CHAPTEE 1:On Adrenal Insufficiency

I N T R 0 D 17 C T I 0 N.

CHAPTER 1.

On Adrenal Insufficiency.

Adrenal insufficiency in animals.

After adrenaleotomy.

The fact that the adrenals are essential for the preservation of life has long been known. As early as 1856 BROWN- SEQUARD made it clear by experimental extirpations that animals can survive the loss of their adrenals for a short time only, The results obtained by him have since been confirmed by a great number of investigators. The complete removal of the adrenals is accompanied by symptoms which are characteristic and now well known. They develop fairly alike in different animals, such as cats, dogs and rabbits. Numerous experiments have shown that it is the removal of the adrenal cortex, not the medulla, that causes these symptoms and the death of the animals. The symptoms are best studied in experiments in which the adrenalectomy has been performed in two sittings. The experiments have often been so arranged that after a total adrenalectomy cortical hormone has been administered to the animal during a certain period in which it has recovered after the operation. When the administration of cortical hormone is then discontinued the conditions are most favourable for a "clean" clinical picture to be obtained. The animals survive a total adrenalectomy differently but cats, dogs, and rabbits often survive for 5-7 days. The symptoms develop more or less rapidly according to the length of the time of survival.

After the animals have recovered after the operations or when hormone is no longer administered to adrenalectomized animals,

10 ARNE LITHANDER.

they appear to be in good health for, as a rule, 1-4 days. After this latent period symptoms begin to appear, sometimes rapidly, sometimes slowly. It is first found that the appetite of the experimental animals is lessened so that soon total anorexia appears. In later stages vomiting and diarrhoea often occur and the faeces do not seldom contain blood. About simultaneously x i th the decrease of appetite signs of muscular weakness begin to appear. The weakness gradually increases so that the animals can rise only with difficulty. Finally they lie stretched limply on the bedding. Even in cases of considerable muscular weakness it is possible to excite them to quite lively movements though of short duration after which they are exhausted, Quite early spasticity is observed in the muscles, muscular twitchings develop gradually and, in the final stages, cramps are quite frequent. The breathing seems to be affected comparatively early. In the beginning i t is more rapid than usual. Later i t becomes retarded, often uneven and sometimes in the final stages of the Clheyne- Stoke’s type, In most cases the body temperature falls progress- ively. The decrease in temperature is often considerable, not seldom up to 5 degrees below normal. It also belongs to the early symptoms but, as a rule, sets in later than the loss of appetite and muscular weakness. Circulatory changes soon make themselves felt. It becomes increasingly difficult to draw blood from minor vessels. This is most evident in rabbits whose ears become cold and pale when the circulatory changes commence. The vessels appear collapsed and do not fill when the ear is excited by meansof heat, benzol or other agents. dfter incision of a vein in the ear the blood flows slowly or no blood is obtained. Even to the naked eye the blood appears thick. The blood concentration is augmented which is inter alia demonstrated by the increased number of red blood-cells, The increase progresses with growing symptoms of insufficiency. The amount of plasma measured by haematocrite determinations definitely decreases a t the same time. The volume of the blood is diminished and its specific gravity augmented. Largely in consequence of the decreased volume of blood there is early a decline in the blood pressure. The pulse, which first shows greater rate, becomes slower when the symptoms of insufficiency become pronounced and is often irregular in the final stages. I n cases of insufficiency even small losses of blood may be deleterious in that they appear to enhance the development of circulatory changes. As a sign of general dehydration the skin becomes, in the late

ACUTE ADRENAL INSUFFICIENCY IN RABBITS. 11

stages, dry and wrinkled and loses its elasticity so that lifted folds remain rigid for a long time.

I n a fully developed condition of insufficiency the experimental animals present, on the whole, the following picture. The animal lies limply on the bedding and shows little or no reaction to disturbances. Pronounced adynamia sets in. Breathing is generally slow and superficial and often uneven. Vomiting and diarrhoea often occur, not infrequently accompanied by blood in the faeces. The skin is dry and wrinkled and cold. The coldness of the skin is particularly marked on the limbs and ears which latter is most easily observed in rabbits. hperficial vessels are contracted and do not expand after irritation of the skin. It is difficult or impossible to draw blood from them. The body-weight is lowered owing to the dehydration. Twitchings often occur in the limbs and, in the final stages, tonic and clonic cramps. In the terminal stages somnolency develops after which dcath supervenes, usually after a short period of coma.

