makes it even more dangerous.

The phenomenon of bleeding following estro- genic therapy is recognized by all of us. The prolif- erative endometrium sloughs off with the loss of its stimulating agent. This usually occurs within 7 to 20 days after cessation of therapy. For the reason mentioned above, diethyl-stilbestrol more frequently produces this result than other forms of estrogenic

therapy. If the proliferation of the endometrium becomes too extensive, then sloughing of the ex- ternal layers may occur during the course of estro- genic therapy. This does not occur very often except in patients being treated with diethyl-stil- bestrol, where it occurs fairly commonly. This bleeding occurring in a woman of menopausal age must be investigated to rule out the possibility of cancer, thus complicating the picture. The number of curettements required as a result of bleeding following estrogenic therapy has become impressive. It has been estimated in the past three or four years that as many as one-third of the curettages done in this hospital have been for that reason. The case presented will demonstrate some of the problems involved.

This is a case of a 68-year-old white female ad- mitted with a complaint of vaginal bleeding for the past week. She had had a previous attack one year before while using stilbestrol suppositories for vaginitis. However, she had not been using the stilbestrol for at least one month preceding ad- mission. Examination showed moderate enlargement of the uterus. Curettings were increased in amount and grossly suspicious. Microscopic sections showed

adenocarcinoma as demonstrated in the photo- micrograph. Despite treatment this patient died in about one year.

Obviously, there is no way of being certain if stilbestrol did or did not play a part in this picture, but it makes one somewhat suspicious.

It would seem that all estrogens, and especially diethyl-stilbestrol because of its potency, be adminis- tered with considerable caution.

There are certain conditions that should be met in the administration of estrogens. They should only be administered to the patient with severe vaso- motor phenomena. The patient who complains of only an occasional hot flash or one whose complaints are mainly functional is not a candidate for this

JANUARY, 1948

13

kind of therapy. This applies to the surgical, radi- ation or physiological menopause. The drug should be administered in small doses, just as little as pos- sible to relieve the patient’s symptoms. The dosage we are using at present is 0.25 mgm. of diethyl- stilbestrol three time weekly, and it works very effectively. The administration of the drug should never be continued over an indefinite period of time. The dose should be decreased as rapidly as possible with the idea of complete cessation as early as pos- sible. If it is continued over any length of time, there should be rest periods when no drug is given. The continuous administration of small doses over a prolonged period would seem to be more danger- ous from the available evidence on the subject than larger doses over shorter periods of time.

Patients with a strongly suggestive family history of cancer are not good candidates for estrogenic therapy. Nor are those with any suggestive lesions of the breast, cervix, or endometrium.

The patient must be seen at frequent intervals and instructed to report any abnormal bleeding. If such arises, a diagnostic curettage is indicated. The problem of carcinogenic action of estrogens is far from being proved, but its danger should certainly lead to caution in its use.

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Taylor — Am. Jour. Obstet. and Gyn. 36:332-349. Aug., 1938. Taylor — Surgery. 16:91-107. July, 1944.

Teague — Internat’l. Med. Digest. 41:374-378. Dec., 1942. Turner, Davis and Hamblen — Jour. Clin. Endocrinol. 3:453- 454, 455-456. Aug., 1943..

Watson — Jour. Clin. Endocrinol. 4:571-574. Dec., 1944. Wollner — Jour. Clin. Endocrinol. 1:228-233. Mar., 1941. Zondek— Jour. A.M.A. 114:1850-1854. May 11, 1940. Zondek — Jour. A.M.A. 118:705-709. Feb. 28, 1942.

Diseases of the heart and blood vessels kill three times as many people as cancer, six times as many as accidents, eight times as many as pneumonia, 11 times as many as tuberculosis, and at least 500 times as many as infantile paralysis, reported Dr. Theodore G. Klumpp, president of

Winthrop-Stearns, Inc., when addressing a meeting of the Michigan Academy of Pharmacy. He urged expansion of research activities in the field of basic medical sciences and deplored the lack of financial support for scientists and equipment.

14

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

DIGITALIS GLYCOSIDES, OUABAIN AND STROPHANTHIN

IN GENERAL PRACTICE

Jesse D. Rising, M.D.*

Kansas City, Kansas

The isolation of active principles from crude drugs is a major contribution of modern chemistry to the science of therapeutics, but the variety and number of active glycosides prepared from digitalis have led to some confusion. These glycosides also differ pharmacologically. These pharmacologic differences, if not appreciated, may also be a source of mis- understanding, hence some conservative authorities advise the use of whole leaf digitalis preparations

'‘Associate in Pharmacology and Medicine. From the Department of Pharmacology, University of Kansas School of Medicine.

SOURCES OF	TABLE I CARDIAC GLYCOSIDES
Source	Natural Glycoside	Hydrolytic Glycoside
Strophanthus gratus or Acocanthera ouabaio	Ouabain (g-Strophanthin)
Strophanthus Kombe	Strophanthin (Strophanthin K)
	Lanatoside A	Digitoxin
Digitalis lanata	Lanatoside B	Gitoxin
	Lanatoside C	Digoxin
	Purpurea Glycoside A	Digitoxin
Digitalis purpurea	Purpurea Glycoside B	Gitoxin
	Purpurea Glycoside C	Gitalin

only. Ouabain and strophanthin must be considered as digitalis substitutes in many cases.

It is our purpose to correlate the research in this field so that the student and general practitioner may better understand the numerous publications, and be able to select that drug which is especially suited to the needs of the individual patient.

Table I presents the source and character of the active principles of digitalis, showing the progres- sion from Digitalis kmata and D. purpurea to the natural glycosides, and to the hydrolytic glycosides.

Many proprietary names are used to designate the same glycoside. We shall limit our discussion largely to those which are recognized by the latest revision of the Pharmacopeia (U.S.P. XIII). Table II lists their composition and proprietary names. Tire use of such trade names should be discouraged.

STANDARDIZATION

Until pure digitalis fractions became available, biological assay and standardization was the ac- cepted method of assuring uniform potency of prep- arations of the crude drug. The cat method of assay is well established, and is official in the U.S.P. So long as one prescribed only whole leaf digitalis preparations by the oral route the cat unit was found to be reliable, but with the advent of purified digitalis principles, considerable difference between

Glycoside Digitoxin, U.S.P.

Gitalin, N.N.R.

Lanatoside C, U.S.P.

Digoxin, U.S.P.

Lanatoside A, B, & C (Mixture)

Ouabain, U.S.P.

TABLE II

PREPARATIONS OF CARDIAC GLYCOSIDES

Proprietary Name Cardigin Crystodigin Digisidin

Digitaline Nativelle Digitoxin

>>

I

”

”

Purodigin

|

Gitalin (amorphous) I Cedilanid, N.N.R.

!

I Digoxin

Digilanid, N.N.R.*

Manufacturer National Drugs Lilly

Winthrop Varick j Abbott

Parke, Davis I Schieffelin Squibb Stearns Upjohn ! Wyeth

I

Rare Chemicals

I

Sandoz

I

Burroughs-Wellcome

Sandoz

Ouabain

Several

Strophanthin, N.F.

Strophanthin-g* * G-strophanthin* *

Strophanthin, Kombe [ Strophanthin-K

‘Mixture: Lanatoside A, 46%; B. 17%; C, 37%.

* ’Not to be confused with strophanthin, N. F. (Strophanthin-K). This product is twice as potent as the official strophanthin.

Burroughs-Wellcome

Abbott

JANUARY, 1948

15

cat units and the effective dosage in human beings was noted.

The answer to this is simple: the cat unit is an intravenous unit and does not distinguish between absorbable and nonabsorbable material. Neither does it take into account the rate of absorption from the gastrointestinal tract and the rate of disappearance from the body. It is obvious that a glycoside which is slowly absorbed and rapidly excreted will have less effect when given orally than when given intravenously. The relative potency of the preparations is indicated in Table IV.

ABSORPTION

The rate and degree of absorption of the various glycosides differ widely. At one extreme are oua- bain and strophanthin, which are so poorly and so irregularly absorbed as to be entirely unsuitable for oral medications. Digitoxin, on the other hand, is so well absorbed that parenteral injection is rarely indicated. The degree of gastrointestinal absorp- tion of the chief cardiac glycosides is presented in Table III.

ONSET OF ACTION

When given orally, the onset of action of the cardiac glycosides is largely a function of the speed of absorption. The literature contains very little accurate data by which we are able to rank the drugs according to the speed of action when oral administration is employed, but they show only minor differences in this respect.

When it is essential to digitalize a patient rapidly the intravenous route should be used, and on this procedure fairly accurate information is available. The approximate time of development of maximal electrocardiographic effect is listed in Table III. These figures represent the findings of different investigators, but are sufficiently exact to form the basis of therapeutic practice. It should be appreci- ated that the development of maximal cardiographic effect does not coincide with maximal therapeutic effect. Therapeutic effect begins before or about the same time as maximal cardiographic effect, but it continues to develop thereafter, and is partly determined by the condition of the patient.

It will be seen from Table III that the intravenous administration of ouabain or strophanthin produces an almost immediate cardiac response. Digoxin and lanatoside C are somewhat slower in action, and the effects of the other drugs are much delayed. Digitoxin, digilanid and whole leaf digitalis prep- arations develop their effects only slightly more rapidly on intravenous than on oral administration. The time required for fixation by the heart muscle (the latent period) is more important than the speed of absorption in determining the onset of action.

EXCRETION AND CUMULATIVE ACTION

It is significant that patients do not eliminate any definite amount of digitalis each day, but rather a diminishing percentage of the digitalis remaining in the body. The full digitalizing dose of whole leaf digitalis is eliminated in 10 to 15 days. The same is true of digitoxin, whereas lanatoside C and digoxin are excreted in two or three days. Ouabain and strophanthin are virtually completely eliminated in 24 hours.

These relationships can be visualized by compar- ing the daily maintenance dose with the intravenous digitalizing dose as shown in Table IV. The smaller the maintenance dose in relation to the digitalizing dose, the slower the excretion and the greater the cumulative effect.

DURATION OF ACTION

The approximate duration of the electrocardio- graphic effects is presented in Table III. The per- sistence of cardiographic changes does not agree with the duration of therapeutic effects. When compensation has been restored in a patient it may not be lost again for weeks, depending on the cardiac reserve and the load on the heart. After a single digitalizing dose of ouabain in a patient in moderately severe failure, compensation may be maintained for as long as five days. The drug is eliminated in 24 hours, but compensation continues, and this patient can tolerate another full dose at the end of the 24 hours without developing toxic symptoms.

Whole leaf digitalis, digitoxin and digilanid have

TABLE III

PHARMACOLOGIC PROPERTIES OF CARDIAC GLYCOSIDES

	Onset	Duration
	of	of	Degree of
	Maximal	EKG	Intestinal
Preparation	EKG-Effect*	Effect	Absorption
Digitalis purpurea	10 hrs.	over 72 hrs.	20%
Digitoxin	10 hrs.	over 72 hrs.	100%
Gitalin	8 hrs. (?)	72 hrs. (?)	50%
Digilanid	3 hrs.	72 hrs.	65%
Lanatoside C	iy2 hrs.	24 hrs.	10%
			(irregular)
Digoxin	1 hr.	24 hrs.	80%
Ouabain	10 min.	8 hrs.	Poor
Strophanthin	10 min.	8 hrs.	Poor

All values are approximate. * Intravenous admin stration.

16

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

the most sustained effects. Lanatoside C and digoxin are short-acting by comparison. Ouabin and stro- phanthin effects are so brief that they are practically non-cumulative.

CARDIAC EFFECTS

All members of this group of drugs act on the heart in two ways: (1) Traditionally they have been employed to depress the excito-conductor sys- tem : that is, to slow the pacemaker, and to decrease auriculo-ventricular conduction. These effects are largely vagal in origin. (2) More important is the myocardial effect of the drugs. The myocardial responses are attributed to the direct action of the drug on the muscular function of the failing heart causing increased contractility, tonus and irritability. This produces a shorter and more powerful systolic contraction, and permits a longer diastolic rest and filling period. Increased cardiac efficiency is the result. When the output is increased, the venous, return is better accommodated and the venous pressure falls.

The different cardiac glycosides have qualitatively the same cardiac effects. Some authorities believe that the glycosides derived from digitalis are rela- tively more effective in depressing the excito-con- ductor system, and that ouabain and strophanthin excel in stimulating the myocardial contractility and tonus. Their contention may be correct, and there is clinical evidence that seems to support it. We shall reserve judgment on this point, because there is no careful experimental evidence of a definite difference between the glycosides in this respect. Conflicting reports possibly result from failure to use strictly comparable dosage.

TOXIC EFFECTS

All digitaloid glycosides are capable of causing nausea and vomiting by two mechanisms. (1) A cardiac reflex is initiated when an excessive amount of the drug is fixed by the myocardium. This occurs regardless of the route of administration of the drug, and can only be prevented by avoiding overdosage. (2) These glycosides cause local irrita- tion in the gastrointestinal canal which may be sufficient to result in nausea and vomiting within a few minutes to an hour or two. In this case vomiting is usually expected after the administration of relatively large doses, and can be minimized by the use of a well absorbed drug, for if a poorly absorbed drug is given, larger dosage will be re- quired to secure the therapeutic effect.

More important toxic effects are those of cardiac origin: excessive slowing and irregularities. The irregularities are especially significant for they indicate the development of toxic irritability of the myocardium. The first arrhythmia noted is usually the occurrence of ventricular premature sys- toles. These prematurities frequently appear at

regular intervals so that a bigeminal or trigeminal rhythm results. If the overdosage is continued there is danger of ventricular fibrillation and arrest of the heart in diastole.

Many claims have been made for the relatively low toxicity of one or another of the cardiac glyco- sides. Clinical toxicity cannot be measured by determining the absolute toxic dose of the glyco- sides, but rather by ascertaining the therapeutic index. This is the ratio between the toxic and the therapeutic dose of the drug. Reports based on care- ful studies indicate that the therapeutic range of the various glycosides is the same, approximately two to one. In patients with poor cardiac reserve the margin of safety is smaller.

A word of caution is necessary in this connection : acute toxicity is partly determined by the speed of fixation of the glycoside in the myocardium. Since ouabain and stophanthin are rapidly fixed by the heart muscle, these drugs may, in toxic dose, cause fatal arrhythmias without warning. For this reason one must inject a dilute solution of the drug very slowly, and never in full therapeutic dosage if there is any chance that the patient has received a digitaloid drug within seven to ten days. When there is any doubt on this point, it is wise to em- ploy only about one-sixth the therapeutic dose, and to repeat the injection at hourly intervals until the desired effect is secured.

Similar caution is necessary when any rapidly acting glycoside is used. Therefore intravenous digoxin and lanatoside C, although slightly safer in this respect, should be given with the same caution as ouabain. If toxicity is observed with these rapidly effective drugs, it is not so prolonged because these glycosides are also more rapidly excreted.

In order to understand the practical implications of the therapeutic index, it must be remembered that the margin between the minimum therapeutic and the minimum toxic dose is relatively wide in patients who are only moderately ill; it is smaller in patients with severe failure.

