Elevated Plasma Histamine Concentrations in Surgery: Causes and Clinical Significance* Originalien

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Originalien

Elevated Plasma Histamine Concentrations in Surgery:

Causes and Clinical Significance*

W . Lorenz, W . Seidel, A. D o e n i c k e , 1%. T a u b e r , H . - J . R e i m a n n , 1% Uhlig, G. Mann, P. D o r m a n n , A. S c h m a l , G. H/ifner, a n d H. H a m e l m a n n

Division of Experimental Surgery and Pathological Biochemistry and Surgical Clinic of the University, Marburg/Lahn, and Division of Anaesthesiology, Surgical Outpatient Clinic of the University, Munich, Federal Republic of Germany Summary. Histamine concentrations in plasma, whole

blood and various tissues of human subjects, monkeys, pigs and dogs were determined by fluorometric methods before, during and after surgical operations. Following intraab- dominM surgery in 6 of 22 patients elevated plasma histamine levels were found several hours after the end of operation.

Some of the causes of histamine release in surgery were found to be premeditation by atropine, intravenously administered anaesthetics, infusion of plasma substitutes and manipulation on the gut. Acute blood losses were without effect on the plasma histamine levels. Clinical symptoms and pathophysiological reactions, such as taehyeardia, hypotension, increased gastric secretion and anaphylactoid reactions could be related to the release of histamine in some circumstances.

Key words: Plasma histamine, operations, anaesthesia, plasma substitutes, acute gastro intestinal ulcers.

Erh6hte Plasmahistamiuspiegel bei chirurgischen Ein- gri//en: Ursachen und klinische Bedeutung.

Zusammen]assung. Histaminkonzentrationen in Plasma, Vollblut und versehiedenen Geweben yon Mensch, Affe, Sehwein und Hund wurden vor, w/ihrend und nach 0perationen mit fluorometrischen Methoden gemessen. Nach intraab- dominellen Eingriffen wurden bei 6 yon 22 Patienten erh6hte Plasmahistaminspiegel noch Stunden naeh der Operation ge- funden.

Als Ursachen der Histaminfreisetzung bei Operationen warden nachgewiesen: Pr~medikation durch Atropin, An- i~sthesieeinleitung mit intravenSs verabreichten Kurznarkotika, Infusion yon Plasmasubstituten und Manipulationen am Darm.

Akuter Blutverlust war ohne EinfluB anf die Plasmahistamin- spiegel. Klinische Symptome und pathophysiologische Re- aktionen, wie Taehykardie, arterielle Hypotension, erhShte Magensekretion und anaphylaktoide Reaktionen konnten auf Histaminfreisetzung unter bestimmten Umst~nden zuriiek- gefiihrt werden.

Schli~sselw6rter: Plasmahistaminspiegel, Operationen, Nar- kose, Blutersatzmittel, StreBuleus.

V a s o a c t i v e biogenic amines, such as h i s t a m i n e , s e r o t o n i n a n d t h e c a t e e h o l a m i n e s , are u b i q u i t o u s l y d i s t r i b u t e d in t h e tissues of n e a r l y all v e r t e b r a t e s i n v e s t i g a t e d so f a r (Lorenz et al., 1973). M a n y w o r k e r s h a v e s h o w n t h e i r release or i n c r e a s e d f o r m a t i o n in local processes, like i n f l a m m a t i o n , i s c h a e m i a or t r a u m a . T h e y a r e also l i b e r a t e d in g e n e r a l r e a c t i o n s , such as shock a n d a n a p h y l a x i s [for a s u r v e y see R o c h a e S i l v a (1955), S c h a y e r (1961), E r s p a m e r (1966), t I o l t z a n d P a l m (1966)]. H o w e v e r , t h e clinical significance of t h e s e tissue h o r m o n e s , e s p e c i a l l y in t h e ease of h i s t a m i n e a n d serotonin, r e m a i n s l a r g e l y u n k n o w n .