Changes occur also in the chemical composition of the blood. An increase of non-protein nitrogen and blood urea is considered most frequently to be about simultaneous tvith the fall in blood pressure and, according to some authors, this phenomenon conti- nues with the development of the symptoms. In the final stages the non-protein nitrogen often attains high values. The values recorded for chloride and sodium in the blood fall while the potassium content rises in the final stages. The changes in these values are more or less marked in different cases. The blood sugar mostly shows considerable changes. According to the majority of authors a decrease sets in early and becomes aggravated as the animal gets worse so that a t death a considerable hypoglycaemia is established. At this time the liver contains little or no glycogen.

Numerous endeavours have been made to elaborate an effective therapy for the conditions of insufficiency prevailing in adrenalectomized animals. Injections of adrenalin sometimes effect a short improvement, which has been established in cats by, among others, BRITTON and SILVETTE (1931/32). The blood pressure may then be maintained for a short period. I n cases of insufficiency injections of adrenalin cause no or insignificant increases in blood sugar. As distinguished from adrenalin cortical hormone has considerable effect on conditions of insufficiency. The administration of this hormone works a definite change after a certain atent period. The symptoms of insufficiency abate so that the

12 ARNE LITHANDEX.

animal appears to recover its health as before adrenal removal. The symptoms of insufficiency return only when the administration of cortical hormone ceases. If cortical hormone is only given in the final stages: the result is negligible.

In the autopsy of animals that have died from adrenal insufficiency after total adrenalectomy the changes in the abdominal viscera have been the primary object of examination. BANTING and GAIRNS (1926) found a pronounced congestion of the abclo- minal viscera, the mucous membranes of which displayed stasis and petechial haemorrhages. In the liver cells degeneration and necroses were established. The renal parenchyma was haemorrhagic and showed signs of acute degeneration. Sometimes ulcera- tions Were observed in the stomach and duodenum. In the niucous membranes of the stomach and intestines congestion and haemorrhages occurred. However, the changes in the kidneys were not considered sufficient t o explain the variations in non-protein nitrogen and blood urea.

The literature sets forth widely differing opinions on the essential features in the development of adrenal insufficiency. Disturbances in the carbohydrate metabolism, in the electrolyte balance, in the fluid balance or in the circulation have been mentioned.

Comparisons have often been made between the symptoms resulting from shock and those of a condition of insufficiency after adrenalectomy. HARROP and WEINSTEIN et al. (1933 a and b) consider that the symptoms developing when adrenalectomized dogs are no longer given cortical hormone resemble those of shock. By big dosages of cortical hormone they were able to remove the condition of insufficiency but the effect of the hormone was apparent after 12-24 hours only. They considered that the cause of the death of adrenalectornized animals mas loss of fluid involving a shock-like state. They further pointed out that the symptoms of insufficiency resembled those displayed by Addisonian patients in the critical stage. SWINGLE, PFIFFNER et al. (1933 b), too, established great resemblance between the symptoms of shock and those of adrenal insufficiency. They considered, in view of their findings, that fluid is removed from the circulation, probably by transudation, when the administration of cortical hormone to adrenalectoinized animals is discontinued. This prevents the animals from maintaining the normal amount of blood and the blood concentration rises. Death supervenes owing to collapse of circulation through the decrease in the amount of circulating fluid.