THERAPEUTIC APPLICATIONS

The cardiotonic glycosides are of primary value in the treatment of congestive heart failure, actual or potential, by virtue of their myocardial actions. They are also useful in the treatment of patients with rapid arrhythmias (auricular fibrillation, auric- ular flutter and paroxysmal auricular tachycardia) because of the depressing effect on the excito- conductor system. This action permits a slower and more efficient ventricular response, thereby de- creasing myocardial fatigue.

The indications for the different glycosides are determined by their pharmacologic properties. When

JANUARY, 1948

17

rapid digitalization is essential, ouabain or strophan- thin should be employed. Somewhat slower digital- ization can be accomplished with digoxin or lanato- side C, so these drugs are valuable in patients where fairly rapid action is necessary but possible toxic effects must be minimized.

Digitoxin, on the other hand, is superior when slow digitalization is indicated, and for routine maintenance administration. Absorption of this drug is excellent and gastrointestinal irritation is imperceptible. The slow excretion prevents fluctu- ation of the amount of the glycoside action on the myocardium, but prolongs toxic reactions which sometimes occur.

There is some evidence that ouabain and stro- phanthin are superior to any digitalis glycoside when only the myocardial actions are required.

One more aspect of the problem requires con- sideration. The coronary constrictor effect of these drugs is not marked, and is insufficient to contra- indicate their use in the face of decompensation, even in patients who have severe coronary disease. Much has been written about the dangers of using digitalis in the treatment of patients with coronary thrombosis. These dangers are said to be ( 1 ) cardiac rupture at the site of a fresh infarct and ( 2 ) the initiation of a fatal arrhythmia. The first danger seems to be remote indeed; the second can be con- trolled by the frequent administration of small doses of quinidine to prevent hyperirritability of the myo- cardium. By far the gravest danger is that the patient might die 'of acute heart failure resulting from omission of ouabain when he needs it.

A patient with a fresh infarct may survive because of prompt, cautious, administration of ouabain or strophanthin; or he may die as a result of the physi- cian’s timidity in withholding ouabain when the heart is rapidly failing.

The combined use of digitaloid glycosides is of particular importance when a patient has been given ouabain as an emergency measure. Ouabain and strophanthin have the advantage of a very short latent period, and the disadvantage (in some respects) of being rapidly excreted. The patient may be given one or many injections of ouabain, and then must be shifted to digitalis or one of its glycosides for maintenance. For this purpose he must receive more than the maintenance dose of digitalis, but he will not require the amount usually necessary for full digitalization.

Rather than discontinue ouabain at once under such circumstances, it is better to decrease it over a period of three or four days, during which time a digitalis glycoside is given in sufficient dosage to have the desired cumulative effect. This procedure should be conducted under careful observation, for

no rule will give adequate approximation to the doses required.

In summary, ouabain or strophanthin are indicated for: 1 . Acute heart failure. 2. Paroxysmal nocturnal dyspnea and acute pulmonary edema in patients with ventricular failure. 3. Chronic left ventricular failure with gallop rhythm or pulsus alternans.

Digitalis glycosides give better results in: 1. Con- gestive failure with pronounced tachycardia, espe- cially auricular fibrillation. 2. Rheumatic heart dis- ease and chronic valvular disease in young patients. 3. Maintenance dosage.

ADMINISTRATION

For routine use, the oral route of administration is preferable, but the condition of the patient and the charactertistics of the individual glycosides must be considered. As a general rule digitalis glyco- sides should be given by mouth, unless rapid effect is required or unless vomiting renders oral adminis- tration impractical. Ouabain and strophanthin should never be given by mouth; absorption of these drugs is wholly irregular and unsatisfactory.

When the digitalis glycosides are not tolerated by mouth, they may be given rectally. Absorption is satisfactory, and these drugs may be administered by this route in the customary oral dosage. Either the suppository or a microenema may be used. Tincture of digitalis in two to four ounces of warm milk is acceptable, and the pure glycosides can be given in the same manner. Such a retention enema is a less expensive and a more flexible dosage form than the suppository.

Intramuscular administration of digitalis glyco- sides is not advised because the irritating properties of the drug cause local tissue reaction and impede absorption. Ouabain, however, may be given in the muscle ( never hypodermically ) ; only a small amount of the drug is required, and the tissue re- action is proportionately decreased. When emer- gency digitalization is required, and the physician is in the patient’s home with only limited equipment, it is best to give ouabain intramuscularly. The effect is comparable to that of a slow intravenous injection.

DOSAGE

Each patient is an individual problem regarding optimum digitalis dosage. In general, the more severe the failure, the larger the dose required. In Table IV the average single digitalizing dose (oral) is given. This will serve as a guide to the physician, but one should almost never administer a single digitalizing dose by mouth. This procedure is not a substitute for ouabain when rapid digitalization is indicated. It is desirable to spread the digitalizing dose over two or more days, and, for each day required in digitalization, to add the average daily maintenance dose (Table IV) to replace the drug excreted. This simplified dosage scheme may be

18

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

reduced to the following formula which is applicable to all digitaloids when given by mouth or by rectum :

d

x= 1- in

n

When x equals the daily dose for digitalization, d equals the oral single digitalizing dose, m equals the daily maintenance dose, and n equals the number of days to be used in digitalizing the patient.

The intravenous digitalizing dose may be given by a single slow injection, or may be fractioned and given at short intervals. Only the rapidly effective glycosides should be given by vein in ordinary prac- tice. Little time is saved by giving drugs intra- venously that have a long latent period before the cardiotonic effects begin.

After digitalization has been produced, it is usually necessary to maintain the effect to prevent a return of decompensation. Table IV lists the average daily maintenance dose, but individual requirements may differ widely, and the appropriate dose must be determined for each patient.

The dosages given in Table IV are for an average adult (130-160 pounds). Children and small adults may be given a digitalizing dose consisting of about one unit for each ten pounds of body weight. Age and sex do not significantly affect digitalis require- ments, and body weight is no longer regarded as an absolute standard for dosage calculation.

SUMMARY

The physician now has at his disposal many purified digitaloid principles which have an advan- tage over whole leaf digitalis because of their uni- form potency. The various glycosides also have distinguishing pharmacologic properties which al- low greater therapeutic flexibility.

No one glycoside is better than the others; it is only different. The differences in the glycosides must be well understood by the physician if he is to give his patient the best treatment that modern chemistry places at his disposal. At first it may seem that the subject is too complex for the average doctor to understand, but it can be simplified by using

accepted names of the glycosides, and by adherence to a few fundamentals of pharmacology and thera- peutics.

The general principles of the subject have been discussed, so that we may now summarize the partic- ular cardiac glycosides and glycoside mixtures:

1. Digitoxin (U.S.P.) has a long latent period, and therefore is undesirable for intravenous medica- tion. It is contraindicated when rapid digitalization is necessary. The drug is nearly 10 per cent ab- sorbed when given by mouth. The long duration of action makes smaller maintenance doses possible. This may be an advantage in routine medication. However, toxic effects, when they occur, are more prolonged. For this reason the drug may be danger- ous for a patient who requires a therapeutic dose approaching the toxic dose.

2. Gitalin (N.N.R.) has received less attention than the other glycosides, but it seems that the drug has a shorter latent period, and is somewhat less cumulative than digitoxin. Gitalin may prove to be better for routine slow digitalization than digi- toxin, but it is certainly not indicated for rapid digitalization. More exact information must be available before this drug can be properly appraised.

3. Digilanid (N.N.R.) is a mixture of glycosides from Digitalis lanata. It has the advantage over whole leaf digitalis of being a mixture of constant proportions. Lanatosides A and B have long latent periods and are slowly excreted; lanatoside C has a short latent period and is rapidly dissipated. Be- cause of this "balancing” effect the drug is a com- promise, being partly rapidly acting and relatively non-cumulative and partly slowly acting and more cumulative. Although such a compromise drug may satisfy the requirements of the majority of patients, it would seem more logical to select a specific glyco- side appropriate to the needs of the particular patient.

4. Digoxin (U.S.P.) is quickly effective, well absorbed, and rapidly dissipated. This drug may be given by mouth for initial digitalization and main- tenance, or by vein for emergency medication. If toxic effects are encountered, they are of short dur-

TABLE IV

POTENCY AND DOSAGE OF CARDIAC GLYCOSIDES

	Milligrams Equivalent	Intravenous Single Di gitalizing	Oral Single Digitalizing	Daily Maintenance
	to One	Dose* *	Dose* *	Dose* *
Preparation	Cat Unit*	(Mg.)	(Mg.)	1 (Mg.)
Digitalis	100	300-500	1500-2000	100-150
Digitoxin	0.4	1.2	1.2	0.1-0. 2
Gitalin	0.25	2.25	5	0.25
Digilanid	0.3	1.5	6.25	0.3
Lanatoside C	0.25	1.6	6.25-10	0.5-1.25
Digoxin	0.2	1.0	1.5-2. 5	0.5
Ouabain	0.1	0.25-0.375	Not used	0.25 (I.V.)
Stophanthin | 0.2 • One cat unit equals 0.8 U.S.P. digitalis unit. ’ * Dosage Figures are Averages.	0.5-0.75	Not used	0.5 (I.V.)

JANUARY, 1948

19

ation because of the rapid excretion. This is a distinct advantage when the patient has a very low cardiac reserve and requires nearly toxic doses be- fore favorable cardiac effects can be secured. On the other hand it may be a disadvantage, for routine cases, to have the concentration of the drug in the tissues subject to rapid variations.

5. Lanatoside C (U.S.P.) is similar to digoxin, except that it is not as well absorbed from the gastrointestinal tract.

6. Ouabain (U.S.P.) is never given by mouth; only intravenously, or intramuscularly. It is almost instantly effective, and is therefore the drug of choice for the emergency treatment of acute de- compensation, acute pulmonary edema of cardiac origin (acute cardiac asthma), and selected cases of coronary thrombosis with decompensation. Oua- bain is so rapidly excreted that it is virtually non- cumulative. It is often used in combination with an orally administered digitaloid drug of long latent period, and which is slowly dissipated. Ouabain is of such importance that every physician should be familiar with its use. It belongs in every doctor’s emergency kit.

7. Stropbantbin (N.F. ) is an amorphous mixture of glycosides, and is pharmacologically like ouabain except that it is just half as potent. It has the dis- advantage of uncertain stability in ampules. The physician must be certain that the ampule labeled "Strophanthin” is the official strophanthin, not g- strophanthin which is the synonym for ouabain, as the ratio of potency is 1:2. Dangerous poisoning will result if g-strophanthin (ouabain) is given in the dosage intended for the official strophanthin. The exclusive use of ouabain in appropriate dosage will avoid confusion.

SELECTED REFERENCES

1. Batterman, R. C., and Engstrom, W. W. : Persistence of effect after digitalizat'on by combined use of digitalis and ouabain. Am. Heart I. 24:458-471. Oct., l°42.

2. Batterman, R. C., Rose, O A. and De Graff, A. C.: The

combined use of ouabain and digitalis in the treatment of congestive heart failure. Am. Heart J. 20:443-453, Oct., 1940.

3. Brams, W. A., Golden, J. S., Sanders, A. and Kaplan, L. A.: Observations on toxicity and cl nical value of strophanthin. Ann Int. Med., 13:618-628. Oct., 1939.

4. Cattell, McK, and Gold, H.: Studies on Digitalis Glycosides III. The relationship between therapeutic and toxic potency. J. Pharmacol, and Exper. Therap. 71:114-125, Feb., 1941.

5. Chavez, I.: The comparative value of digitalis and ouabain in

treatment of heart failure. Arch. Int. Med. 72:168-175, Aug,

1943.

6. E chna, L. W. and Taube, H.: The effect of intravenously administered digoxin and ouabain on the systematic venous pressure of patients with congestive heart failure. Am. Heart J. 27:641-656, May, 1944.

7. Gefter, W. I. and Leaman, W. G. : The use of ouabain in

rapid cardiac arrhythmias. Am. J. Med. Sci. 205:190-197 Feb

1943.

8. Ginsberg, A. M., Stoland, O. O. and Siler, K. A.: The effect of some members of the digitalis group on the coronary circulation. Am. Heart J. 16:663-674, Dec., 1938.

9. Gold, H. and Cattell, McK.: Mechanism of digitals action

in abolishing heart failure. Arch. Int. Med. '65:263-278 Feb

1940.

10. Gold. H., Cattell, McK., Model!, W., Kwit, N. T., and Kramer, M. L.: A comparison of the speed, the intensity and the duration of action of four digitalis glycosides by intravenous injection in man. Federated Proceedings, 2:80, 1943.

11. Gold, H., Cattell, McK., Modell, W.. Kwit, N. T., Kramer, M. I. and Zahm, W.: Clinical studies on digitoxin (Digitaline Nat velle) with further observations on its use in the single average full dose method of digitalization. J Pharmacol, and Exper Therap. 82:187-195, Oct., 1944.

12. Gold, H. and DeGraff, A. C.: Studies on digitalis in ambu- latory cardiac patients; elimination of dig talis in man. J. Clin. Invest. 6:613-626, Feb., 1929.

13. Gold, H. and DeGraff, A. C.: Studies on digitalis in ambu- latory cardiac patients; newer principles of d gitalis dosage JAMA 95:1237-1243, Oct. 25, 1930.

14. Gold, H., Hitzig, W., Gelfond, B. and Glassman, H : Qualitative comparison of various digitalis bodies. Am Heart T 6:237-254, Nov., 1930.

15. Gold. H., Kwit, N. T., Cattell, McK. and Travell, J.: Stud es on purified digitalis glycosides IV. The single dose method of digitalization. J.A.M.A. 119:928-932, July 18, 1942.

16. Katz, L. N., Wise, W., Ginsburg, H, A.. Schiff, I., and Krause, F. : Oral single dose digitalization with digitalis leaf and Digitaline Nativelle. Am. Heart J. 30: 125-133, Aug., 1945.

17. Kwit, N. T.. Gold, H. and Cattell. McK.: Studies on purif'ed digitalis glycosides II. Potency and dosage of lanatoside C in man. J. Pharmacol, and Exper. Therap. 70:254-269, Nov., 1940.

18. LaDue, J. S.: Intravenous use of digitalis glycosides South Med. J. 36:124-133. Feb., 1943.

19. Rose, O. A., Batterman. R. C. and DeGraff, A. C.; Clinical stud es on digoxin, a purified digitalis glycoside. Am Heart I 24:435-457, Oct., 1942.

20. Rykert, H. E. and Hepburn, J.: The use of strophanthin in

of auricular fibrillation. Canad. Med. Assn I 34-281- 283, Mar.. 1936.

21. Stroud, W. D., Livingston, A. E., Brown, A. W., Vanderveer, J. B. and Griffith, G. C. : Use of verodigin in cardiovascular disease; its biological assay and pharmacological action. Ann Int Med 8:710-726, Dec., 1934.

22. Tandowsky. R. M.: An electrocardiographic and clinical study of lanatoside C. Am. Heart J. 24:472-482, Oct., 1942.

23. Tandowsky, R. M. and Anderson, N. : An electrocardiograph c and clinical study of various so-called cardiac drugs. Am Heart I 28:298-310. Sept.. 1944.