D u r i n g o p e r a t i o n s in h u m a n s u b j e c t s a n d in l a b o r a t o r y a n i m a l s , r e a c t i o n s occur w h i c h m i g h t be d u e to a release of h i s t a m i n e - - f o r e x a m p l e s u d d e n l y d e v e l o p i n g h y p o t e n s i v e r e a c t i o n s , i n c r e a s e of b r o n c h i a l resistence w i t h b r o n c h o s p a s m , v o m i t i n g of s t r o n g l y a c i d g a s t r i c juice d e s p i t e p r e c e d i n g f a s t i n g a n d de- v e l o p m e n t of p o s t o p e r a t i v e stress ulcers. I n t h i s s t u d y , t h e a p p e a r a n c e of free, p h a r m a c o l o g i c a l l y - a c t i v e h i s t a m i n e in t h e p l a s m a h a s b e e n d e t e r m i n e d before, d u r i n g a n d a f t e r o p e r a t i o n s in p a t i e n t s a n d i n ex- p e r i m e n t a l animals. Causes of such a h i s t a m i n e release h a v e b e e n e v a l u a t e d a n d t h e i r elinicM significance

*Supported by a grant of Deutsche Forsehungsgemeinschaft (Lo 199/3).

assessed b y m e a n s of c o m p a r i n g t h e i n c r e a s e of t h e p l a s m a h i s t a m i n e c o n c e n t r a t i o n u n d e r such circum- s t a n c e s w i t h t h a t o b s e r v e d following t h e infusion of h i s t a m i n e in v a r i o u s b i o l o g i c a l l y - e f f e c t i v e doses.

M a t e r i a l s a n d Methods Materials

Normal human tissues (examined by histology) were obtained from 93 patients (both sexes, 52-87 kg, aging from 20 to 54 years) during various operations (anaesthesia by thiopentone, suxamethonium, Alloferin ® , fluothane-nitrous oxide). Tissues from animals were withdrawn from 6 monkeys 1 (Macaca actoides, both sexes, 7-12 kg), anaesthesized by Parkesernyl, 5 adult pigs (German landrace, femal, 100- 150 kg), and 7 adult mongrel dogs (both sexes, 21-38 kg) anaesthesized by pentobarbitone (15-20mg/kg i.v.). The tissues were frozen immediately after withdrawal by CO~ snow and kept for maximum 4 weeks in a deep-freeze before testing their histamine content.

Blood for the determination of histamine in plasma and whole blood was collected and prepared according to the method of Lorenz etal. (1972 b). I t was obtained from 22 patients (see Table 2) and 104 test persons (male students, 57-94 kg, 22-28 years old, healthy by case history), as well as from 6 monkeys (see above), 16 young pigs (both sexes, 25-34 kg), and 42 adult mongrel dogs (both sexes, 14-36 kg) following fasting for at least 12 hours.

i We thank very much the Behringwerke, Marburg, for the generous gift of the animals.

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Drugs and Reagents. Thiopentone (Abbott), propanidid (Bayer), methohexitone (Lilly), Althesin CT 1341 ® (Glaxo), Etomidate ® (Janssen), pentobarbitone (Abbott), Parke®

(Parka and Davis), fluothane (Rheinpharma), suxamethonium (Lentia), Alloferin ® (Roche), atropine (university's pharmacy), pethidin (Hoechst), heparin for biochemical research (180 L U . / rag, Roche), dextran-60 (Makrodex ®, Knoll, batches No.

K 169 and 3262/A 3), gelatin (Haemaccel ® , Behringwerke, batches No. 2551 in human subjects, No. 2406, 2551, 2559, 3000 and V 183/I in dogs, and No. 3000 and V 183/I in monkeys), Ringer's solution (pH 6.0, university's pharmacy).

Reagents were employed according to Lorenz et at. (1972 b).

Only twice distilled water was used.

Experimental Arrangements

For a single determination of the plasma histamine concentration 19.5 ml of blood were withdrawn from a cubital vein by a polyethylene syringe containing 2 mg heparin dis- solved in 0.5 ml of physiological saline. In all experimental arrangements this procedure was identical, both in human subjects and in animals, but the time of collection of the blood samples was different:

1. O p e r a t i o n s i n H u m a n S u b j e c t s

Blood was obtained immediately before and few minutes, 4, 8 and 20 hrs. after operations (Table 2) which were all carried out by the same experienced surgeon (W.S.) under general anaesthesia as described in materials. For the determination of histamine in the whole blood, an additional 5 m l of blood were withdrawn immediately after collecting the samples for the plasma histamine determination.

2. I n j e c t i o n of A n a e s t h e t i c D r u g s a n d A t r o p i n e i n H e a l t h y T e s t P e r s o n s

Using the arrangements as described by Lorenz et al., 1972, atropine (0.01 mg/kg i.v.) was injected 10 min before the administration of the hypnotics. Blood was collected before, and 1, 5 and 10 min after giving atropine. Then methohexitone (2.5 mg/kg in 60 sec), propanidid (5 mg/kg in 20 sac), Althesin CT 1341@ (0.075 ml/kg in 60 sec), and Etomidate® (0.2 mg/kg in 20 sec) was injected and further blood samples were withdrawn at 1, 5, 10, 20 and 30 min following administration of the anaesthetic.