ACUTE APRENAL INSUFFICIENCY I N RABBITS. 13

They also declare that the increase of non-protein nitrogen must be due to reduced functioning of the kidneys on account of the circulatory change. The fact that adrenalectomized animals show greater sensitivity to even small losses of blood and slight traumata is regarded by SWINGLE, PFIFFNER et al. (1933 b) and YARKINS (1935) as enhancing the resemblance to shock. According to the former, the only palpable difference between the two conditions is that in shock the blood sugar value is normal or augmented while in adrenal insufficiency it is low. Pinally they emphasized the similar results of cortical hormone as a therapeutic in shock and adrenal insufficiency. Also the pathologico-anatomical changes display a certain resemblance. MOON (1942) pointed out that the likeness between the symptoms and pathologico-anatomical findings in adrenal insufficiency and those characteristic of shock from traumata or other injuries commands considerable attention. He further states that it supports the opinion held by SWINGLE and his co-workers, viz. that insufficiency of the adrenal cortex is the fundamental cause of shock. To this theory, says MOON, the objection may be raised that after adrenalectomy in two sittings the animals survive for many days while in shock the collapse occurs after a few hours.

After injootion of bacteria and their toxins.

The literature contains many statements that adrenal injuries may be produced by the injection of bacteria or their toxins into various animals. The effects of diphtheria toxin have been the most common subjects of study. The descriptions of the experiments seldom comprise both the symptoms and the pathologico- anatomical changes. Descriptions of the symptoms resulting from intoxications are scarce and, generally, incomplete. In those experiments the reports on which embrace descriptions of the symptoms, diphtheria toxin has been injected into rabbits, e. 9 . ROSENTHAL (1913/14) and SCHWENTKER and NOEL (1930). The symptoms mentioned in their reports are falling temperature, reduced weight, muscular asthenia, anorexia towards the end and cramps and coma immediately before death. I n the final stages the blood sugar values generally diminished to hypoglycaemic figures. The glycogen supply of the liver was greatly reduced a t death. SCHUMANN (1939) found, after severe diphtherial intoxication, cyanosis in the nose and ears of guinea pigs and laboured

14 ARNE LITHANDER.

and superficial respiration. He brought up the suggestion that there was a possible adrenal insufficiency. Other authors state they have established reduction of the amount of plasma, increase of the haemoglobin value and of the number of red and white blood- cells, With regard to the electrolyte balance it has been indicated that the content of sodium and chloride in the blood is lowered. Some authors state that the non-protein nitrogen displays an increase in the final stages. RIGDON (1939) has found reduced blood pressure and changes in the adrenals after intravenous injection of staphylococcic toxin into rabbits. UELAFIELI) (1934) stated that circulatory changes and adrenal haeinorrhages may arise in rabbits after the injection of toxic fractions of bact. aes- trycke. No description of the other symptoms is given in the works of these authors.

The pathologico-anatomical changes in experiments when bacterial toxins or bacteria have been injected into animals are most frequently stated to be hyperaemia, haemorrhages and necroses in the adrenals and haemorrhages in the intestines and mesentery.

Adrenal insufficiency in man.

In man we distinguish between two principal forms of adrenal insufficiency, the chronic and the acute. While the knowledge of the chronic form, Addison’s disease, has long been widely spread, the acute one has been fairly unknown to the majority of phy- sicians until 15-20 years ago.

The acute adrenal insufaciency

has been given various names. The disease is often called adrenal apoplexy. There is a certain tendency to employ this name only for acute adrenal insufficiency in small children. This will be ex plained by the fact that the cases earliest described have mainly referred t o infants. This also applies to the name now most com- monly used and suggested by GLANZMANN (1933): the WATER- HOUSE-PRIDERICHSEN syndrome (W.P.). In view of the fact that MARCHAND waR the first to describe a case of this syndrome and WATERROUSE and FRIDERICHSEN have mainly contributed by compilations of cases, THOMAS suggested in 1934 the name MARCHAND- WATERHOUSE syndrome.

The clinical picture has now been accounted for by a great number of authors. With but few deviations it is uniform for cases

ACUTE ADRENAL INSUFFICIENCY IN R.ABBITS. 15

in the tender and adult ages. The most detailed descriptions refer to infant cases. It is a striking fact that in the majority of cases diagnosis has been made post mortem.