24. Travell, J. and Gold, H.: Studies on the absorption of some digitalis preparations from the gastro-intestinal tract in man. J. Pharmacol, and Exper. Therap. 72:41, May, 1941.

MASS CHEST SURVEY AT THE UNIVERSITY OF KANSAS MEDICAL CENTER OUT PATIENT DISPENSARY

Joseph W. Burnett, M.D., and G. M. Tice, M.D.*

Kansas City, Kansas

It has been quite well established that it would be an ideal procedure for all patients entering a doc- tor’s office, a hospital or clinic, for all employees of an industrial concern, and for all students enter- ing a college or university, to be submitted to roent- genographic examination of the chest. Approxi-

* Department of Radiology, University of Kansas School of Medi- cine.

mately 35 per cent of all general hospital or clinic admissions show chest disease1, not necessarily active, on routine examination. This percentage of positive findings is higher than that of routine blood and urine examination. Routine radiographic examina- tion of the chest on admission saves the patient and the hospital time and expense by early and rapid diagnosis.

20

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

Tuberculosis survey work began in the clinic of the University of Kansas hospitals in the summer of 1945. At this time a photo-fluorographic unit was installed by the Kansas State Health Department. Since the pioneer work has been done by the Army and Navy and by many mobile units under control of the various state health departments, serving com- munities all over the nation, a description of the apparatus used will not be given. This description may be found in many pamphlets and texts1. The machine used in this survey is a standard Westing- house photo-fluorographic unit of the 35 mm. film type. The films are taken by a state employed tech- nician and are interpreted by a resident in the de- partment of radiology under the direct supervision of the department head.

Following is the outline sheet used in making the report. The film interpretations were classified into four categories. The outline sheet is that recom- mended by the Kansas State Health Department.

Group A— POSITIVE FOR TUBERCULOSIS: Those in which there are definite shadows typ- ical of tuberculous lesions. These cases will usually be confirmed on re-examination with the large films.

Group B— SUSPICIOUS FOR TUBERCULOSIS: Bi — Those with basal and atypical mid-lung lesions not thought to be tuberculous, but in which tuberculosis is included in the differ- ential diagnosis.

B2 — Those cases in which there are indefinite apical or other parenchymal shadows which are suspicious for tuberculosis. The majority of these cases are found to be entirely nega- tive on examination with 14" by 17" films. However, in this group will be included the very early minimal lesions; therefore, it is highly important that all of these cases be examined with the large films. "Over-reading” of the small films is prac- ticed so as to miss fewer cases.

Group C — ABNORMAL: Those with significant abnormal non-tuberculous chest and cardiac conditions.

Group D— ESSENTIALLY NEGATIVE FOR TUBERCULOSIS: Includes the following: Strictly negative chests — indicated by a check mark

Calcification indicated by number ( 2 )

Old Pleurisy indicated by number ( 3 )

Fibrosis indicated by number (4)

Anomalies and other non-significant pathology indicated by number ( 5 )

Unsatisfactory film (poor positioning, develop- ing, etc.) indicated by number (6)

The following is an example of the report card

on which the report of the film reading is filed with the patient s clinic record.

K.U.H. — PF Survey Records Film No

Name

Age , Sex . , Color ,

Address

Cl. No Cl. Ref

X-ray Fluorographic Findings

1 Negative 13 Cardiac 16 Reser. Diag.

2 Minimal 14 Aortic 17 Unsat.

3 Mod. Adv. 15 Other Path. 18 Not Done

4 Far Adv.

5 Pneumo.

6 Thoraco.

7 Pleurisy

8 Primary

9 Fibrosis

10 Calcification **

1 1 Susp. Tbc.

1 2 Pneumoconiosis

Remarks

A definite procedure was followed for recording the interpretation of the miniature film for the fol- low up examination if indicated. Report of path- ology seen on the 35 mm. film was placed on the clinic record. If the patient's report was classified as A, Bi, B2, he was referred to the x-ray department for a 14 x 17 film of the chest. This report was also placed on the clinic record. When the extent of pathology as seen on the 35 mm. film warranted further investigation for a process other than tuber- culosis, the patient was classified as C and further fluoroscopic and possibly radiographic study was conducted. This examination often led to unsus- pected non-tuberculous pathology. It is of interest to note that not all persons, even though in contact with adequate medical care, do avail themselves of medical attention. An outstanding example of this was that of a 31year-old woman who was work- ing as a nurse’s aid in our institution. She had been feeling rather badly but had not consulted a doctor. On routine photo fluoroscopic survey she was found to have moderately far advanced tuberculosis which was proven to be active. A film taken 18 months before was reviewed and was considered to be nor- mal. The periodic survey picked up an individual who would have eventually presented herself for medical help, but who in the meantime would ex- pose non-tuberculous patients and medical personnel to tuberculosis.

This report deals with 5,218 clinic patients who were examined by the photo fluorographic procedure from August 1, 1945, to August 1, 1946. Of these patients it was possible to get a follow up on 4,491 cases, 87 per cent. Of the 4,491 cases, 229 were diag- nosed from the 35 mm. film as having definite sig- nificant pathology. The remainder were considered

Group A : Tbc. definite **

Group B: Tbc.

(indef. & susp. )

Group C: Other path.

(pos. & susp.)

Group D : Negative * *

* *

JANUARY, 1948

21

to be within normal limits. Of the number we were able to follow, 53 or 1.18 per cent were found to have pulmonary tuberculosis (Class B2). Of these cases 14 or 26.4 per cent of the cases diagnosed tu- berculosis were classified as advanced tuberculosis (Class A). The 121 cases that were diagnosed as having lesions suspicious of tuberculosis were found on re-examination, using 14 x 17 films, to have es- sentially normal chests. It can be seen that from 160 cases that were diagnosed as being suspicious of tuberculosis on the 35 mm. film, only 39 or 24.3 per cent were found to have a chest lesion that was con- sidered tuberculous by subsequent examination. This means that of the cases that were suspected of being tuberculous approximately 75 per cent were "over read.” This percentage decreased materially as ex- perience in the interpretation of the small film was developed. Eighteen patients were suspected of hav- ing tuberculosis but were later diagnosed other path- ology by means of the larger film. A study of these 18 patients shows a value in routine chest examina- tion other than inherent in a search for the tubercu- losis patient. These 18 patients were ultimately diag- nosed as follows:

Primary carcinoma of the lung	2	cases
Secondary lung carcinoma	3	cases
Spontaneous pneumothorax	1	case
Cardiac dilitation and decompensation	4	cases
Pneumoconiosis	1	case
Pneumonia	1	case
Lung fibrosis	4	cases
Lung abscess	1	case
The third classification of pathology	is	the

group or patients with abnormal chest and heart findings of a significant nature other than tuber- culosis. The 37 cases in this group under suspicion were ultimately diagnosed as follows:

Relatively normal 12

Lymphoma 2

Minimal tuberculosis 4

Cardiac hypertrophy and decompensation 4

Primary lung tumor 2

Metastatic lung tumor 4

Aneurysm of the thoracic aorta 3

Broncho pneumonia 3

Hydrothorax 2

Fourteen cases who were diagnosed as having tu- berculosis were followed through to a substantiation of the diagnosis with sputum examination. The greatest discrepancy in the diagnosis was in the Group B lesions, lesions suspicious for tuberculosis. No cases of basilar tuberculosis were diagnosed al- though 14 cases were so suggested from study of the small films. Seventy-five per cent of the cases thought to have a suspicious apical lesion did not have such a lesion when the 14 x 17 film was

studied. Approximately 25 per cent positive find- ings were realized in this classification. Obviously the greatest number of cases fell in Group D. Ap- proximately 4,200 cases were classified in this group.

Many of the earlier cases in which definite path- ology was found, including those with tuberculosis, had little or no chest symptoms. It is for this reason that despite steady improvement in diagnostic fa- cilities in the last 25 years, little substantial progress has been made in finding early cases of tuberculosis and other lung disease. This is due to the fact that early disease of the chest rarely gives rise to symp- toms, and individuals who feel well seldom consult a physician. Reports from physicians’ offices and clinics show that one-third of tuberculosis lesions found are classified as of some clinical significance. Approximately half of these will eventually be classi- fied as arrested2.

Our experience at the University of Kansas Med- ical Center shows that 76.4 per cent of the cases of pulmonary tuberculosis that were found by the 35 mm. photo fluorographic method were minimal. These were therefore amenable to adequate treat- ment. The experience of the United States Public Health Service is that less than 10 per cent of the minimal cases are missed with the miniature film and the advanced cases are picked up as accurately as with the large film3. Even though there is con- siderable "over reading” of the small film, it is thought by many authorities to be more adequate than an occasional reading with the large film.

From the epidemiological or public health point of view, only five per cent to 10 per cent of minimal cases picked up by the miniature film were pre- viously known to have tuberculosis, and although the small film is admittedly less accurate it is possi- ble to pick up 10 to 20 times as many cases of mini- mal tuberculosis than by any other commonly used method3.

An effective program for stamping out tubercu- losis should embrace four phases: 1. Case finding. 2. Medical care and isolation. 3. After care and rehabilitation. 4. Protection of the tuberculous fam- ily against economic distress. Case finding is nat- urally the first step. Diagnosis must be confirmed and proper treatment carried out until the disease has been arrested and the individual is back in pro- ductive employment. Until recently this has been centered on families of known tuberculous patients, thus missing many unsuspected cases. The second factor in case finding is a search for the disease without relationship to an infection focus. All seg- ments of the population may be reached with an organized campaign, patients admitted to a general hospital, patients admitted to the hospital for the insane or mentally deficient, workers in industry,

22

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

students and faculty in elementary schools, high schools and universities.

Advantages attending the use of the 35 mm. film include the fact that accurate interpretation can be made and a large group of patients may be surveyed rapidly. At the University of Kansas Medical Center the relative number of cases that have passed through the chest survey is for the first year relatively small, but the figures derived from this study of 5,000 cases compare favorably with those given from other clinics in this country and abroad. At the University of Michigan where many more have been examined, pulmonary tuberculosis was found in about 1.5 per cent of cases and abnormal non-tuberculosis cases constituted 9.3 per cent of the cases examined4. Re- ports of statistics obtained from mobile units op- erating in Wales revealed 1.25 per cent abnormal non-tuberculous conditions and 1.1 per cent of def- inite pulmonary tuberculosis5. The mass survey car- ried on in New York City from 1933 to 1943 by the New York Public Health Department reported on over one-half million individuals examined2 and revealed that tuberculosis was found in two per cent of cases but no figure was given for the non-tuber- culous lesions. At the University of Kansas Medical Center pulmonary tuberculosis was diagnosed in 1.18 per cent of cases and other abnormal findings in four per cent of the cases.

SUMMARY AND CONCLUSIONS

1. 5,218 cases have been studied by photo fluoro- graphic methods for pulmonary tuberculosis in the University of Kansas Medical Center out patient clinic. The expense of the project including the in- stallation and operation of the machine has been assumed by the Kansas State Health Department. These cases were studied from August 1, 1945, to August 1, 1946. We were able to follow 4,491 of these cases. Of this number, 229 showed chest path- ology. Fifty-three were diagnosed on subsequent examination with a 14 x 17 film as having pul- monary tuberculosis. Fourteen of them were mod- erately or far advanced and 39 had minimal lesions. "Over reading” of 35 mm. films was noted on 75 per

cent of the cases studied. This has been considerably reduced with experience.

2. A method of classification and reporting these cases has been presented as suggested by the Kansas State Health Department.

3. The statistics obtained from the University of Kansas Medical Center study compare favorably with those obtained in other clinics here and abroad.

4. Many significant abnormal non-tuberculous chest findings were found. Four per cent of those examined had significant non-tuberculous chest lesions. In a large per cent of these cases the lesions were unsuspected and possibly might have gone un- suspected and untreated. It would seem that these cases found should lend added weight to the ade- quacy and necessity of routine photo-fluoroscopic examination of the chest.

5. Adequate isolation and treatment should be available in every state and community. The reward for such action will be measured not only in human life and happiness but in sound financial returns for money expended. Tuberculosis and non-tuber- culous parhology frequently strike in the prime of life. Most of the victims are between 20 and 50. These are the years of greatest productivity and these individuals should be given every opportunity to lead productive, efficient lives, instead of being a liability to themselves, their families and their com- munity. The photo fluorographic examination may become eventually a part of every physical examina- tion and may rank with blood chemistry and serology as a routine diagnostic study. In the hands of trained personnel it is accurate in permitting a diagnosis of lung pathology even though the nature of the path- ology will usually be obscure until a larger film is procured.

BIBLIOGRAPHY

1. Scatchard, G. N., Miniature Chest X-Ray Films in General Hospitals. J.A.M.A. 127:746-748. March 31, 1945.

2. Edwards, H. R. Place of Mass Survey in Tuberculosis Control Program. New York State J. Med. 269-273. Feb. 1, 1945.

3. Robins, A. B., Chest X-Ray Survey Methods in Practice Am. J. Pub. Health. 34:637-642. June, 1944.

4. Hodges, F. J. Fluorographic Examination of the Chest as a Routine Hospital Procedure. Radiology 38:453-461. April, 1942.

5. Davies, T. W., and Davies, M. Mass Rad’ography in Wales. Brit. J. Tbc. and Dis. of Chest. 39:23. January, 1945.

During the late war it was my privilege to see many patients who were receiving or had received atabrine therapy. By most, it was well tolerated, the only unto- ward sign being the yellow color imparted by the dye to the skin. By a few it was not tolerated, and it is of various manifestations produced by the drug in this latter group that we wish to speak.

Atabrine has been said to produce fewer toxic symptoms than quinine. With this we disagree. Vomiting occurred as frequently as it does in quinine therapy but was usually of shorter duration. Nausea lasted longer. Some patients complained bitterly of "nervousness,” a symptom not common with quinine. . . .

The skin manifestations were interesting and variable.

Urticaria and exfoliative dermatitis occurred, the former usually transitory.

More spectacular were those cases which resembled lichen planus and were so labeled by many dermatologists, though the atabrine source of these cases was early recog- nized.— Albert G. Bower, M.D., in California Medicine, October, 1946.

Preventive medicine requires the cooperation of the pa- tient, and this in turn predicates the existence of a per- sonal and confidential relationship between the physician, who served as health advisor, and the family. — The Com- monwealth Fund, 1947.

JANUARY, 1948

23

Kansas Cancer Registry and Follow-Up Program

The Kansas State Board of Health with the cooperation of the Kansas Medical Society, the Kansas Division of the American Cancer Society and Kansas hos- pitals inaugurated on July 1, 1947, a statewide cancer registry and follow-up program. Thirty-five general hospitals are now participating in this program. Each hospital maintains a local registry and follow-up service which reports all cases of cancer to a central registry in the State Board of Health at Topeka.

Hospitals report all cases receiving cancer care in any department of the hos- pital, including out-patients receiving diagnostic or treatment service.