3. A c u t e B l o o d L o s s e s a n d B l o o d l ~ e p l a c e m e n t i n H e a l t h y T e s t P e r s o n s

According to the technique of Messmer et al. (1970), 500 ml of venous blood were obtained within about 3 rain (ca. 2 ml/kg and rain) using an equipment for blood donation.

The same volume of plasma substitutes (500 ml of dextran, gelatin, Ringer's solution, ca. 2 ml/kg and rain, 37°C) was in- fused under pressure 30 sac later. Blood was withdrawn for histamine assay before and after the blood donation as well as 1, 5, 10, 20 and 30 rain following infusion of plasma substitutes.

4. A c u t e B l o o d L o s s e s a n d I n f u s i o n of P l a s m a S u b s t i t u t e s in M o n k e y s , P i g s a n d D o g s

I n anaesthesia as described under materials, according to the method of Messmer et at. (1970), 150-200 ml of arterial blood in monkeys and 500 ml in pigs and dogs was withdrawn within about 3 min via a catheter in the femoral artery (6-7 ml/kg and rain). I t was replaced in the same time as used for bleeding by the same volume of the plasma substitutes using a catheter in the v. cava inferior. Blood for histamine assay was withdrawn from the right atrium before and after bleeding, as well as 1, 5, 10 and 20 rain following the pressure infusion.

5. A n a e s t h e s i a a n d O p e r a t i o n Stress in M o n k e y s a n d D o g s

Following anaesthesia as described in Materials, in 6 monkeys and 9 dogs catheters were inserted in the femoral vein and after laparotomy, in dogs also in the portal and hepatic veins. Blood for histamine assay was collected from the right atrium immediately after introduction of anaesthesia, 30 min later at the end of operation, and 30 rain after the end of operation.

6. A n a e s t h e s i a a n d E a r l y P h a s e of L i v e r T r a n s p l a n t a t i o n s i n P i g s

I n 7 pigs, anaesthesia was introduced by pentobarbitone (15-25 mg/kg i.v.) and continued as described by Lorenz et at.

(1972). Before and after laparotomy, splenectomy, applying a porta-caval by-pass and exposing the liver vessels according to Lorenz et al. (1972) blood for histamine assay was withdrawn from the right atrium via a catheter in a jugular vein.

Methods

1. D e t e r m i n a t i o n of H i s t a m i n e i n Tissues, W h o l e B l o o d a n d P l a s m a

Following precipitation of the proteins by perchloric acid histamine in all tissue extracts and whole blood as well as in the plasma of pigs was isolated by cation-exchange chromato- graphy on Dowcx 50 W-X 8 and determined fluorometrical]y after condensation with o-phthaldialdehyde according to Lorenz et at. (1971). Histamine in the plasma of human subjects, dogs and monkeys was isolated by ion-exchange chro- matography on Dowex 50 and subsequent solvent partition according to Lorenz et al. (1972b). Histamine in tissues and whole blood was given in fxg histamine dihydrochloride/g fresh weight or ml, plasma histamine in mg histamine base/ml.

Histamine release was considered only as significant, when plasma histamine levels higher than 1 ng/ml were reached.

2. D e t e r m i n a t i o n of Arterial B l o o d P r e s s u r e a n d H e a r t R a t e

In h u m a n subjects, the blood pressure w a s determined b y the s p h y g m o m a n o m e t r i c m e t h o d at 1 m i n intervals according to Lorenz et at., 1972. In m o n k e y s a n d dogs, the systolic arterial blood pressure w a s m e a s u r e d via a catheter in the femoral artery b y a S t a t h a m pressure transducer P 23 D b a n d recorded b y a IIellige compensograph, in pigs via a catheter in the carotid artery b y the s a m e experimental arrangement.

T h e heart rate w a s determined with the aid of the E C G (lead II), (Lorenz et at., 1972).

3. D e t e r m i n a t i o n of G a s t r i c A c i d S e c r e t i o n i n T e s t P e r s o n s

A Levin tube was inserted into the stomach and its position controlled by X-rays. Gastric juice was collected during the same intervals as blood was taken for the plasma histamine determination. The acid output was measured by titration to p H 7.0 using the glass electrode and expressed in meq HC1/min.