The onset of the disease is most frequently without prodromes. When a prodromal stage has been observed it has been brief and not characteristic, Then it is often stated that fatigue and pale colour have been observed in the child and now and then slightly raised temperature. However, as mentioned, there is most often a change from good health to acute illness. The child usually awakes in the night and cries out, is agitated and looks ill. The temperature is much raised, not seldom hyperpyrexia; in many cases the temperature is high from the beginning. The skin is pale and cyanotic, its colour varies between lividity and cyanosis. Nausea, vomiting, frequently diarrhoea, sometimes abdominal pains. The consciousness is more or less affected, later unconsciousness and collapse. Sometimes meningism. The respiration is rapid, superficial and sometimes of the Cheyne-Stoke’s type, often rattling. The pulmonary findings are often normal or rattling is heard a t the bases. Often cramps of a tonic-clonic type. The pulse is weak and rapid, not seldom about 200, often irregular. Cardiac sounds weak, blood pressure low. Usually exanthems of purpura type on the skin. None of these symptoms is alone pathognomonic according t o MAGNUSSON (1934 b) but together they present a characteristic picture which makes diagnosis possible in life.

The patient is often admitted into hospital only when this stage has been reached. An examination of the nervous condition then discloses few definite symptoms beyond unconsciousness and tonic and clonic cramps. The tendon and pupillary reflexes are most often normal, sometimes they are absent. I n most cases there is no stiffness in the back of the neck. There is rather a striking limpness and muscular hypotonia. The cerebrospinal fluid generally normal; sometimes positive protein reactions and increased number of cells.

The disease proceeds rapidly. The child gets definitely worse in a few hours. The pupils no longer react to light. The pulse grows worse and the heart’s action very irregular. The breathing is uneven, often of Cheyne-Stoke’s type. Sometimes the temperature falls before death. The duration of the disease is usually 6-24 hours.

A few hours before death, changes of great importance appear in the skin. The colour of the skin is much varied, sometimes pale

16 ARNE LITHANDER.

sometimes of a pronounced cyanotic hue; there ma.y also be cyanotic spots in the face and on the body which likewise vary considerably. These are almost always present and appear most frequently when the other symptoms of insufficiency are evident. The exanthems vary very much in appearance. They develop as morbilliform eruptions, petechial exanthems, sometimes as suffu- sions, the size of the palm of a hand, purpura-resembling spots in the face, on the body and on the limbs. Now and then the mucous membrane of the mouth and the tongue are dark blue. Some- times the changesin colour and the exanthems disappear complete- ly for a while, only to return again. The above-mentioned changes in the skin and particularly the variable cyanoses are very characteristic for acute adrenal insufficiency. They are very important for a diagnosis intra vitam (Magnusson). The changes in the colour of the skin partly depend on the position of the body. On low parts of the body discolourations appear resembling post- mortem staining “intra-vital post-mortem staining” (Magnusson), which change places according to the patient’s position. MAGNUS- SON (1934 b) regarded these as hypostatic phenomena arising when the circulation fails. As pointed out by BAUMANN (1931) and MAGNUSSON (1934 b) the temperature in different parts of the skin may vary considerably. In one of his cases MAGNUSSON noted a skin temperature on the chest of 40.8” while that on the thigh was 34.7 and the rectal temperature 37.

In the literature we find few reports on blood examinations in W.F. MAGNUSSON emphasizes that owing to the circulatory changes the value of the red blood-cell count is limited. The number of white blood-cells is usually increased, the records vary between 7,400 and 85,500. Some authors, GLANZMANN (1933) and G. MUHL (1934), have ascertained a considerable decrease in the number of thrombocytes. MAGNUSSON (1934 b) found that the haemorrhagic conditions are abnormal in W.P., in that he obtained blood from a puncture 45 minutes old when that part of the body was lowered. He considers that this can only be explained by a prolonged time of bleeding.

The changes in the chemistry of the blood in W.F. have partly formed the subject of thorough study. Prom the point of view of diagnosis the changes in the carbohydrate metabolism are most important. Hypoglycaemia, most often in a high degree, is established almost without exception. The determinations of blood sugar then generally refer to specimens taken shortly before death.

-4CUTF: ADRENAL INSUFFICIICNCP I N RABBITS. 17

In the few cases where the blood sugar value has been determined earlier the results have varied. In one case BAMATTER (1935 b) found a value of 132 mg% 6 hours before death, while MAGNUSSON (1934 a) in one ca,se found a value of 27 mg% 4 hours before death. According to MAGNUSSON (1934 a) another important fact is that in W.F. adrenalin injections do not result in an increase of blood sugar.