Information reported by the local registry consists chiefly of basic statistical facts and an outline of the type of diagnostic treatment and follow-up serv- ice rendered to each patient.

Follow-up of cases is accomplished by the local hospital registry secretary ac- cording to the desires of each physician.

Approximately 2,500 cases of cancer were reported to the central registry dur- ing 1947.

The purpose of the registry and follow-up program is to provide facts for ( 1 ) determining the extent and nature of the cancer control problem, ( 2 ) de- termining the availability of present cancer diagnostic and treatment facilities and services, (3) evaluating results of the present program, (4) measuring the benefits derived from any new services which may be inaugurated, ( 5 ) assisting with the planning of a future program of cancer control.

At least eighty per cent of cancer patients are at some time registered for some diagnostic or treatment service with a hospital. Thus the program is cen- tered in the agency where the facts about cancer are most likely to be readily available.

The registry and follow-up program is more than a reporting system. It focuses attention on each patient with cancer or suspected of having cancer and stimulates the physician and his professional co-workers to give cancer patients the best available diagnostic and treatment service. The program localizes the cancer problem in each community and stimulates local action. It is therefore an educational as well as a service program.

Hospitals are being paid to participate in the program, which provides a means of distributing appropriated and contributed funds throughout the state, and thus citizens in all parts of the state receive benefits.

Prepared by Committee on Control of Cancer.

24

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

PRESIDENT'S PAGE

There is a growing scientific knowledge that whole blood transfusions excel any other material in almost all of the instances where replacement is needed or deficiency exists. Because of this and the rapidly depleting plasma supply, there is all over the land a plan evolving where whole blood may be available. It requires only cooperation between the medical societies and the Red Cross and laboratory facilities.

The Red Cross has approved the plan for the whole United States subject only to local medical society approval or, in smaller centers, approval of the individual doctor or doctors. The plan, in brief, is for the Red Cross to keep a list of avail- able serologically negative donors and transport them whenever and wherever needed. The donor makes this contribution to his fellow man without remunera- tion. There is a service charge for typing. Whatever charge the physician makes is for his services and is a matter between him and his patient, as it has always been.

In larger communities blood is drawn daily and the average need supplied; excess when outdated is processed into dried plasma. In smaller communities walking donors who can be called day or night furnish needed blood. An active Red Cross committee advertises and encourages this contribution.

Advantages:

1. To be able to give blood when and where needed.

A. Burns

B. Replacing blood loss as in obstetrics and surgery

C. Severe depletion due to disease

2. Revealing blood dyscrasias and disease.

3. Finding Rh negative bloods for infant use.

4. It is intelligent for everyone to know his blood type. It is like knowing how to swim. One might never need to know, yet knowing might save a life.

5. ENCOURAGE FREER USE OF WHOLE BLOOD TO REPLACE THE RAPIDLY DECREASING STOCK OF DRIED PLASMA.

Such a plan has been prepared by a committee from the Society. Upon presen- tation to the Council, it was given full approval, and we understand that a sim- ilar outline on a national basis has been approved by the A.M.A. and the Red Cross.

President.

JANUARY, 1948

25

EDITORIALS

American Academy of General Practice

On June 10, 1947, at Atlantic City the American Academy of General Practice was founded. The first annual meeting of this organization will have been held at Cleveland a few days before this issue of the Journal is received. At that meeting national headquarters will probably be selected, and accord- ing to rumors heard at present, Kansas City is being favorably considered. The selection of Kansas City would be of particular interest to the many physi- cians practicing general medicine in Kansas, as would the selection of Mr. Mac F. Cahal as execu- tive secretary. Mr. Cahal, presently secretary of the American College of Radiology and prior to that executive secretary of the Sedgwick County Medical Society, is well known to many Kansas physicians. He is at present legal counsel and acting manager of the new organization and may or may not be a candidate for this position on a permanent basis.

The Kansas Medical Society recently received a statement from Stanley R. Truman, M.D., president of the American Academy of General Practice, in which he introduces the new organization to the physicians of the United States. His letter says in part that the Academy was founded by a group of men firmly convinced that General Practice is the backbone of the finest medical system the world has ever known; and that General Practice is econom- ically and medically the soundest means of distribut- ing care to the American people. They believed that the fine things in General Practice could not be pre- served and that medical science and art could not be advanced without the organized effort of the Gen- eral Practitioners. . . .

"The Academy has no official connection with the American Medical Association, except that members must be members of the American Medical Associa- tion. The Academy plans to support the A.M.A. in its high ideals and will also support every other group whose aims are unselfish and for the best in- terests of individual and public health. . . .

"The requirements for membership are high but simple. For those older men who may not be able to fulfill the letter of the requirements, but have more than fulfilled them by years of experience and study, the Board of Directors by vote may waive any specific requirement. To be eligible for member- ship the physician must be engaged in General Prac- tice. He must be duly licensed in the state in which he practices, and must be of high moral and pro- fessional character. He must have had at least one year of rotating internship at an approved hospital, or the equivalent in postgraduate training. He must

have been in General Practice for at least three years. (Special consideration is being given by the Mem- bership Committee to military service.) He must have shown interest in continuing his medical ad- vancement by engaging in postgraduate educational activities. . . .

"A feature of great interest to prospective mem- bers is the requirement that in each three-year pe- riod a member must complete 150 hours of post- graduate work. The Membership Committee has not yet published the accepted list of work fulfilling this requirement, but it is expected that the plan will follow the plan of allowing about one-third of the hours at staff meetings, one-third at conventions, and one-third at postgraduate courses. . . .

"Since its inception the progress in organizing has been remarkable. After only three months the membership is larger than all but the two or three largest specialty groups, and the Academy is repre- sented in forty-one of the states, and Hawaii.

"Every General Practitioner owes it to himself, and to the profession to which he has been called, to qualify for membership in the American Academy of General Practice; and when he has become a member, to do everything in his power to further its development and aims.”

Postgraduate Fund Applications

The Journal has previously announced the post- graduate education fund created by the Kansas Med- ical Society to assist members returning from service in obtaining graduate education. This fund was raised entirely by voluntary donations and repre- sents an expression of gratitude by the physicians of this state to the doctors who entered the service from Kansas.

By action of the House of Delegates, disbursement of this money is directed by the Committee on Post- graduate Education, now included as a subcommittee under the Committee on Medical Schools. This com- mittee has worked diligently in an effort to dis- tribute the fund on an equitable basis. While in- dividual grants are not large enough to offer com- plete support to a physician taking graduate educa- tion, it is hoped that this supplement to other grants that are available to returned medical officers will aid in defraying expenses.

The committee is now of the opinion that this phase of the graduate program of Kansas should not continue indefinitely and has tentatively agreed upon the following regulations. It is urgently requested that every eligible physician take advantage of the benefits, but because a time limit must be placed somewhere, all applications should be on file prior to May 12, 1948. This does not mean that graduate work must be completed or even begun by that date.

26

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

It is merely intended that every eligible physician who wishes to receive this benefit and who expects to take graduate work should have placed his ap- plication with the medical society prior to May 12. The actual study need not begin until considerably later, but it is the plan of the committee that ap- plications shall not be accepted after that time.

To be eligible a physician shall have served in the armed forces during the recent conflict and shall have graduated from a school of medicine not later than the spring of 1944 and shall have entered the armed forces as from Kansas. Benefits from the Kansas Medical Society fund have no bearing on other benefits that might be received, nor is the length of the course a limiting factor, except that a larger grant is generally offered in those instances where an extended course is taken.

More than 100 Kansas physicians have already re- ceived payment from the graduate fund, and it is hoped that many more will avail themselves of this opportunity. The regulations announced above are subject to approval by the House of Delegates and, after consideration by that body, might be altered. However, this committee feels that the House of Delegates should set a definite termination date, after which time it may be discharged of its duties, and in anticipation of such action begs to report its invitation for eligible physicians contemplating graduate work who as yet have not received a bene- fit from this program to file an application prior to May 12, 1948.

A New Year for the Journal

With this issue the Journal begins publication of Volume XLIX, and a glance over its activities dur- ing the past year seems appropriate.

From a commercial standpoint the Journal has progressed. Each issue now carries more advertise- ments than issues for corresponding months in other years, and there is a decided increase in the use of color in advertising pages. For this progress the Journal takes no credit, since advertising sales are largely handled by the Cooperative Medical Adver- tising Bureau, located in the A.M.A. offices in Chi- cago. The Bureau had a most successful year in 1947 with Mr. Alfred J. Jackson as director, and did splen- did work in arranging advertisements for 33 state medical journals. Contracts now in force indicate thta the year 1948 will be equally successful.

Increased revenue from advertising has made pos- sible a bigger and more creditable Journal for the Kansas Medical Society. Four scientific papers are now published in each issue, a page on cancer has been included through the cooperation of the Com- mittee on Control of Cancer, and more editorial

pages are provided. Although there is still a short- age of the enameled paper stock on which the Jour- nal is printed, a large enough supply was purchased in 1947 to print a total of 816 pages, a number far larger than any previous total for a 12-months pe- riod.

The first annual University of Kansas School of Medicine number was published in the March issue of the Journal, and a scientific paper with four-color illustrations, an article on cancer diagnosis by Dr. Wendell A. Grosjean of Winfield, was printed in October. During the year the Journal published also a series of articles on state institutions to answer many questions from physicians who wanted in- formation on commitments, releases, and eligibility requirements. Since July each issue of the Journal has included a section of abstracts of current medical literature. Other new features will be added from time to time.

At a meeting of the Council of the Kansas Medi- cal Society in May, two associate editors were ap- pointed to the Editorial Board, Dr. C. A. Helhvig of Wichita and Dr. James B. Weaver of Kansas City. Both have been helpful in securing scientific ma- terial for the Journal, and Dr. Weaver has accepted responsibility for assembling copy for the second an- nual University of Kansas School of Medicine num- ber, to be published in March, 1948. Other mem- bers of the Editorial Board, all of whom live in To- peka, have given freely of their time to attend Board meetings, read proofs, and make decisions on the problems that come up in the day-to-day operation of the Journal.

In addition to these, many members of the So- ciety throughout the state cooperate to produce the Journal. One group has unfailingly provided copy for the abstract section, others submit scientific pa- pers, county secretaries report their local meetings, and individual doctors often send in news items. Such help is gratefully received. It is the hope of the Editorial Board that the Journal will be the kind of publication the Society is proud to publish, and sug- gestions for making it a better journal in 1948 will be welcomed at any time.

Milk Consumption at High Level

More than 60 million quarts of fresh milk and cream are now being used daily by U. S. consumers, a larger amount than at any time before the war, according to new figures developed by the Milk Industry Foundation. Per- capita consumption is 16 per cent above the pre-war level, and milk and dairy products now comprise more than 25 per cent of all foods consumed by the average American.

Today, 57 billion quarts of milk are produced annually by 26 million cows on three-quarters of the nation's six million farms. Half of this supply is used as milk and cream and the other half for butter, cheese, ice cream and a myriad of other products.

JANUARY, 1948

27

comprehensive protection with a

SINGLE

INJECTION

The use of Diphtheria and Tetanus Toxoids, Alum Precipitated, and Pertussis Vaccine Combined, has largely replaced the practice of repeated injections for immunization against specific infections. These combined antigens produce an immune titer equal to or greater t?han that effected by the antigen injected individually. The simultaneous triple defense provided by this comprehensive treatment greatly reduces the incidence of contagion in a community and makes possible a reduction of infant mortality rate.

Recommended for infants and pre-school age children, immunization consists of three 0.5 cc. subcutaneous injections at intervals of from four to six weeks.

Antigenic content of H. pertussis increased to 45,000 million, organisms per immunizing treatment.

SUPPLIED:

Single Immunization package contains three V& cc. Vials Five Immunizations package contains three 2% cc. Vials.

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PHARMACEUTICALS, BIOIOGICAIS, BIOCHEMICAIS TOR THE MEDICAl PROFESSION

DIPHTHERIA and TETANUS TOXOIDS,	- \x
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1

28

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

VETERANS ADMINISTRATION AGREEMENT

Veterans’ Program Improved

A new agreement has been made between the Kansas Medical Society and the Veterans Administration. This became effective on December 28, 1947, and involves a number of changes in operational procedure. The Council of the Kansas Medical Society and various officials of the Veterans Administration agree that the revised program will operate more effectively in many ways. Most of the alterations refer to the office of the Medical Coordinator and the Executive Office of the Medical Society rather than the participating physician. Indirectly, each physician will notice an increased efficiency in operational procedure and therefore also will welcome the alterations.

A new fee schedule has been approved and adopted. This is a comprehensive outline listing approximately 700 sep- arate services. In comparing the new schedule with that previously used, it will be noted that many of the items have been raised, some remain as they were, and a few have been reduced. Generally speaking, however, the more common procedures have been increased in value so that the physician will now be reimbursed at a rate generally considered equal to the average fee charged patients in pri- vate practice in this state. The old fee schedule, the pam- phlet with the blue cover, is no longer in operation and should be discarded or destroyed. The new fee schedule will be mailed to each physician cooperating in this pro- gram as soon as copies are received from the V. A.

The Medical Coordinator in Topeka was, until now, under the jurisdiction of the regional office at Wichita. Technical difficulties arising from his attempt to serve also the Kansas City regional office have always caused con- fusion, which retarded efficiency even though everyone attempted to cooperate. Under the new agreement, the Medical Coordinator is directly under the supervision of the area office in St. Louis. The Medical Coordinator will remain in Topeka and will continue to serve physicians of Kansas as before. He will be the liaison officer between the members of the Medical Society and the two regional offices serving Kansas. As far as physicians are concerned, his services have not changed. Under the new program, however, his work can be expedited so that authorization will be made more quickly and more efficiently.

Examinations for pension purposes, as in the past, will be made by the regional office whenever possible. Those that the regional offices are unable to care for will be sent to approved examiners in rotation within a given locality, as in the past. In other words, the examiner will receive the authorization and the examination blank, together with a summary of the medical record, directly from the regional office. The regional office will notify the veteran of his appointment and will arrange his transportation. When the examination is completed, it should be returned NOT to the regional office but to the Medical Coordinator in To- peka where it will be reviewed and, if further information or corrections are needed, the examination will be returned to the physician by the Medical Society. When an examina- tion is returned for correction, it should be sent again to the Medical Coordinator who will forward it to the appro- priate regional office. Along with the examination, the bill for services rendered should also be submitted to the Med- ical Coordinator.

It has been stated repeatedly that the Veterans Adminis- tration does not question the examiner’s medical judgment. Work for the Veterans Administration involves much more

than medical care since a major responsibility in this work is classified as legal. It is the legal requirement that ne- cessitates the return of numerous examinations for correc- tion. The Medical Society wishes to emphasize that when examinations are returned, nothing therein should be con- strued as an attempt to alter the physician's medical judg- ment. This remains the examiner’s individual responsi- bility. Sometimes diagnoses are requested to be given in more detail. At other times it is necessary to list findings that will support diagnoses, etc. It is always the legal por- tion of the examination that needs correction and not the physician's medical judgment.

