Zeitschr. f. Hygiene, Bd. 134, S. 591--597 (1952).

Dept. of Bacteriology, :Faculty of Medicine, Cairo.

Blood Sugar Level in Relation to Histamine and Allergic Shock.

By )I. A. GOHAR and M. ~]AKKAWI.

(Eingegangen am 19. November 1951.)

G~.~rr and G~D~LL~" (1951) 1 suggested that the state of shock is one of profound interference with carbohydrate metabolism. Also STONER, G~.v.N and TH~L~'Ar_~ {1950) 2 produced some chemical evidence of an interference with carbohydrate utilization in shock.

This prompted us to t ry and find out whether this applies also to histamine and anaphylactie shock and determine the effect of raising or lowering the blood sugar level on these conditions.

:For this purpose 32 rabbits weighing on the average 1 kgm. each were divided into 8 batches of 4 animals each. The fasting blood sugar was estimated in all of them. These 8 batches were then treated in the follo- wing way: ---

Batch 1. All 4animals were injected subcutaneously with 2 gm. glucose dissolved in water

Batch 2 was treated similarly except that 2 units insulin were injected as well into each animal, again by the subcutaneous route

Batch 3 was treated in the same way as batch 2 except that 0.05 ml. of 1/1000 adrenaline hydroehloride was injected subcutaneously in addition to the glucose and insulin

Batch 4 received a subcutaneous injection of 2 units insulin only Batch 5 received a subcutaneous injection of 0.05 1/1000 adrenaline

hydrochloride Batch 6 was treated in the same way as batch 5 except that 2 gin.

glucose were injected as weii Batch 7 received a sublethal dose of histamine hydrochloride (0.2 mgm.)

injected intramuscularly Batch 8 served as untreated control. All batches except batch 7 were challenged with histamine hydro-

chloride. Before doing so the LD100 for rabbits was determined and found to be 2 mgm. injected by the intravenous route. One hour after the above treatment all animals in the 7 batches were injected intravenously with this amount dissolved in water. The blood sugar level for each animal in all 8 batches was estimated before, half an hour, and one hour after

592 M.A. GO~AR and M. MA~ZAWI:

t r ea tmen t with the above substances, his tamine being given immediate ly af ter taking the last sample. I n animals t h a t survived, blood sugar es t imat ion was carried out for a fur ther period of 1 hour.

While the control un t rea ted ba tch and batches 2 (which received glucose and insulin) and 4 (which received insulin only) died, batches 1 (which received glucose only) and 3 (which received glucose, insulin and adrenaline) showed 50~, survival, and b~tch 5 (treated with adrenaline only) and 6 ( treated with glucose and adrenaline) showed 100~/o survival .

The result of the blood sugar est imations is given in table 1 f rom which it is seen t h a t in batches 1, 3, 5 and 6 which survived there was a state of hyperglycaemia, while in batches 2 and 4 which succumbed there was a state of hypoglycaemia . Ba tch 7 which was t rea ted with a suble-

Table 1. Showing average blood sugar levels o/ the 8 batches in mgm. % at various periods.

Time Batch 11 Batch 21 Batch 3 Batch 41 Batch 51 Batch 61 Batch 71 Batch 8

Fasting . . . . . . 30. rain . . . . . . 6 0 . ~ , . . . . .

110 200 180

9 0 ~ ~ . . . . .

120 . . . . . . . . No. of survivals

after hist . . . . . ~o survivals . . . .