According to various investigators the content of non-protein nitrogen varies considerably. Normal or slightly increased values are often observed. In other cases values above 100 mg% have been noted. The statements of the contents of sodium, potassium and chloride are few and the changes observed are not characteristic.

Of the pathologico-anatomical changes those arising in the adrenals command the main interest. Even a t first sight these changes are striking. The adrenals are generally somewhat enlarged, appear swollen and have a stretched to firm consistency. The colour is mostly dark red so that they sometimes resemble blood clots. Asection shows that the parenchyma is saturated Bith blood. In almost all cases described both adrenals are changed. In the microscopic examination haemorrhagic infarcts are evident both in the cortex and the medulla. The cells are separated by blood and are partly necrotic. The vessels are greatly dilated and quite full of blood. Here and there the walls are broken so that bleeding has occurred into the parenchyma. As a rule, no inflammatory infiltrations of cells have been observed.

The histological examination of parts of the skin with haemorrhagic changes discloses strong dilatation of the vessels with escape of blood into the tissues. One exception has been reported by MAGNUSSON (1934 b) . In one of his cases, an unconscious mori- bund patient, a purpura-like efflorescence was excised and exam- ined histologically. The vessels proved to be filled with red blood- cells but none could be found extravascularly. Besides in the skin petechiae can be observed in the mucous membrane, particularly in the cavity of the mouth, in the pharynx and intestinal canal, in the trachea and bronchi, in the endocardium and pleurae, on the surface of the liver and in the renal pelvis.

The spleen is greatly hyperaemic, often having the appeardnce of infection. The liver is sometimes stated to be of normal appedr- ance but many authors have found changes as in hepatitis acuta. The lymphatic glands in the mesentery are often heavily swollen. The changes in the central nervous system are generally little

2-4508S3

18 . ARNE LITHANDER.

pronounced. A more or less prominent hypcraemia is found. As a rule no inflammatory changes can be disclosed. I n isolated cases the Cerebrospinal fluid has been slightly turbid.

The etiology of W.P. has now on the whole been agreed upon. The opinion at present held is that W.F. develops from a hyperacute septicaemia in that this is accompanied by a complicating adrenal haemorrhage. In most cases the septicaemia is caused by meningococci but cases of other bacteriological etiology are not uncommon. In many cases, however, no bacteria can be demonstrated, which does not exclude the possibility of a general bacterial infection. Even in septicaemia it is not always possible to show by means of cultures or otherwise the micro-organism concerned. As most cases of W.F. are considered to be caused by meningococci the negative bacterial findings are thus explainable. As is generally known meningococci are difficult to culture owing to their great demands on the composition of the substrate and their sensitivity to low temperature. Further, in many, perhaps in most cases of W.F. the experiments made in order to demonstrate possible bacteria by culture have only been carried out at the autopsy. By that time the meningococci have mostly died so the culture becomes negative, Even where cultures are prepare'd from blood, cerebrospinal fluid, etc., while the patient is alive, a negative result does not signify that it cannot be a case of meningococcic septicaemia. Moreover, technical errors often occur in culture, in that, for instance, too big a quantity of blood is added to the substrate, the bactericidal properties of the serum preventing the growth of meningococci. To avoid loss of time and to ensure better results endeavours are instead made to prove the existence of bacteria in direct smears of blood, cerebrospinal fluid, skin changes, etc. It has then been possible to a great extent to demonstrate bacteria in life. In W.P. meningococci have been found in specimens of pharyngeal secretions, spleen juice, as bacterial emboli in the kidneys and adrenals, in cerebrospinal fluid and blood, and, particularly, in efflorescences in the skin. In most cases no detailed examination of the rneningococci has been made. BAMATTER (1934) proved by agglutination that the strain of meningococci isolated in one of his cases belonged to Type B, in another to Type D. In view of the difficulty of demonstrating the presence of meningococci i t is now generally assumed that even where the presence of bacteria can in no way be proved it is nevertheless generally a question of the effect of meningococci.