Treatment outside a Veterans Administration hospital may be paid for by the Veterans Administration only if certain requirements have been met in advance. For in- stance, the disability must have been listed at the Veterans Administration as service connected unless the veteran is being educated under Public Law 16 (not to be confused with Public Law 346, the G. I. Bill of Rights) or, if a female, treatment may be authorized for any condition ex- cept pregnancy or syphilis. Office care or home calls for female veterans are governed by the same regulations as apply to male veterans. To the above brief statement there are a few exceptions but, generally, that outline will hold.

Other regulations governing treatment are that author- ization for such treatment must be received prior to render- ing the service. All authorizations should be obtained through the Medical Coordinator at Topeka. Address com- munications to E. H. Gibbons, M.D., Medical Coordinator, Medical Service Center, 215 West Tenth Street, Topeka, Kansas. In case of emergency the Medical Coordinator may accept collect long distance calls, No. 2-9319. If the Medical Coordinator cannot be reached and an immediate emergency exists, the physician should call the Chief Med- ical Officer of the nearest regional office for authorization. However, for the purpose of unifying the program, it is recommended that authorizations uniformly be applied for through the Medical Coordinator at Topeka.

At times the veteran will apply directly to the regional office for medical care and, if service cannot be granted there, the Chief Medical Officer may authorize treatment by an approved Kansas physician. This, however, will work only in emergencies after which the formal author- ization will be received from the Medical Coordinator, as described above. All statements for services rendered should be sent to the Medical Coordinator.

In review, the new program will operate under the new fee schedule but except for that there is almost no change affecting physicians. When examinations are required, the physicians will be assigned in rotation. It will immediately be apparent to everyone that the patient should not select his own physician where an examination for compensation purposes is authorized. In all treatment cases the veteran will select the physician of his choice. Treatment author- ized will be that determined by the physician except that eligibility must have been established by the veteran be- fore the Veterans Administration will authorize payment. In order to be certain of this, authorizations should be obtained prior to the treatment. And, finally, to simplify procedures, the physicians of Kansas will now deal through one person in all matters pertaining to the program.

The Committee on Veterans Administration Affairs of the Kansas Medical Society will continue to function as before and will be glad to receive suggestions from mem- bers with reference to ways in which the program may be improved. If questions arise with reference to any phase of this program, the Executive Office will be glad to obtain information for any member upon request.

JANUARY, 1948

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30

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

COUNTY SOCIETIES

The Sedgwick County Medical Society held its regular meeting December 2 at the English room of the Broadview hotel, Wichita. Dr. Paul W. Shafer, of the University of Kansas School of Medicine, spoke on "The Surgical Treat- ment of Carcinoma of the Esophagus,” and Dr. Edward H. Hashinger, also from the university, discussed "The Many Manifestations of Hypothyroidism — A Prevalent Disorder.” # * *

Members of the Shawnee County Society entertained the Auxiliary at a dinner meeting and program at the Elotel Jayhawk, Topeka, December 1. A short business session was held and the following officers were elected : presi- dent, Dr. Floyd C. Taggart; president-elect, Dr. Leo A. Smith; vice president, Dr. Orville R. Clark; secretary, Dr. Dwight Lawson; treasurer, Dr. George F. Helwig. Dr. Orville R. Clark will continue to edit the county society’s bulletin.

* * *

A dinner meeting of the Marion County Society was held at the Green Parrot, Marion, December 10. Dr. C. R. Magee, Marion, discussed "Chemotherapy of Tuberculosis,” and Dr. Eldon S. Rich, Goessel, gave abstracts of papers presented at the last meeting of the Kansas City Southwest Clinical Society.

* # #

The Lyon County Society met December 2 at Newman hospital, Emporia. The following officers were elected: president, Dr. C. H. Munger; vice president, Dr. E. J. Ryan; secretary-treasurer, Dr. F. W. Foncannon; board of censors. Dr. C. C. Underwood, Dr. Rodger A. Moon and Dr. Clyde Wilson.

# # #

Members of the Franklin County Society entertained members of the county dental society at a dinner meeting at the Ottawa country club November 25. Dr. Sloan Wil- son, Kansas City, discussed hemorrhagic diseases.

* * *

A meeting of the doctors in the counties comprising the first district of the Kansas Medical Society was held at the Sabetha country club November 20. Dr. R. T. Nichols, councilor, presided and welcomed the guests, members of the Auxiliary. Mrs. M. A. Brawley, Frankfort, reported on activities at the A.M.A. convention in Atlantic City, and Dr. Conrad M. Barnes, Seneca, chairman of the Committee on Rural Health, spoke on methods of improving rural health and means of encouraging doctors to practice in rural areas. Recognition was given Dr. S. M. Myers, Corn- ing, who has completed 52 years of medical practice.

* # #

The Mitchell County Society met at the Community hospital, Beloit, November 18, for afternoon and evening sessions. Scientific papers were presented by guests from the University of Kansas School of Medicine. Dr. Edward H. Hashinger spoke on "The Use of Antibiotics” and "Evaluation of Some Newer Therapeutic Procedures,” and Dr. Mahlon H. Delp discussed "When Is the Heart Case Ready for Surgery” and "Virus Hepatitis.” Twenty-five doctors were present for the program and dinner meeting. * * *

Dr. David T. Loy was elected president of the Barton County Society at a meeting held at the Zarah hotel, Great Bend, December 8. Dr. James Gaume, Ellinwood, was named vice president, and Dr. Robert Poison was named

secretary. Dr. L. R. McGill was re-elected delegate to the annual meeting of the Kansas Medical Society.

# # #

The Brown County Society held a dinner meeting at Camp Rulo December 5 and elected the following officers for 1948: president, Dr. Ray Meidinger, Hiawatha; vice president. Dr. Alfred Dietrich, Horton; secretary-treasurer, Dr. R. T. Nichols, Hiawatha.

* # #

The following officers for 1948 were elected at a meet- ing of the McPherson County Society held December 1 1 : president, Dr. Robert Watterson, McPherson; vice presi- dent, Dr. M. C. Murfitt, Lindsborg; secretary, Dr. A. M. Lohrentz, McPherson; treasurer, Dr. Delbert Preheim, Moundridge.

# * *

The Finney County Society invited the public to a meet- ing held December 12 at the Warren hotel. Garden City. Dr. F. C. Beelman, secretary of the Kansas State Board of Health, spoke on "Public Health in Action in Kansas.”

# * #

Dr. John W. Hertzler, Newton, was elected president of the Harvey County Society at a meeting held in Decem- ber. Dr. C. R. Schmidt, Halstead, will serve as vice presi- dent and Dr. Robert W. Myers, Newton, will be secretary- treasurer. The program for the December meeting con- sisted of a paper, "Peptic Ulcer,” by Dr. G. A. Westfall and a paper, "Fitting and Indications for Contest Lenses,” by Dr. Harold E. Morgan.

* * #

Members of the Marshall County Society entertained the Auxiliary at a dinner meeting at the Marysville country club December 17. Mr. Robert Galloway spoke on Com- munism, after which there was a short business meeting. Dr. W. J. Stewart was re-elected president, and Dr. H. H. Haerle was named secretary-treasurer. Delegates to the state meeting are Dr. M. A. Brawley and Dr. R. I. Thacher. * * #

The Clay County Society was host to the Golden Belt Medical Society at the Clay Center country club January 8. A scientific program was given in the afternoon, followed by a dinner meeting. The papers presented were as fol- lows:. "Convulsive Seizures,” Dr. D. B. Foster, Topeka; "Radiological Diagnosis of Intestinal Tract Lesions,” Dr. C. E. Virden, Kansas City, Missouri; "Cytological Diag- nosis for Malignancy,” Dr. Russell W. Kerr, Kansas City, Missouri; "Feeding Problems in Infancy and Childhood,”

Dr. Herbert C. Miller, Kansas City.

# * #

The Wilson County Society entertained the Auxiliary and nurses of the Wilson county hospital at a dinner at the Blue Tea Room, Neodesha, December 18. A film showing how energy is released from food was shown through the courtesy of the Upjohn company.

Cancer Series to Continue

A popular feature in the Journal during the year 1947, a series of short articles on cancer, will be continued this year through the efforts of the Society’s Committee on Control of Cancer. The articles will be found in each issue immediately following the scientific section.

Physicians found many diagnostic aids in the articles and welcomed their appearance in the Journal. The Editorial Board is happy to announce that the committee, under the chairmanship of Dr. Howard E. Snyder of Winfield, will continue to make the articles available in 1948.

THE SMITH-DORSEY CO Lincoln, Nebraska

BRANCHES AT LOS ANGELES A

32

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

MEMBERS

Dr. Irene Koeneke and Dr. Cora Dyck of the Hertzler clinic, Halstead, and Dr. Frances H. Schiltz, Wichita, have returned from Mexico City where they attended a meeting of the Pan American Medical Association.

* # *

Dr. William B. Scimeca, Moline, announces that his father. Dr. S. Albert Scimeca, is now associated with him in practice and in the operation of the Scimeca hospital in Caney.

* * *

Dr. Fred Mayes, who has been serving as assistant state health officer, has been named director of public health for the city of Wichita. He will assume his new duties next June when he completes work on a master's degree in public health, for which he is now studying at Harvard.

* * #

Dr. Richard S. McKee, Leavenworth, was elected to the board of directors of the American Society of Anesthesi- ologists at a meeting held in New York City in December.

# # *

Dr. David E. Gray, who has been a resident in ob- stetrics and gynecology at the University of Iowa hospitals since his release from the Army medical corps, has returned to Topeka and is practicing in association with Dr. Lucien R. Pyle.

# *

Dr. M. W. Wells, who has been practicing in LeRoy, has moved to Winfield and is preparing to open an office there.

Dr. A. J. Brier, who recently returned to Kansas after serving on the staff of veterans’ hospital at Hot Springs, South Dakota, has been named head of the Security Bene- fit Association clinic, Topeka.

* * *

Dr. John S. Betz, who has been associated with Dr. John A. Billingsley, director of the department of ophthalmology at the University of Kansas Medical Center, for the past eight years, has opened an office for private practice in Kansas City.

* * #

Dr. E. W. Tallman, Gaylord, celebrated his 42nd anni- versary in the practice of medicine there on October 27.

* =* *

Dr. R. R. Clutz, Bendena, has been named health offi- cer of Doniphan county to fill the vacancy caused by the death of Dr. G. W. Benitz.

# # #

Dr. D. R. Wilson, formerly of Mound Valley, is now associated with the Veterans Administration in Wichita.

# * #

Dr. Wendell A. Grosjean, Winfield, has become a diplomate of the American Board of Surgery.

# * #

Dr. Austin J. Adams, who has been associated with Win-

ter General Hospital, Topeka, for the past two years, has returned to Wichita and is with the Veterans Hospital there.

Conference on Cancer

On February 23 and 24 a special conference on cancer will be held at Topeka. This will be divided into two ses- sions, one appealing primarily to lay persons and the other to physicians. Attending will be representatives of the

Field Army from each county in Kansas and the medical director of each county. Besides those, all Kansas physi- cians are invited to attend. Welcome also will be physi- cians from neighboring states.

The scientific program has been arranged through the cooperation of the Committee on Control of Cancer of the Kansas Medical Society and the Kansas Division of the American Cancer Society. Details are not completed at present and may be changed slightly when the final pro- gram is issued. At present the committee expects to pre- sent to the physicians attending this meeting E. W. Bert- ner, M.D., Houston, Texas; Charles S. Cameron, M.D., medical director, American Cancer Society; Alton Ochsner, M.D., New Orleans; C. P. Rhoads, M.D., Memorial Hos- pital, New York.

The meeting has been cleared with the Topeka Chamber of Commerce and has been announced to both the Jay- hawk and the Kansan hotels of Topeka so that room reser- vations for this meeting should be relatively easy to ob- tain. It is recommended that reservations be applied for early. If any difficulty is experienced, those planning to attend are asked to inquire further of either the Kansas Division of the American Cancer Society or the Kansas Medical Society.

Fifty Year Club

Indiana physicians who have practiced medicine for 50 years or more are members of the newly organized "Fifty Year Club” of the Indiana State Medical Association. Cer- tificates of distinction and gold lapel pins were presented 175 members of the club recently, and other physicians will become members as they reach their fiftieth milestone of medical practice.

Professional Relations

Fundamental to good professional relations among mem- bers of state or local medical societies is a good feeling and understanding among individual physicians, reports the Council on Medical Service of the A.M.A. in its News Let- ter. Seven deadly sins to be avoided are listed as inertia, reaction, cliques, discord, provincialism, smugness and de- featism. The seven characteristics to offset the vices are enterprise, progress, friendship, harmony, vision, leader- ship and courage.

DEATH NOTICES

FRED CLIFFORD CAVE, M.D.

Dr. Fred C. Cave, 71, who had practiced in Ox- ford for 20 years, died in Chicago December 12 after an illness of four months. He was graduated from Barnes Medical College in St. Louis in 1903. He served as superintendent of the state training school in Winfield in 1916 and 1917, leaving to serve with the medical corps during World War I. He was a member of the Sumner County Society.

# # #

ANTHONY WAYNE FAIRCHILD, M.D.

Dr. A. W. Fairchild, 69, died at his home in Osa- watomie December 15 after a short illness. He was an active member of the Miami County Medical So- ciety. A graduate of the Medical Department of the National University of Arts and Sciences, St. Louis, in 1913, Dr. Fairchild practiced first in St. Louis and then in Fall River. He opened an office in Osa- watomie in 1921, confining his practice to oph- thalmology, and had practiced there since that time.

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34

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY •

New Doctors of Medicine Twenty-nine doctors of medicine have been licensed to practice in Kansas by the Kansas State Board of Medical Registration and Examination, five by examination and 24 by reciprocity. The names of the 29 are as follows:

By examination

Arthur H. Bacon, Wichita David A. Lasley, Goodland David A. Laury, Garnett Edward A. Stapleton, Jr., Topeka Edward C. Tilka, East Chicago, Indiana By reciprocity

Francis Anderson, Anthony

James A. Atkins, Pittsburg

Porter E. Barbero, Independence

Norton H. Bare, Osawatomie

Donald D. Bauer, Topeka

Ernest C. Brandsted, McPherson

Clarence P. Bringle, Enterprise

Peter T. Brooks, Winfield

Ben H. Buck, Jr., Wichita

Herbert L. Bunker, Jr., Junction City

William P. Callahan, Jr., Wichita

Robert S. Darrow, Mission

Charles R. Dickinson, Coffeyville

Carl M. Epstein, Topeka

Maurice E. Gross, Lawrence

Edward T. Haslam, Chelsea, Massachusetts

Thomas L. Hill, Topeka

Warford B. Johnson, Detroit, Michigan

James T. Makinson, La Crosse

Albert Owers, Topeka

William F. Roth, Jr., Kansas City

Thomas C. Todd, Arkansas City

David R. Wall, Wichita

Richard H. Weddle, Somerset, Kentucky

Examination in Obstetrics and Gynecology

The next written examination and review of case his- tories (Part I) for candidates for the American Board of Obstetrics and Gynecology, Inc., will be held in various cities of the United States and Canada on Friday, February 6, 1948. Arrangements will be made for candidates to take the Part I examination at places convenient for them, whenever possible.