For further details see Lorenz et al. (1972).

Statistical Evaluation

The results were statistically evaluated by means of the Student-t-test and the t-test on paired data.

Results

Histamine Concentrations in Tissues, Blood and Plasma in the Course o/Operations H i s t a m i n e c o n c e n t r a t i o n s i n h u m a n t i s s u e s a n d i n t h o s e of l a b o r a t o r y a n i m a l s f r e q u e n t l y u s e d i n ex-

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Table 1. Histamine content of various tissues in man, monkeys, pigs a n d dogs

Tissue n Histamine content in ~g/g fresh weight

M a n Monkey Pig Dog

( n = 6 ) ( n = 5 ) ( n = 7 )

Stomach

F u n d u s 5 14.84- 5.6 82.64- 43.5 1 5 0 . 4 ± 6 7 101 ± 1 5

Corpus 23 16.2-L 8.0 97.0~: 55.3 99.74-26.5 117 =t=40

A n t r u m 24 10.0:L 4.4 5 9 . 9 ± 33.4 102 ~:49 6 9 . 3 ± 2 4 . 7

Duodenum 3 10.4eL 8.2 113 4 - 4 6 140 4-13 115 4-18

J e j u n u m 10 13.74- 7.9 138 4- 75 234 4-78 145 4-26

Ileum 13 16.54- 6.0 7 0 . 7 ± 36.3 198 ~-54 8 3 . 4 ± 1 6 . 8

Appendix 3 11.94- 1.1 37.14- 10.3 127 4-53 - -

Colon 9 9.14- 5.5 51.04- 9.9 109 4-23 71.64-21.3

Sigma 16 7.6~: 3.8 - - - - - -

R e c t u m 17 7.94- 5.0 41.24- 15.4 73.34-42.5 31.24- 8.8

Liver 33 3.94- 2.6 2.74- 1.7 2 1 . 4 ~ 7.8 38.3=t=16.0

Spleen 6 3.74- 1.5 3 . 3 ± 3.4 44.8=j= 5,4 2 0 . 9 ± 10.5

Lungs 10 22.7~:17.1 263 4-224 222 4-35 63.84-45.4

K i d n e y 3 1.8=L 0.5 9 . 5 ± 8.1 1.84- 0.9 1.14- 0.8

Abdominal skin 3 5 . 3 ± 3.8 6.84- 4.4 29.64- 6.2 18.54- 7.0

Muscle

(Rectus abdominis) 7 1.84- 0.8 4.4-}= 3.2 2.34-1.0 1.9 4- 0.8

Mean values4- S.D. I n m a n n = n u m b e r of organs tested, 1-3 being obtained from the same subject. I n animals n = n u m b e r of individuals tested. For further conditions see Materials and Methods.

Table 2. Plasma histamine concentrations in patients before and after various operations No. Pat. Sex Day of Diagnosis/Operation

Name oper-

ation

Plasma histamine concentrations (ng/ml) Before After the end of the operation oper-

ation Few 4 hrs 8 hrs 20 hrs minutes

1 Sch.H. ~ 23. 2.72 2 F . A . d' 2. 5.72 3 B.M. ~ 23. 6. 72

4 G.K. d~ 4.12. 72

5 G.K. ~ 5 . 1 2 . 7 2 6 L.A. ~ 1 3 . 1 2 . 7 2 7 W . K . ~ 1 . 1 2 . 7 2 8 K . H . ~ 2 . 1 2 . 7 2 9 A.S. ~ 8 . 1 2 . 7 2 10 A . F . ~ 4. 4. 72 11 G.H. ~ 27. 4. 72

12 D.M. ~ 22. 6.72

13 J . H . ~ 26. 6.72 14 K . W . ~ 6. 12.72

15 N.A. ~ 6. 12.72

16 S.N. ~ 22. 6. 72 17 G . K . ~ 4. 4.72 18 H . H . 2 29. 6.72

19 M.A. 2 2. 5.72

20 P . H . ~ 27. 6.72

21 G.E. (~ 27. 3.72

22 S.E. 2 3. 5.72

Duodenal ulcer/select, vagotomy 0.3 0.9 1.3 0.4 0.4

÷ p y l o r o p l a s t y

Gastric ulcer/2/3 resection + B I I 0.5 0.8 0.4 - - 0.4 Duodenal ulcer/select, v a g o t o m y + B I 0.5 0.8 0.8 0.5 - -