In not a few cases of W.F. streptococci and pneumococci have been shown and considered to be the cause of the disease. The bacteria have been found in skin purpura, cerebrospinal fluid, kidneys and adrenals. Also influenza, staphylococcic septicaemia, dysentery, typhoid, measles, whooping-cough, diphtheria, scarlatina and other infectious diseases are supposed to give rise to adrenal haemorrhages, although meningococci are without comparison the most common cause.

Many serious septic conditions cause a haemorrhagic diathesis manifested in bleedings in the skin and mucous membrane. As mentioned W.P. is considered to be caused by a hyperacute septicaemia with haemorrhages in the adrenals and haemorrhagic manifestations in the skin and mucous membrane. It would be reasonable, therefore, to regard the adrenal haemorrhages as one of the sites for the haemorrhagic diathesis. The location in the adrenals is explained by FRIDERICHSEN among others, who postulates that the adrenals are predisposed to haemorrhages owing to the considerable amount of blood passing through them, the weak blood vessels, for which the gland substance forms an insufficient support, and the small resistance offered by the gland parenchyma. K A M s E R (1937) considered paralysis of the vasomotor mechanism and vasodilatation, bacterial-embolic injuries, capillary toxicosis and toxic bloodinjuries to be the factors that contribute to haemorrhages in places disposed for bleeding. KUNSTADTER (1939) was of the opinion that haemorrhages in the adrenals of adults and big children are caused by thrombosis in the adrenal veins or by infection or toxic effects. He presumed that owing to the detoxi- cating activity of the adrenals, toxin is drawn from the blood and concentrated to the adrenals, producing capillary injuries. GLANZ- MANN (1933) referred the haemorrhagic manifestations to capillary injuries. When the capillaries break, bleedings arise. The adrenal capillaries are particularly sensitive in children. MCLAGAN and COOKE (1916) propounded the idea that the bacteria active in W.F. have an affinity for organs of ectodermal origin. This pro- perty is above all attributed to meningococci.

Status thymolymphaticus appears to be of importance for the pathogenesis in W.F. which has been emphasized by inter alia BAUMANN, MAGNUSSON, BAMATTER, AEGERTER and SACRS. GLANZ- MANN (1916) and BAMATTER (1934) considered also thrombopoenia to be an important factor of predisposition.

The skin symptoms in W.F. are, as mentioned above, a moment-

20 ARNE LITHANDER.

ous part of the clinical picture. The haemorrhagic skin changes are a reason for considering the differential diagnosis purpcru fulmiiaans. According to certain authors these symptoms may be present in scarlatina, varicellae, diphtheria and septicaemia. Purpura fulminans has also been described in meningococcic infections. BATTLEY (1987) and LATTES (1931) each recited one case of purpura fulniinans with ‘adrenal apoplexy in meningococcic infection. These cases must, according to RAMATTER. b e regarded as a W.F. syndrome. It appears likely that there is an intimate connection between W.F. and purpura fulminans. Both diseases are caused by septicaemias. Schematically the connection might be shown as follows: If in septicaemias both haemorrhagic skin manifestations and adrenal apoplexy develop this is a W.F. syndrome. If there is no adrenal apoplexy but haemorrhagic skin changes appear, the diagnosis should be purpura fulminans. The question whether adrenal apoplexy develops or not is then decided by factors hitherto unknown. It would, of course, be valuable to have a more thorough study made of purpura fulminans as compared with W.F. MAGNUSSON observes that systematic examinations of the blood sugar and pathologico-anatomical examinations of the adrenals in all meningococcic infections might lead to some knowledge o l the relationship between these two clinical pictures.

KIRKETERP (1944) considers that the adrenal haemorrhage in merely one of several symptoms in septicaemia and that it further- more is of no very great importance for the development of the picture. He supports his opinion on three cases of his own anti, among other things, also upon the observations of ANDRESEN and GORMSEN (1‘344). A study of his material discloses that it does not allow of any real conclusions.