Candidates who successfully complete Part I, proceed automatically to the Part II examination to be given May 16-22, 1948, in Washington, D. C.

Complete information may be secured from Dr. Paul Titus, secretary, 1015 Highland Building, Pittsburgh, Pennsylvania.

Unifying Pharmacopoeias

A committee of experts named to study unification of Pharmacopoeias of the nations included in the World Health Organization held a meeting in Geneva in October and placed 244 items on its primary list of medicinal sub- stances. These, they believe, are of sufficient importance for inclusion in a book of "Standards Recommended for Adoption by the Pharmacopoeias of the World.” The pri- mary list will be submitted to authoritative medical groups in a number of countries for review.

A secondary list of 89 drugs was drawn up, and 201 items that were studied were dropped from further con- sideration on the ground that they have become obsolete and find little use in modern medical practice.

The committee completed the first drafts of 72 mono- graphs of the drugs selected for the primary list, and will

prepare monographs on all items as soon as possible. These suggested texts will also be submitted for review by inter- national experts in pharmacopoeial revision.

It is expected that the membership of the committee will be increased by next summer, when another meeting will be held, so that additional countries will be repre- sented. The committee member representing this country is Professor E. Fullerton Cook, chairman of the Committee of Revision of the United States Pharmacopoeia.

Rural Health Conference Planned

The third annual National Conference on Rural Health will be held in Chicago, February 6 and 7, 1948, under the sponsorship of the Committee on Rural Medical Ser- vice of the A.M.A., the American Academy of Pediatrics, and representative farm organizations. Forty speakers will take part in the two-day session, including four farm youths representing the National Farmers Union, the American Farm Bureau Federation, the National Grange and the National Cooperative Milk Producers Federation, who will discuss "Rural Youth Looks at Health.”

Parke-Davis Medical Consultant Announcement that Dr. J. P. Gray has joined the staff of Parke, Davis and Company in the capacity of medical consultant to the sales and promotion division has been made by Harry J. Loynd, vice president of the company.

Dr. Gray has held many public health posts over the country and has served as dean of the School of Medicine of the Medical College of Virginia and as dean of the School of Medicine of the University of Oklahoma.

Mississippi Valley Society to Meet The 13th annual meeting of the Mississippi Valley Med- ical Society will be held at Springfield, Illinois, September 29 and 30 and October 1, 1948, under the presidency of Dr. W. O. Thompson, professor of medicine. University of Illinois. The society now has a membership of nearly 1,000, and is continuing its campaign for life member- ships.

Medical Essay Contest The eighth annual essay contest of the Mississippi Valley Medical Society will be held in 1948, with a cash prize of $100, a gold medal, and a certificate of award for the best unpublished essay on any subject of general medical in- terest and practical value to the general practitioner of medicine. Contestants, who must be members of the American Medical Association residing in the United States, should submit five copies of each essay, not ex- ceeding 5,000 words in length, before May 1, 1948.

Complete information on the contest may be secured from Dr. Harold Swanberg, secretary, 209 W.C.U. Build- ing, Quincy, Illinois.

Woman Elected President

Dr. Leslie S. Kent of Eugene, Oregon, is president elect of the Oregon State Medical Society, and is believed to be the first woman elected to such an office.

Fellowships in Tnbercnlosis Study

The National Jewish Hospital at Denver has announced a program of fellowships for postgraduate study in tuber- culosis and allied diseases. Fellows will be appointed for periods of three months, six months or one year. Informa- tion may be secured from Dr. Edgar Mayer, Chairman, National Medical Board, 470 Park Avenue, New York.

JANUARY, 1948

35

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36

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

This Week in Chicago Medicine A weekly publication, "This Week in Chicago Medi- cine,” has been inaugurated by the Chicago Medical So- ciety to keep the profession posted on events of interest, clinics, conferences and meetings. Copies are being mailed to all medical libraries, medical schools and city medical societies. Doctors who plan to be in Chicago and are in- terested in securing copies may do so by writing the Chi- cago Medical Society, 30 North Michigan Avenue, Chi- cago 2, Illinois.

Medical Officers Needed

Medical officers for the National Guard and the Organ- ized Reserve Corps in Kansas are needed now, according to a report issued recently by Major Ira D. S. Kelly, public information officer, Topeka. The Department of the Army has authorized the assignment of medical officers, and ap- plications may be made at any time.

The National Guard needs in Kansas at present are as follows: Topeka, one major; Hiawatha, one captain; Ot- tawa, one captain; Wichita, one captain; Hutchinson, one major and one captain; Dodge City, one captain; Hays, two captains; St. Marys, one captain; Iola, one major; Fort Scott, one captain; Coffeyville, one captain. Applications may be made to the local commanding officer or to the Adjutant General, State of Kansas.

Needs of the Organized Reserve Corps are listed as fol- lows: Wichita, five majors and four captains; Iola, one captain; Salina, one captain. Former officers of the medical corps of any of the armed services who are not over 60 years of age may apply. Also eligible are former warrant officers, flight officers or enlisted men of the first three grades who have been in active service for six months or more between December 7, 1941, and June 30, 1947, and are not more than 28 years of age. The third group eligi- ble for assignment includes persons lacking prior military service but who possess professional qualifications essential to the Army and whose age is between 2 1 and 32 years. Each applicant must possess a license to practice medicine in a state, district or territory of the United States or a diploma from the National Board of Medical Examiners, and must be engaged in the ethical practice of medicine, with the exception of graduates who present evidence of completion of a prescribed four-year course of medical in- struction at an approved school requiring a hospital in- ternship.

Complete information on openings now available to medical officers may be secured from Major Kelly, Kansas State Senior Instructor Organized Reserves, 117 East Sev- enth Street, Topeka, Kansas.

Schering Announces Triple Sulfonamide

A new step in the recently discovered principle of safer sulfonamide therapy has been announced by Schering Corporation, in the form of a new type of sulfa treatment. Based upon original work by New York Medical College’s Dr. David Lehr, carried out under Schering grant, the preparation consists of three sulfonamides — sulfadiazine, sulfathiazole and sulfamerazine — incorporated into a tablet or into a liquid suspension, in equal parts. As Combisul and Combisul Liquid, respectively, each 0.5 Gm. tablet, or teaspoonful containing a total of 0.5 Gm., is to be used in any indication for which single sulfonamides formerly had been used.

Dr. Lehr found that the concentration or solubility of one sulfonamide in a solution does not affect and is not

affected by the amount of another sulfonamide in the same solution. This principle has been carried through and has been found to hold true if there are three sulfonamides present. Thus, only one-third the usual whole dosage of each sulfonamide need be given to obtain a potentiated therapeutic effect. The probability of crystalluria now is also extremely remote. Combination of sulfonamides has proven more effective, in shorter periods of time, with smaller dosage.

Winthrop-Stearns, Inc., Formed Formation of Winthrop-Stearns, Inc., as a new sub- sidiary to integrate its major pharmaceutical interests has been announced by the parent company, Sterling Drug, Inc. The new company will conduct the business form- erly carried on by Winthrop Chemical Company, Inc., organized by Sterling in 1919, and the pharmaceutical operations of the Frederick Stearns and Company Divi- sion, Detroit. Dr. Theodore G. Klumpp has been elected president of the new subsidiary.

Consolidation of the sales staffs of the two units has already been effected and transfer of other business func- tions was completed November 1.

Heart Clinic in Topeka More than 100 Kansas doctors were in Topeka Decem- ber 11 to attend a heart clinic at Winter Veterans Admin- istration hospital, sponsored by the Committee on the Study of Heart Disease of the Kansas Medical Society, Kansas membership of the American College of Physicians, and the Winter hospital staff. Dr. Philip W. Morgan, Emporia, president of the Kansas Heart Association and chairman of the Committee on the Study of Heart Disease, directed the day’s program.

Texas Secretary-Editor Dies Dr. Holman Taylor, 73, executive secretary of the Texas Medical Association and editor of the Texas State Journal of Medicine, died December 4 at the conclusion of a din- ner given in his honor by the Tarrant County Medical Society, of which he had been a member since 1910. Death was attributed to coronary occlusion. Speakers at the ban- quet that evening had named Dr. Taylor as the physician who had contributed most to organized medicine in the state of Texas.

ANNOUNCEMENTS

February 6-7 — Third Annual National' Conference on Rural Health, under auspices of Committee on Rural Medical Ser- vice. A.M.A., Chicago.

February 6-7 — Midwest Radiologic Conference, Hotel Schroeder, Milwaukee, Wisconsin. Address inquiries to Dr. A. Melamed, Milwaukee Roentgen Ray Society, 425 East Wisconsin Ave- nue, Milwaukee 2, Wisconsin.

February 8 — Annual Conference of Teachers of Radiology, Chi- cago.

March 2-5 — Chicago Clinical Conference, under auspices of Chi- cago Medical Society, Palmer House, Chicago.

April 19-23, 1948 — Twenty-ninth annual session, American Col- lege of Physicians, Civic Auditorium, San Francisco, California.

May 6-8, 1948 — Annual Meeting, American Association for the Study of Goiter, King Edward Hotel, Toronto, -Canada.

MAY 10-13— ANNUAL MEETING, KANSAS MEDICAL SO- CIETY, WICHITA, KANSAS.

September 29-October 1 — 13th Annual Meeting, Mississippi Val- ley Medical Society, Springfield, Illinois.

JANUARY, 1948

37

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38

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

ABSTRACTS

Thyrotoxicosis

Barfred, Arne. Methylthiouracil in the Treatment of Thyrotoxicosis. Am. Jnl. Med. Sc., 214-4:349-362 ( Octo- ber) 1947.

The author working in The City and County Hospital, Odense, Denmark, reports his experiences with methyl- thiouracil in thyrotoxicosis since 1944, says work in Eng- land was carried on at the same time but due to the war without knowledge of the Danish experiments. His own series of 61 cases is discussed along with a review of the literature. Methylthiouracil was given in daily doses that averaged 1.2 grams to a group of patients and reactions were frequent (78%) and some severe. A larger group of patients received average initial daily doses of 0.57 grams with therapeutic results comparable with other reports on methylthiouracil and incidence of reaction was less (47%). He believes .4 gram day should be the maximum daily dose. Some patients are resistant to methylthiouracil (four of the author’s cases, six reported by Rose and 14 from various other writers ) . Methylthouracil has no advantages clinically over propylthiouracil and the dosage of both, he believes, should be about the same. A positive urobilin test is considered evidence of toxicity and the test is advo- cated as a check. Methylthiouracil is a potent antithyroid drug.

Indications for antithyroid drugs: (1) Cases too great a surgical risk. (2) Cases in which operation is refused. (3) Relapse after thyroidectomy. (4) Preoperative treat- ment (Methylthiouracil with iodine for 10 days preopera- tively seems to lower the post operative risk of thyrotoxic crisis). (5) Those cases in whom one can expect a cure.

"Cures” range from 20 to 82 per cent in reported series. The best prognosis is in patients in whom the disease was not long standing, the goitre small, and the patient in the younger age group. Maintenance therapy should not ex- ceed one to one and a half years and at all times the danger of agranulocytosis must be kept in mind and frequently checked for.

Contraindications to antithyroid drugs: (1) Large intra- thoracic goitres; (2) Large adenomatous or diffuse goitre which is rapidly increasing; (3) In non-cooperative pa- tients in whom control is difficult; (4) Thyrotoxicosis due to acromegaly; (5) Thyrotoxicosis in pregnancy (and though this is unsettled, it is known thiouracil passes the placental barrier and is found in the milk). — P.W.M.

# * #

Peritoneal Irrigation

Muirhead, E. E.; Small, A. B.; Haley, A. E.; Hill, J. M. Peritoneal Irrigation for Acute Renal Damage following Incompatible Blood Transfusion: A Discussion Based on Three Cases. Jnl. Lab. Clin. Med., 32-8:988-1001 (August) 1947.

These workers first review the technique of "peritoneal kidney.” Through a low lateral McBurney incision, and under local anesthesia, a small "sump” drain was inserted into the RLQ and placed in the right paracolic gutter ad- jacent to the cecum. Through a trochar, a No. 18 French catheter was introduced well into the peritoneal cavity at a point in the ULQ two inches below the costal margin. The irrigating solutions were introduced through the catheter, chiefly mamalian Tyrode’s solution but also for brief in- tervals glucose in water, sixth-molar sodium lactate, and Ringers solution. 25,000 units of penicillin and 1 mg. of

heparin were added to each liter of solution, and penicillin (and streptomycin in two cases) were given during the irrigation. The rate of flow was nearly 1000 cc per hour.

Three cases of acute renal failure resulting from trans- fusion of incompatible blood, were treated. Case 1 re- covered. In 5.5 days of irrigation, 76.84 gm. of urea were cleared in the peritoneal washings. However, toward the end of irrigation, the patient became more edematous and acidotic, associated with continued peritoneal absorption of salts and water, greatly benefitted by substituting as the irrigating solution five per cent glucose in water. By this means, 60-70 gms. of NaCl were removed, followed by diuresis and recovery. Peritonitis in this case, due to Proteus morgani, was successfully treated with strepto- mycin, which resulted in vestibular damage.

Case 2 demonstrated marked and repeated hemolysis with transfusions in spite of carefully matched blood. The peritoneal irrigation was started earlier, and glucose in water was used first, followed by Tyrode’s solution and small amounts of lactate-Ringer’s solution .115 gm. of urea were measured in the outflow in seven and one-half days. Subcutaneous edema appeared, attributed to peritoneal ab- sorption of water and salt. Acidosis became very severe. A localized peritonitis developed, treated by streptomycin. Exitus occurred after a convulsion on the fifteenth day after the original transfusion. Autopsy revealed characteristic renal damage.

Case 3 ran essentially the same course. 71.5 gm. of urea were cleared in three days of irrigation. Pronounced acido- sis developed. The patient succumbed when 3000 cc. of blood were introduced into the mediastinum and pleural spaces during an attempted sternal transfusion.

In summary, two major complications were related to the irrigation in each case: (1) Severe acidosis and (2) the absorption of water and salts from the peritoneal sur- faces. Indications were |hat the acidosis resulted from differential washing out of base while neutral salts were absorbed. Generalized edema developed or became ac- centuated, and threat of pulmonary edema remained con- stant.

These workers conclude that peritoneal irrigation as out- lined is not a satisfactory method of treatment in acute renal damage from transfusion reaction. They prefer:

( 1 ) Transfusion of compatible blood during the first phase of hemolysis and hypotension; (2) Restricted fluid intake, salt restriction, and added sodium bicarbonate during the second phase of renal insufficiency; ( 3 ) Replacement of the water-salt loss during the third phase of copious diur- esis, appearing about the eighth to fourteenth day. — E.J.R. # # #

Parenteral Nutrition

Complete Parenteral Nutrition for the Surgical Patient. Paper read by Robert Elman at International Medical As- sembly of Interstate Postgraduate Medical Association of North America, St. Louis, October 14, 1947.