190 180

2 50

100 I 115 105 100 1 1 0 90 150 75 I40 160 60 135 50 130 150

Histamine injected

0 0

140 120

2 50

- - 140 125

0 4 0 100

170 170

4 100

105 110 120 - - 1 0 0 - -

l l5 (after death)

100 95

Batch 1 injected with glucose, batch 2 with glucose and insulin, batch 3 with glucose, insulin & adrenaline, batch 4 with insulin, batch 5 with adrenaline, batch 6 with glucose & adrenaline, batch 7 with histamine, batch 8 untreated control.

tha l dose of his tamine bu t no t challenged with the lethal one showed also a low degree of hyperg lycaemia which, however, was soon followed by a fall in the blood sugar level. I n the case of the control un t rea ted ba tch blood samples were t aken after death f rom hi~tamine shock and showed a low degree o f hyperglycaemia, apparen t ly analogous to the t ransient hyperg lycaemia encountered in batch 7.

The above expcr iments were repeated, subst i tut ing horse serum shock, after previous sensitization with the same serum, for his tamine shock, and pract ical ly the same results were obtained, the survival ra te and the blood sugar levels being more or less the same as in the his tamine shocked animals. Samples of blood taken f rom animals t h a t died f rom anaphy- lactic serum shock, like those taken f rom animals dead f rom histamine shock (Batch 8), showed a low degree of hyperglycaemia. However , the animals t h a t survived in bo th experiments showed a higher degree o f

:Blood Sugar Level in Relation to Histamine and Allergic Shock. 593

hyperglycaemia. Thus it would seem that a maintained state of hyper- glyeaemia interferes with histamine or anaphylactic shock.

The E//ect ot Some Antihistaminics on Blood Sugar Level in Rabbits.

In view of the extensive use of antihistaminics in the treatment of allergic diseases we thought tha t it might be of interest to test their effect on blood sugar level which, as mentioned above, seems to influence or be influenced by allergic conditions. For this purpose blood samples were taken from 8 rabbits weighing on the average 1 kgm. each, and the blood sugar level estimated. Four of them were injected intramuscularly with 1 mgm. neo-antergan dissolved in water, and the other four were treated in the same way except that phenergan was used instead ofneo-antergan. Blood samples were taken half and one hour after injection, and the blood sugar level estimated. The result is shown in table 2 from which it is seen that both antihistaminics caused a certain rise in the blood sugar level.

Because of the interest aroused around cortisone in the last few years, and on account of its recognized anti-allergic property, we thought

Table 2. Showing blood sugar level in rabbits in mgm.% be/ore and alter i.m. injection ol I mgm. neo-antergan or pheuergan.

Rabbit No. treatcd by: Bcforc injection

Blood sugarlcvel

After injection � 8 9 1 hr.

1 2 3 4 1 2 3 4

1%o-antergan

Phenergan

120 ll0 85 90

120 103 90

100

140 135 85

100 180 140 100 110

140 130 90

100 170 140 100 110

also of testing its effect on the blood sugar level of, and induction of histamine shock in, rabbits.

For this purpose four rabbits weighing also about 1 kgm. each were injected intramuscularly with 0,1 ml. cortisone suspension {2,5 units) after taking a blood sample for the estimation of their fasting blood sugar levels. Samples were also taken for the same purpose half hourly for a period of three hours after injection. This relatively long period was deliberately chosen in order to give a chance to the insoluble compound to act on the animal's system.

At the end of these three hours the rabbits were challenged with 2 mgm. histamine (LD 100) intravenously each; and two out of the 4

594 M.A. Go~At~ and M. I-~{AKKAWI:

animals survived. The average blood sugar levels of these four animals were found to be:

Before injection 110 mgm.~o Half an hour after injection 110 ,, One hour . . . . 115 ,, One & half hour after injection 120 ,, Two hours . . . . 140 ,, Two & hMf hours . . . . 150 ,, Three hours . . . . 156

In order to find out how long does the hyperglycaemia following cor- tisone injection last, the blood sugar levels in one rabbit injected with 0,1 ml. cortisone and not challenged with histamine was followed for as long as 24 hours after injection. At the end of this period the blood sugar level was as high as 162 m g m . ~ , against ] 19 mgm.9~ before cortisone injection, showing the persistenthypcrglycaemia produced by this sub- stance, and apparently caused by a slow but continious absorption lasting for a relatively long period.