It is difficult to define in the W.F. syndrome which syniptoms are caused by the adrenal injury as such, the syniptoiiis of insuff’i- ciency. Good assistance in such a definition would h~ afforded by the study of a disease almost solely due to adrenal injuries. The abacterial adrenal apoplexy, pseudo-pneumonia in new-born or very young children, as GOLDZIEHER has called this disease, gives a comparatively “clean” picture of acute adrenal insufficiency. This clinical picture is, as emphasized by many authors, entirchy different from that of W.F. GOLDZIEHER and GORDON (1932 and 1933) have studied in detail a great number of cases and described them. The etiology is stated to be traumata in connection with

ACUTE ADKENAL INSUFFICIENCY IN RABBITS. 21

the delivery, such as instrumental measures, long and difficult labour, eclampsia in the mother and asphyxia. Bleedings and haemorrhagic infarcts then develop in the adrenals. The illness breaks out suddenly, in new-born babies usually a few hours or days after delivery. The symptoms are high temperature, rapid, and not seldom uneven breathing so that sometimes pneumonia is suspected. A physical examination of the lungs gives a negative result. The child doep not eat, becomes apathetic and the colour of the skin cyanotic. Purpura-like exanthems appear in the skin and petechial efflorescences on the body and limbs. There is not seldom a shock-resembling picture with weak and irregular pulse, cold limbs and increasing pallor. Vomiting, cramps and twitches often occur, sometimes diarrhoea and icterus. Often i t is possible to palpate in one or both renal regions a resistance corresponding to the adrenal distended with blood. I n some of the cases the changes in the chemistry of the blood have been investigated. These have been found to be reduced blood sugar value, sometimes to hypoglycaemia, augmented non-protein nitrogen and the changes in the concentration of sodium and potassium in the blood typical of adrenal insufficiency.

After analysis of the clinical picture of pseudo-pneumonia in infants GOLDZIEHER and GORDON divided the symptoms into those which were caused by adrenal insufficiency and those which arose from the loss of blood through adrenal haemorrhages. Of the symptoms of adrenal insufficiency, respiratory changes, increased temperature, changes in the colour of the skin, skin exanthems, and metabolic disturbances (changes in contents of blood sugar, non-protein nitrogen, sodium and potassium) were considered to be directly depending on endocrin derangements. The gastro-intestinal disturbances and the nervous symptoms, coma, cramps and twitches, were regarded as syniptoms intimately connected with the adrenal insufficiency. The shock symptoms were considered by them to Iollow from the haemorrhage. They thought the reduction of blood sugar was the most important of the metabolic disturbances. I n one of GORDON’S cases the blood sugar value at the onset of the symptoms was 50 mg% and 6 hours before death 10 mg%. They found themselves unable to determine whether the cramps and twitches are due t o hypoglycaeinia or an increase of the non-protein nitrogen. With the exception of the palpable resistence in the renal region all these symptoms are covered by the clinical picture of W.F. According to these authors

22 ARNE LITHANDER.

the symptorns of pseudo-pneumonia in infants would appear t o be on the whole identical with those of W.P. BAUMANN (1938), however, holds the opinion that skin haemorrhages do not occur in adrenal apoplexies in new-born children.

In view of the symptoms of pseudo-pneumonia in infants the symptoms of adrenal insufficiency in W.F. should be: Sudden illness with high temperature, apathy, changes in the colour of the skin, respiratory changes, gastro-intestinal disturbances, such as anorexia, vomiting and diarrhoea, nervous symptoms in the form of cramps and twitches, and coma; also reduced blood sugar value and increased non-protein nitrogen. BAUMANN considered that the haemorrhagic skin changes in W.F. are not caused by adrenal insufficiency but by capillary toxicosis. In W.F. adynamia also develops which symptom is not noted in pseudo-pneumonia. This will not exclude the presence of adynamia but is possibly due t o the difficulties involved in the examination of babies. The symptoms of shock present in pseudo-pneumonia, which are by GOLD- ZIEHER and G o ~ ~ o ~ s t a t e d to be a direct effect of the adrenal haemorrhage comprise, collapse, weak and irregular pulse, cold limbs and pallor and occur also in W.F. In W.F. other symptoms of shock are also described such as the collapse of the peripheral blood vessels and the difficulty of drawing blood from them. The latter symptoms are not mentioned in pseudo-pneumonia in infants.