Dr. Elman’s discussion was directed primarily to the needs of the patient with intestinal fistula, but it applies equally well to any patient in whom resort must be had to parenteral feeding. The problem is considered with respect to daily needs as follows:

( 1 ) Minerals: for most patients, 2 grams of NaCl; other minerals may be disregarded over short periods of time.

(2) Vitamins: the Vit. B complex, including 5 mgm. each of Bi and B2, 50 mgm. of niacin, plus 1000 mgm. of Vit. C are administered by single i.v. injection.

(3) Water: two liters are regarded as adequate for the average patient without excessive loss of fluids; "one quart for urine, and one for sweat.”

JANUARY, 1948

39

JExp

ertence ts

the Best Teacher

JOHN HUGHES BENNETT (1812-1875) proved it in histology

Bennett’s experiences, gained by linking physiology with clinical medicine, led him to institute the practical study of histology, to recognize the medicinal value of cod liver oil, and to be the first to describe the blood condition leukemia — Bennett’s disease.

R. J. Reynolds Tobacco Company, Winston-Salem, N. 0.

! And

DURING the wartime cigarette shortage, people smoked many different brands — any brand they could get. And as they smoked — they

naturally compared the different brands for

taste, for mildness, for coolness . . . for all-round smoking enjoyment. More and more smokers found from the experience of those comparisons that Camels suit them best.

Result? More people are smoking Camels than ever before!

According to a Nationwide survey:

AMore Doctors Smoke HAAIEMjS

than any other cigarette

Three nationally known independent research organizations asked 113,597 doctors — in every branch of medicine — to name the cigarette they smoked. More doctors named Camel than any other brand.

40

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

(4) Foodstuffs:

(a) Glucose: 100 gms are enough for adequate fat metabolism to yield the required number of calories, when the caloric value of the amino acids administered is added.

(Note: one gram of glucose will metabolize fully one gram of fat.) Thus:

100 gms of glucose @ 4 cal./gm = 400 cals.

100 gms of fat @ 9 cal./gm — 900

(b) Protein, as amino acids, 5%, sol. is given i.v., 2000 cc. Thus 100 gms will give positive nitrogen bal. @ 4 cal./gm. = 400

Total calories for 24 hrs., 1700

(c) Fat: this is derived from the body stores; some 90,000 cals, are thus available in an average body (20 lbs. of fat). (If these have been depleted they may be supplemented by i.v. alcohol, 5% sol.)

Clinical application: Only two items are necessary to supply the above:

(a) Vitamins are administered as in (2) above.

(b) Amigen (Mead Johnson & Co.) contains 5% glucose, 5% amino acids, and 0.25% salt. Two liters, administered daily at a rate of about 3 hours per liter, will thus yield :

glucose 100 gms

protein 100 gms

salt 5 gms

Comment:

Reactions: these are rare and not usually severe, 0.8% as compared with an incidence of about 2% for plasma in Dr. Elman's series.

Nitrogen balance is positive on the above intake of 36 gms in 5 days, as opposed to an output of 26 gms in this time. Under these conditions any weight loss is due to loss of fat; the body protein is not sacrificed.

Earlier general recovery, less edema with consequent earlier functioning of surgical stoma, better gastro-intes- tinal motility, and earlier ability to handle oral diet are re- ported by Dr. Elman. On this regime a patient may be prepared for surgery who might otherwise be unable to withstand operation. — T.P.B.

# =* #

Sodium Bicarbonate with Sulfonamides

foseph FI. Rohr and Paul S. Rhoads, Quarterly Bulletin of Northwestern University Medical School, 21:130-134, 1947.

The summary in the November, 1947, Digest of Treat- ment points out the following:

1. If sufficient alkali is given to maintain a urinary ph of 7.5, the sulfonamide can pass through the renal tubules in a 1000 mg. per cent concentration in solution without precipitation.

2. If the urine is less alkaline than ph 7.5, sulfonamide concentrations as low as 100 to 300 mg. per cent may pre- cipitate with resultant anuria and death.

3. Ingested alkali dosage necessary to produce urine ph 7.5 may vary with the patient and the disease.

4. Sodium bicarbonate, 24 grams daily divided into four or six equally spaced doses, kept the urine alkaline in most patients without clinical or chemical alkalosis. Where oral medication was not possible, intravenous 1/6 molar sodium lactate or sodium bicarbonate was used.

5. Effervescent alkali was more acceptable to patients and proved as effective, therefore was considered the alka- line preparation of choice.- — P.W.M.

Curare: Its Past and Present

Stuart C. Cullen, Anesthesiology, 8:479-488, September, 1947.

The author has reviewed the history of curare from its first use by South American Indians to its present clinical use in medicine. The Indians were aware of the powers and limitations of the crude drug. While we have a purer and more predictable product today, we have not altered the conception of the drug’s fundamental properties that was held by investigators and clinicians of the early 19th century. Sir Walter Raleigh in 1584 presented Queen Elizabeth with some of the crude drug. The author relates that in 1745 De La Condimine, a French investigator, con- ducted the first reliable physiologic experiments with the drug. Little progress was made until 1828 when two French physicians, Roulin and Roussingault, isolated an active principle to which they gave the name curarin.

In 1844 Claude Bernard, the eminent French physiolo- gist, established the fact that curare paralyzed the motor nerves. These researches were extended by Virchow and Munter, German investigators, who found that it induced a stupor and a paralysis of voluntary muscles and that it was only effective when introduced into the body paren- terally, and that death from curare was due to paralysis of respiratory muscles and not to central nervous system poisoning as had been previously thought.

Clinical application of curare was first attempted in 1866 by two French physicians, Tiercelin and Benedict, for the relief of the convulsions of epilepsy, and in 1878 H. Hunter, a British physician, used curare in the treatment of the spasticity of tetanus and hydrophobia. The results were uncertain and the drug was given up.

In 1932 Ranyard West, an English physician, used curare in the treatment of certain spastic disorders, such as Parkinson’s disease, parathyroid tetany, epilepsy and hemi- plegia. His clinical results were not encouraging, but he did add much to our knowledge concerning curare.

In 1939 intercostin, a predictable and stable preparation, was introduced. This product was the result of coordina- tion and cooperation of Richard Gill, an explorer and nat- uralist, and Dr. McIntyre, pharmacologist at the University of Nebraska. Intercostin is now clinically accepted and, with its active principle d-tubocurarine, makes up prepara- tions that allow research workers and clinicians to rely upon them for consistent action.

In 1940 at the meeting of the A.M.A., Bennett had an exhibit regarding the use of curare during metrazol and electric shock therapy. This stimulated much interest and speculation as to its use in anesthesia as a means of im- proving muscular relaxation.

It is emphasized that it has no analgesic or anesthetic action and is used only in conjunction with anesthetic agents to aid in securing better muscular relaxation. Its principal advantage in anesthesiology is to provide mus- cular relaxation with low concentration of potent anesthetic agents. It has been used in conjunction with cyclopropane, nitrous oxide and pentothal sodium anesthesia.

It was determined during further research that curare does not alter cardiac rhythm, does cause relaxation of the small intestine and does not interfere with certain elements of tissue metabolism.

The author reviews the disadvantages and dangers and especially warns against over-dosage with resulting respira- tory paralysis and peripheral vascular collapse.

Recently Schlesinger (1946) has used a preparation of curare in oil in treatment of certain spastic states with en- couraging results. Also Ransohoff has used curare in the treatment of poliomyelitis.

JANUARY, 1948

The Book of Life ... on one page

" Each person in the world creates a Book of Life. This booh starts with birth and ends with death.. . has many pages for some and is but a few pages in length for others. ,n

A single page tells the life story of those infants who die within the first BO days after birth. It is during this fatal first month that 62.1% of all infant mortality occurs — an increase of almost 10% in the past 20 years. There is urgent need then to utilize every advantage science offers in eliminating the hazards of neonatal life. A good start on the right feeding can do much to minimize the gastrointestinal hazards of excessive fermentation, upset digestion and diarrhea.

'Dexin; has proved an excellent "first carbohydrate" because of its high dextrin content. It (1) resists fermentation by the usual intestinal or- ganisms; (2) tends to hold gas formation, distention and diarrhea to a minimum, and (3) promotes the formation of soft, flocculent, easily di- gested curds. 'Dexin' does make a difference.

1. Dunn, H. L. : Am. J. Pub. Health 36:1412 (Dec.) 1946.

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42

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

Curare has secured a respectable place in the modern armamentarium of therapeutic agents. Much remains to be learned about the drug. It is anticipated that this jungle poison will justify the faith in it that all its ancient and contemporary patrons have had. — H.F.S.

* * *

Streptomycin in Meningitis

Sreptomycin in the Treatment of Meningitis. Tom Fite Paine, Roderick Murray, Albert O. Seeler and Maxwell Finland, Ann. Int. Med., 27:494-518, October, 1947.

These authors report the treatment with streptomycin of 16 cases of meningitis in infants and children due to H. influenza. Fifteen patients recovered. The response was usually prompt, distinct improvement occurring within 24 to 72 hours of starting treatment. Neurologic sequelae deafness, and blindness occurred in only one case. The medication was given intramuscularly and intrathecally.

Eight patients with meningitis due to other gram-nega- tive bacilli were treated with streptomycin, and six recov- ered. Causative organisms included Pseudomonas aerugi- nosa (B. pyocyaneus), Proteus morgani, Aerobacter aero- genes, Escherichia coli communis, H. parainfluenzae, and a ''pleuropneumonia-like” organism. Penicillin with or without sulfadiazine had been given before streptomycin was started. In the recovered patients, response to strepto- mycin was prompt. One resistant strain appeared during treatment.

Three cases of tuberculous meningitis were treated with streptomycin. There was one death.

Among the untoward reactions to streptomycin, fever attributed to the drug was most common, occurring def- initely in 9 of the 24 nontuberculous cases. Atoxia oc- curred in only one case. One patient developed a macular, erythematous rash.

These authors consider streptomycin to be of consider- able value in the treatment of meningitis due to gram- negative bacilli, and recommend that it be given intra- muscularly and intrathecally. In adults an intramuscular dose of 1 gram every 6 hours and a daily single intrathecal dose of 50 mg. appears to be adequate in most cases. In- fants and small children may receive about 25 mg., or slightly more, per pound of body weight per day intra- muscularly and 10 to 50 mg. daily by the intrathecal route. It is suggested that sulfadiazine be given concomitantly if treatment is started late or in seriously ill patients. In cases due to H. influenzae type B, specific antiserum and sulfa- diazine should be added under similar circumstances. — E.J.R.

# * #

Acromegaly with Amyotrophic Lateral Sclerosis

Acromegaly Associated with Amyotrophic Lateral Scler- osis and Acromegaly of the Amyotrophic Type. E. Perry McCullagh and J. S. Hewlett, Jnl. Clin. Endoc., 7:636- 643, September, 1947.

In their preliminary discussion, these authors bring out the fact that an "amyotrophic form of acromegaly” was described by Duchesnau as early as 1891, and that a re- lationship between acromegaly and neuromuscular disor- ders has been stressed by several other workers since. They feel that the coexistence of the two disorders may be of importance in attempting to analyze and study the etiolog- ical factor in amyotrophic lateral sclerosis.

Three cases are presented as follows:

Case 1: An Italian woman, age 41, presented the typical symptoms and signs of acromegaly. Neurological examina- tion showed marked atrophy of both deltoid muscles as well as the muscles of the arms and forearms. Hoffman's

sign was positive bilaterally, and fibrillary twitchings were present in the muscles of both arms. Babinski sign was questionable. Sensory perception was normal.

The patient died four days after pituitary surgery, and autopsy revealed an acidophilic pituitary adenoma and de- generative changes in the spinal cord consistent with a diagnosis of amyotrophic lateral sclerosis.

Case 2 : A woman, age 66 at original examination, pre- sented typical findings of acromegaly, with associated dia- betes and hypermetabolism. In addition she had profound weakness of the musculature of the upper and lower ex- tremities. Neurological examination revealed hyperactivity of all deep reflexes. Babinski’s sign was positive on the left, and abdominal reflexes were absent. There was marked atrophy of muscles of the arms and legs, and a few fibril- lary twitchings were visible. Sensory perception was nor- mal.

She received extensive therapy, including control of the diabetes, x-ray to the pituitary and thyroid, Lugol’s solu- tion, thiamin, liver extract, and Vitamin E. Eight years after original study muscular strength was much improved. She was classified as acromegaly of the amyotrophic type.

Case 3: A man, age 52, presented a typical picture of acromegaly, but complained primarily of progressive weak- ness in both lower extremities.

Neurological examination showed atrophy and weakness in both legs. Fibrillary twitchings were visible in both thighs. Deep reflexes were hyperactive. Abdominal re- flexes were present over the upper half but absent over the lower half of the abdomen.

In an attempt to encourage nitrogen retention, he was given testosterone propionate and a diet containing 125 gms. of protein per day. On this he showed some im- provement in muscular strength prior to his death follow- ing a cerebral vascular accident.

The authors suggest that the increased metabolic de- mand incident to the acromegaly in these three cases was an important factor in the production of the neuromuscular disease which simulated or actually was amyotrophic lateral sclerosis. — E.J.R.

Nutrition Standards Suggested

Because "a majority of Americans suffer from nutritional deficiencies,” enactment of laws to maintain standards of nutrition comparable to the pure food laws was suggested recently by Basil O’Connor, national chairman of the American Red Cross, at the second annual dinner of the National Vitamin Foundation.

Survey estimates, Mr. O’Connor reported, indicate that 15 per cent of our people have frank symptoms of nutri- tional diseases, and nearly 70 per cent of our people are suffering with subclinical disorders indicative of marginal deficiencies.

"Establishing basic nutrition for the mass of people is so vital that it may be wise to have insured nutrition rather than trust all our efforts to education,” he said. "By law, it is required that certain standards of purity be maintained in food items sold to the public. Are not standards of nutrition fully as important as standards of purity?

"Enrichment of flour is already a widespread practice and one that is accomplishing much good. But that good can be enhanced still further by adding other essential nutrients usually lost in the extraction and purifying proc- esses. Other common foods like oleomargarine might well be fortified with the lacking vitamins. Our present techni- cal knowledge would permit us to control vitamins and mineral content of canned and processed fruits and veg- etables.”

JANUARY, 1948

43

was well ahead of his time, for physicians of his day knew little of the function of the heart or the treatment of its diseases, although da Vinci’s knowledge of such anatomy was extensive.

Physicians of today prescribe

SEARLE AMINOPHYLLIN*

— a modern treatment for congestive heart failure, bronchial asthma, paroxysmal dyspnea and Cheyne-Stokes respiration.

Supplied for oral, parenteral and rectal use.

G. D. Searle & Co., Chicago 80, Illinois.

*Searle Aminophyllin contains at least 80% of anhydrous theophylline.

SEARLE

RESEARCH IN THE SERVICE OF MEDICINE

44

THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

BOOK REVIEWS

Sexual Behavior in the Human Male. By Alfred C. Kin- sey, Warded B. Pomeroy and Clyde E. Martin. Published by W. B. Saunders Company, Philadelphia. 804 pages, 173 charts, 159 tables. Price $6.50.