I t is interesting to note also that cortisone saved 3 out of 4 rabbits, sensitized with horse serum, from anaphylactic shock, when it was injected 3 hours before the injection of the anaphylactic dose of this serum.

Some clinical observations.

Five patients, 3 suffering from bronchial asthma and 2 from recurrent urticaria were investigated. Blood samples were taken from all of them and the blood sugar level estimated under normal conditions, and was found to be on the low side. The three asthmatics were admitted to the hospital, and blood samples taken again during attacks, before receiving any treatment, and half an hour after t reatment . One patient was given 25 ml. 50% glucose solution intravenously, the second was given 1 mgm. adrenaline hydrochloride a n d the third 30 mgm. ephedrine hydrochloride subcutaneously. The result is shown in table 3 from which it is seen that the blood sugar level which is rather low under normal conditions is still lower during an attack of asthma; and that by the above treatment it became higher than it was during the attack. The asthmatic symptoms

Table 3. Showing blood sugar level in asthma patients in mgm. % under normal con- dition, during attack and after treatment.

Case No. Treated by:

glucose . . . . . . . Adrenaline . . . . . Ephedrine . . . . . .

normal

80 90 75

Blood sugar level

during attack I after treatment [

60 85 75 95 50 60

Blood Sugar Level in Relation to Histamine and Allergic Shock. 595

were relieved, adrenaline being the most effective, thenephedr ine and then glucose.

In order to find out whether antihistaminies raise the blood sugar level in man as they do in rabbits, two of the three asthmatics were treated with neo-antergan or phenergan, and blood samples taken before and half an hour after intramuscular injection with these compounds. I n one patient a blood sugar level of 70 mgm.~o before injection of 2 ml. 2~o neo-antergan rose to 90 Ingm.U/o after injection. In the other patient a leveI of 80 m g m . ~ before injection of 2 ml. 2.5o/o phene.rgan rose to 110 mgm. ~ after injection.

Also the two urticaria patients were treated with the same antihista- minics and blood samples taken both before and half an hour after intramuscular injection with these drugs. In one patient a blood sugar level of 90 mgrn.~ during an attack rose to 100 mgm.~o after injection

Tab le 4. Showing blood sugar level in asthma aTwl urticaria patients in mgm.% under normal condition, duriny attack and after in~ection of antihistaminics;

Blood sugar level Case/r "Treated by" f

normal ] during attack after treatment

Asthma 1 Neo-antergan' . . . , 80 1 70 90 Asthma 2 Phenergan . . . . . . 90 1 80 ll0 Urticaria 1 Neo-antergan . . . . 100 90 100

,, 2 Phenergan. . . . . . 80 60 80

of 2 ml. 2% neo-antergan. In the other urticaria case a blood sugar level of 60 mgm.% before injection of2ml. 2.5~o phenergan rose to 80 mgm. % after injection. The result is shown in table 4.

Discussion.

It seems that an animal in a state of hyperglycaemia is more refrac- tory to histamine and anaphylactic shock than an animal in a normal or hypoglycaemic state. Thus while animals that received glucose only, or adrenaline only, or glucose and adrenaline, or glucose, insulin and adrenaline~ or cortisone showed a good percentage of survivals, all other animals succumbed in shock. In all the former animals there was a state of hyperglycaemia and in the latter animals there was a state of hypo- glycaemia. Hbwever, the blood of the control animals that died from histamine shock showed a slight rise in the sugar level. This would not be surprising if we remember that histamine when given to human beings in a dose sufficient to cause hypotension stimulates the suprarenals to secrete adrenaline, thus raising the blood pressure as well as the blood sugar level. '

One of the functionl . . . . . . . ~obilization of glycogen and its subsequent conversion into glucose, thus inducing a state of hyper-