As in adrenal insufficiency in adrenalectomized animals the clinical picture of W.F. invites comparison with that displayed in cases of shock. MAGNUSSON (1934 b) stated that he interpreted his first case as shock and made determinations of the blood sugar value, as it very much resembled insulin shock. Many other authors stress the similarity between W.F. and shock. Both a s a whole and in many particular details do the series of symptoms agree. This is most clearly manifest in the circulatory disturbances. The blood vessels are collapsed and empty of blood and it is difficult or impossible to obtain blood from them. The blood that flows out is dark, thick and concentrated, the pressure reduced and the pulse weak. Also in W.F. the temperature is not seldom lower in the final stages. In regard to blood sugar W.F. differs from shock in the same manner as does adrenal insufficiency in adrenalectomized animals. The examinations of the non-protein nitrogen, sodium, potassium and chloride values in W.F. are too few and the results too uncertain to serve as a basis of comparison. The


comparisons made between the autopsy findings in shock and W.P. are mainly restricted t o the abdominal viscera. I n both conditions occur hyperaemia and congestion of the liver, kidneys, spleen, pancreas and lymphatic glands with degenerative changes in the liver, spleen and kidneys. The results obtained from examinations in W.F. are too meagre to afford material for a more detailed comparison.

As already mentioned, the acute adrenal insufficiency, W.F., is by far most comrnon in small children. The majority of the cases reported refer to children below two years of age. In a compila- tion of 61 cases KAMBER (1937) found that 66 % of the patients were less than two years old. This agrees well with a statement by SACHS (1936/37) that 70 % of the cases were children below two years of age, while only 10 yo were adults.

The prognosis of' W.P. is regarded as very grave and until 10 years ago the mortality was considered to be 100 per cent. Almost without exception the therapeutic measures have failed; these have earlier been the administration of ordinary stimulants and glucose and saline solutions. Since it became possible to produce preparations of cortical hormone both natural and synthetic ones have been employed. Both sulfapyridin and sulfatiaeol have been tried of late. In cases where meningococci have been supposed to form the etiology certain authors have used meningococcic serum. In most cases all therapeutic measures have been of no avail. Only four citses of recovery from W.P. are mentioned in the literature. These have been described by MAGNUSSON (1934 a), a girl Illz years old, CAREY (1939/40), a woman 27 years of age, BICHEL (1940), a woman 24 pears of age, and RUCKS and HOBSON (1943)) a child.

In this chapter the author has compared the symptoms of acute adrenal insufficiency in man, W.F., and those arising from adrenal insufficiency after adrenalectomy and after bacterial intoxications and infections in animals. L4 study of the clinical picture of acute adrenal insufficiency in man and in animals discloses both symptoms emanating from the adrenal injury as such and intev alia symptoms of shock. Owing to the intimate relationship of the adrenal cortex to the condition of shock and due to its great importance for the development of shock i t is impossible to distinguish between the specific parts played by the symptoms mentioned. I n W.F. in man as well as in adrenal insufficiency in animals in connection with infections and intoxications, the infection or the

24 ARNE LITHANDER.

intoxication itself constitutes a factor that complicates the picture. In the works previously done with intoxication or infection of animals, the experiments have, as a rule, been confined to one stage or another of the process. The available descriptions of the symptoms are fragmentary and the connection between the clinical picture and the pathologico-anatomical changes has generally been only indicated if touched upon at all. Further, the investiga- tions fail t o elucidate that the clinical picture in these experiments is adrenal insufficiency even if i t may be assumed from the descriptions that this is the case.

I n an endeavour to illustrate the course of W.F. the author has performed experiments for the purpose of producing acute adrenal insufficiency in animals by the injection of bacterial toxins, and has thus tried to effect a reproduction of the W.F. syndrome in man and to make a study of it. It has then been possible to study in detail the changes appearing in the experimental animals, and, in consequence, a better foundation is laid for the theory of the development of the disease in the animals. Further the value of a comparison betw-een the symptoms of the intoxicated animals and those of W.P. is enhanced. With this object in mind examinations have been carried out of the blood sugar value, blood chlorides and non-protein nitrogen and circulatory changes have been studied. Special attention has then been paid to disturbances of the carbohydrate metabolism.

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CHAPTEE 1:On Adrenal Insufficiency