Gifford's Textbook of Ophthalmology. Fourth Edition. By Francis H. Adler, M.D. Published by W ■ B. Saunders Company, Philadelphia. 512 pages, 310 illustrations. Price $6.00.

This is a most complete, concise and inclusive book on the subject of ophthalmology. It is designed, as the author states, to be useful as a textbook in the medical curriculum and also as a reference work.

The chapters on ocular disorders due to diseases of the central nervous system and ocular manifestations of gen- eral disease alone, make it a valuable source of reference to the general physician as well as the opthalmologist.- — W.W.R.

# # #

400 Years of a Doctor’s Life. Collected and arranged by George Rosen, M.D., and Beate Caspari-Rosen, M.D. Published by Henry Schuman, New York. 429 pages. Price $5.00.

A reviewer of this book could do no better than to quote from its preface, "The aim is to present an informal por- trait which will show the doctor not only as the Great Healer or Great Scientist but also as a citizen of every- man's world. To achieve this aim, more than 80 personali- ties have been selected from among men and women who have made significant contributions to the literature of medical autobiography. What these doctors say here re- veals to the layman the matrix of a doctor’s life and a sense of the sweeping drama of medical history, with a clarity attainable in no other medium.”

The book is an anthology with excerpts from doctor’s writings divided into the following classifications: Early Years, School Days, The Medical Student, The Practice of Medicine, Scientist-Scholar-Teacher, The Doctor Marries, The Doctor as a Patient, The Doctor Goes to War, Writing and Politics, Reflections on Life and Death.

The span of years provides for contrast in each classifi- cation, and the personalities of the authors are reflected in their writings. There was no attempt to include each doctor in each section, and the selections were made on the basis of interest and insight into the life of the doctor as a per- son. Consequently, the book is one any doctor will enjoy reading, and it is so arranged that it can be picked up for random sampling if preferred.

Among those whose works are quoted are Oliver Wen- dell Holmes, Havelock Ellis, J. Marion Sims, Benjamin Rush, Elizabeth Blackwell, Sigmund Freud, Horace Wells, Arthur E. Hertzler, S. Josephine Baker, Harvey Cushing, Rudolf Virchow, William Osier and Ambrose Pare.

Books Received

Practical Child Guidance and Mental Hygiene. By Sam- uel Kahn, M.D., Grace Kirsten, A.B., and May Elish March, A.B., M.A. Published by Meador Publishing Com- pany, Boston.

Bibliography

Listed below are the references for the paper, "Evalua- tion of Cardiac Patients for Surgery,” by Mahlon H. Delp, M.D., Kansas City, Kansas, which appeared in the De- cember, 1947, issue of the Journal:

1. Marvin, H. M. : The Heart During Anaesthesia and Opera- tive Procedures, New Eng. J. Med. 199:547. (Sept. 10) 1928.

2. Butler, S. , Feeney, M. , and Levine, S. A.: The Patient with Heart Disease as a Surgical Risk, Review of 414 Cases, J.A.M.A. 95:85. (July 12) 1930.

3. Sprague, H. B.: The Heart in Surgery, Surg. Gynec. Obst. 49:54. 1929.

4. Jensen, Julius: The Heart in Pregnancy, The C. V. Mosby Co., St. Louis. 1938.

5. Clawson. B. J.: Incidence of Types of Heart Disease among 30,265 autopsies with Special Reference to Age and Sex, Am. Heart J. 22:607. 1941.

6. Rountree, L. G. : National Program for Physical Fitness Re- vealed and Developed on the Basis of 13,000,000 Physical Examina- tions of Selective Service Registrants, J.A.M.A. 125:821. 1944.

7. Levy, R. L., Stroud, W. D., and White, P. D.: Report of Reexamination of 4,994 Men Disqualified for General Military Service Because of the Diagnosis of Cardiovascular Defect: A Com- bined Study made by the Special Medical Advisory Boards in Bos- ton, Chicago, New York, Philadelphia and San Francisco. J.A.M.A 123:927, 1029- 1943.

8. Massie, Edward and Valle. Anibol, Roberto: Cardiac Ar-

rhythmias Complicating Total Pneumonectomy, Ann. Int. Med. 26:2. Pg. 231-239. Feb. 1947.

9. Harrison, Tinsley R.: Diagnosis of Heart Failure, J.A.M.A.

115:7. Pp. 524-527. Aug. 17, 1940.

10. White, P. D.: Heart Disease: New York. The MacMillan Co. P. 282. 1931.

11. Clendening, Logan: Personal Communication.

12. Levy,- R. L., Patterson, J. E., Clark, T. W., and Bruenn,

H. D : "Anorexia Test” as Index of Coronary Reserve: Serial

Observation on 137 Patients and Their Application to Detection and Clinical Course of Coronary Insuff.ciency, J.A.M.A. 117-2113. (Dec. 20) 1941.

13. Master, A. M., Nuzie, S. , Brown, R. C. , Parker, R. C. : The Electrocardiogram and The "Two-Step” Exercise. A test of Cardiac Function and Coronary Insufficiency. A.J.M.S. 480-485. April 1945.

14. Herrmann, George, and Herrmann, Lows G.: Cardiac Dis- orders in Surgical Patients: Criteria Used in Estimating the Risk Involved. Texas J. Med. 30:3. Pp. 183-191. July 1934.

15. Wirth, Willard R. : Anaesthesia in Heart Disease. New

Orleans Med. and Surg. Jour. 95:6. Pp. 273-278. Dec. 1942.

16. Belinkoff, Stanton: The Cho ce of Anaesthesia in Cardiac

Disease. Anaesthesiology. 7:268. May 1946.

17. Kurtz, C. M., Bennett, J. H., and Shapiro, H. H.: Elec- trocardiographic Studies During Surgical Anaesthesia. J.A.M.A. 106:434. 1936.

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THE JOURNAL

of the

KANSAS MEDICAL SOCIETY

Owned and Published by The Kansas Adedical Society

Volume XLIX

FEBRUARY, 1948

No. 2

PITFALLS IN THE TREATMENT OF DIABETIC COMA*

Alexander Marble, M.D.**

Boston. Massachusetts

The year 1947 marks the twenty-fifth anniver- sary of the clinical use of insulin. During the last quarter-century the outlook for the diabetic has im- proved to an extraordinary degree. He is now able to lead a useful, happy and essentially normal life. His life expectancy after the onset of diabetes has increased so that it compares favorably with that of ncn-diabetics. For the first time in the history of the world, diabetic children are living on and on, so that in our own group alone, there were on January 1, 1946, 249*** with onset at 15.0 years of age or under who had survived the disease for 20 or more years; of these, 237 were still alive.^

Despite these remarkable advances in the insulin era, the fact remains that patients still acquire, and not infrequently die from diabetic coma, that unique complication which represents the end-stage of the uncontrolled disease. It is true that the morbidity and mortality from diabetic coma have been greatly lowered but there is still much room for improve- ment. In Table I are shown data from our own group. It will be noted that whereas in 1898-1914, 63-8 per cent, or more than six of every 10 deaths were in coma, the number in the last 10 years has been reduced to somewhat over three per cent. Yet even better statistics are possible since diabetic coma

* Presented at the 88th Annual Session, Kansas Medical Society, Topeka, May 13, 1947.

* * From the George F. Baker Clinic, Elliott P. Joslin, M.D., Medical Director, New England Deaconess Hospital, Boston, Mass.

***By August 1, 1947, the number had grown to 350.

Table I

Coma as a Cause of Death in 8384 Diabetics* (Experience of Elliott P. Joslin, M.D., and associates)

	Total	Deaths due to Coma
Period	Deaths	Number	Per Cent
1898-1914	32 6	208	63.8
1914-1922	836	347	41.5
1922-1936	3988	336	8.4
1937-1943	2583	87	3.4
1944-1946	651	20	3.1
* Prepared with the cooperation of the Statistical Bureau, Metro- politan Life Insurance Company. See Joslin et al. (IB)

is a preventable condition and, if treated early enough, always remediable.

The above figures refer to the percentage of coma deaths to all deaths among diabetics. Further evi- dence as to trends may be obtained from a study of mortality rates in patients with diabetic coma. In our own series of 651 cases from May, 1923, to Jan- uary, 1946, there were 61 deaths or 9.4 per cent of the total. Mortality has ranged from 21 per cent in the early days of insulin (May, 1923, to March, 1925) to 2.4 per cent in the series of 126 cases from January, 1942, to January, 1946. There have been only four deaths among the last 188 patients ad- mitted in coma.*

The above figures are cited simply to indicate trends in the practice of one group of physicians see- ing diabetic patients. They are not necessarily compa- rable with statistics from other clinics because of the variation in clientele, local conditions and stan- dards of classification. It is important, and indeed imperative, however, that each clinician analyze his own experience and make every attempt to improve methods of diagnosis and treatment in his own prac- tice to the end that throughout the country deaths from diabetic coma may be abolished. This, of course, demands not only increasingly better treat- ment by the physician but also education of the patient and the public.

PREVENTION

It goes without saying that it is the careless pa- tient, the patient with porly controlled diabetes, who is most likely to develop diabetic coma. Herein lies the outstanding value of early and continuous edu- cation of the patient and his family regarding dia- betes, it complications and its home management. This may be accomplished either by class or indi- vidual instruction, depending upon the number of patients concerned. To enable himself to be of

‘Up to January 1, 1948 there were 704 cases of coma with 61 deaths or 8.6 per cent mortality. There were no deaths among the 53 cases in 1946 and 1947.

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THE JOURNAL OF THE KANSAS MEDICAL SOCIETY

greater service, the physician should enlist the aid of a nurse, dietitian or other qualified worker in order that details of management may be explained over and over to patients. At office or hospital visits, the physician must take every opportunity to in- struct and to encourage. The old adage that "the patient who knows the most lives the longest” is thoroughly sound.

This is an appropriate point to state briefly, though emphatically, the belief of the writer and his associates and that of many clinicians over the coun- try that the careful treatment of diabetes pays. We be- lieve that not only are acidosis and coma more com- mon in patients with poorly controlled diabetes but also that the degenerative complications, chiefly ar- teriosclerotic, now seen to such alarming extent after 15 or 20 years of diabetes in certain patients with onset in childhood^, are the result of poorly con- trolled diabetes and are to be avoided or deferred only by continuous, careful treatment. We deplore the teaching that hyperglycemia and glycosuria are not harmful and urge that the aim of treatment be as nearly 100 per cent control and restoration of normal conditions as is possible or practicable in the individual case.

Among errors made by patients which may pre- cipitate diabetic coma, one finds that frequently, even in well-trained patients, insulin is omitted dur- ing times of acute illness when food intake is scant and perhaps nausea and vomiting are present. The patient, fearing hypoglycemia, reasons that "if I don’t eat, I should not take any insulin.” The end- result is increasing hyperglycemia with the develop- ment of acidosis and eventual coma. Consequently, patients must be made to understand that at times of acute illness, insulin must be continued daily. Often, particularly if the illness is accompanied by fever, an even greater dose may be necessary. The dose should not be reduced unless the urine, tested every three or four hours, contains no sugar.

Patients must be taught to make regular visits to the physician for check-up at intervals which may vary from once a month to once or twice a year, depending upon the case. Patients and their fam- ilies must be instructed to get in touch with the physician at once during the early stages of any illness before the development of serious complica- tions.

DIAGNOSIS

Anyone who has had the experience will sympa- thize with the physician confronted with a drowsy or unconscious patient regarding whom no satisfac- tory history can be obtained. However, one goes far if one simply keeps diabetic coma in mind as a possibility and adds it to the list of conditions to be considered, including hypoglycemia, uremia, cerebral hemorrhage, fractured skull, brain tumor, meningitis

and overwhelming infection. Usually clinical find- ings, which will not be detailed here, give leads as to diagnosis which can then be promptly followed up by appropriate laboratory studies. It must be re- membered, however, that often the clinical findings are not typical and may confuse the most experi- enced observer. It is so easy to be misled that the diagnosis should be confirmed by laboratory tests in each case. This need not, and should not, delay treatment in cases of definite diabetic coma because, based on the examination of the urine for sugar and diacetic acid, treatment may be got under way while blood determinations are being carried out.

In a case of diabetic coma there is need for speed of action. Treatment must be started not in 12 hours, not in six hours, not in two or three hours — but within a few minutes after first observation. These few hours may be the ones which mean the difference between a happy, and a fatal, outcome. At first observation, a brief but adequate history and physical examination must be carried out with ex- pediency. If the clinical impression includes diabetic coma as a possbility, then the urine, obtained by catheter if necessary, should be tested for sugar and diacetic acid at once and on the spot. Blood should be drawn for determination which should include at least that for sugar, preferably also for carbon diox- ide content and non-protein nitrogen and, if avail- able, those for chloride and acetone body content. In any well-regulated hospital, facilities for the de- termination of blood constituents, at least those most likely to be needed, should be available nights, Sun- days and holidays. The report of the initial blood studies should be ready for the physician within an hour after admission of the patient.

TREATMENT

1. Insulin. The most treacherous pitfall in the treatment of diabetic coma is the danger of giving too little insulin. Diabetic coma is primarily a con- dition of acute insulin deficiency which can be re- lieved only by the prompt administration of truly adequate doses of insulin. Insulin must be accorded first place in any discussion and other items of treat- ment, however valuable, must be relegated to less important positions. All too often the physician has an unwarranted fear of hypoglycemia. If treat- ment is sensibly and intelligently planned, little basis for such fear exists. In the average case of full- blown coma, insulin must be given boldly and fear- lessly in large doses, particularly in the first three hours after the patient is brought for treatment.

As soon as the diagnosis is made, a preliminary large dose of unmodified insulin, at least 50 units and in most patients 100 units, should be given subcutaneously. In patients in shock or in whom it might be anticipated that absorption from subcu-

FEBRUARY, 1948

55

taneous spaces might be slow, a supplementary dose of like size may be given intravenously. Additional amounts should be given in divided doses during the first three hours of observation, basing the decision as to size of dose upon clinical behavior and the level of the initial blood sugar, according to some such schedule as the following:

If the initial blood sugar is

300-600 mg. per 100 cc., give 50 to 100 addi- tional units

600-1000 mg. per 100 cc., give 200 additional units

Over 1000 mg. per 100 cc., give 300 additional units

After three hours, the blood studies should be re- peated. This is extremely important because thereby at an early stage one can learn the progress of treatment and the response of the patient. One hopes that the blood sugar will be falling and the carbon dioxide content rising but if this proves not to be the case, then one knows that, regardless of the size of previous doses, insulin must be given promptly and in still larger amounts. Some patients in diabetic coma need much more insulin than others but it is fair to state that if enough insulin is given, even exceeding 1000 units over a period of a few hours, a blood sugar-lowering effect will be obtained. It must be borne in mind that in diabetic acidosis, in- sulin, like paper money in times of inflation, does not have its face value. The size of dose must be gauged by the effects obtained rather than by any routine plan.

Comments above as to size of dosage refer to the treatment of young adults or adults in well-marked acidosis and coma. In children or in those patients with