596 M . A . G o i t e r and M. M~KAWI:

glycaemia; and apparent ly it is in this way tha t a go( batches 3 (receiving glucose, insulin and adrenaline) and 5 (receiving adrenaline alone) were saved f rom an otherwise fatal anaphylactic shock. I t is interesting to note in this connection tha t it is a common habi t among people in this country to give excess of sugar, usually in the form of molasses, to patients suffering f rom allergic manifestations such as urticaria. I t is also interesting tha t A]~RAI~AMSON (1942)3 emphasized the infrequency of association of as thma and diabetes and suggested reci- procal relation between the two diseases. He assumed tha t hyerinsulism is one of the conditions necessary for the occurrence of asthmatic attacks, and relates the occurrence of nocturnal asthmatic a t tack to a state of hypoglycaemia.

In the light of these findings one m a y be justified" in recommending the trial of intravenous injection of hypertonic glucose for the relief of allergic diseases in addition to other recognized anti-allergic measures. Indeed in our as thma patients glucose afforded a certain degree of relief. On the other hand GOLT~A~ (1942)4 points out tha t as thma is associated with diabetes more frequently than is usuMly suspected, and recommends the ruling out of diabetes when competent allergic therapy fails to afford relief to the severe asthmatic state, since it m a y aggravate and prolong the disease. WE(~I]~RKO (1935) 5 and VOLLMEa (1939) r go as far as to s tate tha t satisfactory results were obtained by treating as thma with insulin shock. He ascribes the favourable effect of insulin to the formation of adrenaline in the pat ient ' s system and to a possible compensatory hyper- function of the adrenal glands in response to repeated injections. But he recommends the correction of the hypoglycaemic effect of insulin by the administration of glucose either orally or if necessary intravenously.

I t is also interesting to note tha t two of the commonly used anti- histaminics, viz. neo-antergan and phenergan, cause an appreciable rise in the blood sugar level both in man and rabbits, simultaneously with amelioration of the allergic at tacks. The mechanism by which these anti- histaminics raise the blood sugar level is a mat te r of speculation. But it is not unlikely tha t these compounds, in addition to antagonizing hista- mine, probably also stimulate the suprarenal glands to secrete adrena- line, which is known to mobilize glycogen and convert it into glucose. This stimulation, i f it occurs, is apparent ly more permanent than tha t prodiJced by histamine itself.

Summary and Conclusions. 1. Rabbi ts in which the blood sugar level was raised seem to be more

refractory to histamine and anaphylact ic shock than rabbits with normal or low blood sugar level.

Blood Sugar Level in l~elation to Histamine and Allergic Shock. 597

2. Blood sugar level was es t imated in 3 a s thma and 2 ur t icar ia pa- t ients and found, under no rma l conditions, to be on the low side, still lower dur ing at tacks, bu t tends to revert to the normal level after relief.

3. Two of the commonly used ant ih is taminies viz. neo-an te rgan and phenergan were found to raise the blood sugar level both in rabbi t s and

man. 4. The admin i s t r a t ion of glucose to allergic pat ients , in addi t ion to

other measures for rel ieving the allergic state, is suggested for trial.

Re ~erenees. 1 GREE~, I-t. N. ~ GItADIALLY, F. N., ~. •. J., March 1951, 496. - - ~ STONER,

~. ~., H.N. GI~EE~ & C. J. T~RELFALL, 1950, Proe. 18th. Intern. Phys. Cong., 473. - - 3 A~RA~A~SON, E. M.: J. Clin. Endocrin. 1941, 402. - - U. S. Nay. Mcd. Bull. 1943, 711. - - 4 GOLT~A~, A. ~[.: South. Med. J. 35, 854 (1942). - - 6 W]~- GIERKO, J.: Prcsse m6d. 43, 1379 (1935). - - 6 VOLLM~R, H.: Arch. of Pediatr. 56, 223 (1939).

Dr. HI. A. G o ~ , Cairo, Dept. of Bacteriology, Faculty of Medicine.

Zeitscllr. f. Hygiene. Bd, 134. 39