Stress ulcer/select, v a g o t o m y + 0 1.5 0 0 __a

pyloroplasty

Gastric cancer/subtotal gastrectomy 0 0.7 0 - - 0

Gastric ulcer/e/2 r e s e c t i o n + B I I 0 0 0 - - 0

Acute pancreatitis/resection 0 0 0 - - 0

Acute pancreatitis/resection 0.7 0.7 2.6 - - 1.5 a

Pancreatic cyst/pancreatectomy 1.3 1.6 1.9 - - 2.6 a

ChoMithiasis/eholecystectomy 0.3 0.5 0.5 - - 0.3

Biliary obstruction b y stones/ 0,5 0.6 0.5 0.5 - -

revision of the bile ducts

Cholelithiasis/cholecystectomy 0.6 0.8 0.7 0.7 - -

Ca of the coecum/intestinal resection 0.6 0.6 0.4 1.0 - -

Ca of t h e papilla/biliary-dig~stive 0 0 0 - - 0

anastomosis

Perforated appendicitis/appendectomy 0 1.5 0 - - 0 a

Ca of rectum/intestinM resection 0.6 1.4 0.9 1.3 __a

S t r u m a / s t r u m e c t o m y 0.4 0.4 0.4 - - 0.3

S t r u m a / s t r u m e c t o m y 0.8 0.6 0.7 0.7 - -

Bronchial cancer/pneumoresection 0.6 0.7 0.7 0.6 - -

Bronchial cancer/pneumoresection 0.3 0.8 0.6 - - 0.6

Leg t h r o m b o s i s / t h r o m b e c t o m y 0.4 0.5 0.4 - - 0.6 Leg t h r o m b o s i s / t h r o m b e c t o m y 0.5 0.2 0.4 0.8 - - The age of t h e patients was 23-67 years. No significant correlation could be shown between elevated plasma histamine levels and age. F o r f u r t h e r conditions see t e x t under Results and Methods.

a Significantly elevated plasma histamine levels as defined in Methods. 20 hrs after t h e end of the operation meaa~

always the morning of the first postoperative day the end of operation being approximately at noon,

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Table 3. Influence of introduction of anaesthesia and of manipulations at the stomach and gut during abdominal operations on the plasma histamine concentrations in monkeys, pigs and dogs

Animal Plasma histamine concentration [ng/ml]

:No.

Monkey Pig Dog

5 rain 30 min 60 rain 5 min 81 ± 10 min 5 min 30 min 60 min

1 0 0 0 27 13 1.1 0.4 0.5

2 1.2 0.6 0 43 16 0.9 0.8 0.6

3 1.1 0.3 0.3 38 15 1.4 1.6 1.0

4 1.8 1.2 0.6 22 13 1.1 0.8 0.2

5 1.1 1.1 0.6 21 18 0.8 1.0 0.3

6 1.8 0.6 0.6 28 15 1.1 0.4 0.5

7 - - - - - - 22 6 0.5 0.5 0.2

8 . . . 0.8 0.8 0.4

9 . . . 0.6 0.6 0.3

2 ± S . D . 1.24-0.7 0.6±0.5 0.4±0.3 a 29:~8 14~:4 b 0.94-0.3 0 . 8 ± 0 . 4 0.44-0.3 c

The operations in the animals are described in Methods. 5 rain = immediately after introduction of intravenous anaesthesia, 30 r a i n = a f t e r the end of the operation, and 60 r a i n = after an interval of 30 min following the end of operation. In pigs, 81 ± 10 rain means the beginning of the by-pass phase, in the recipient of a transplanted liver.

a p 5/60~0.02; b p~0.005; c p 5/60~0.001 (Student's t-test for paired data).

For further conditions see Materials and Methods.

p e r i m e n t a l s u r g e r y were i n v e s t i g a t e d (Table 1). Gas- t r o - i n t e s t i n a l tissues a n d t h e lungs were e s p e c i a l l y r i c h in h i s t a m i n e , t h e h i g h e s t c o n c e n t r a t i o n s being f o u n d in t h e s m a l l i n t e s t i n e of pigs a n d in t h e lungs of m o n k e y s .

H i s t a m i n e release f r o m t h e s e tissues e v e n being small on a p e r c e n t a g e basis can p r o d u c e h i s t a m i n e o u t p u t s of s e v e r a l nag t h e s t r o n g effects of w h i c h on t h e c i r c u l a t i o n are well k n o w n f r o m p h a r m a c o l o g i c a l e x p e r i m e n t s .

H i s t a m i n e c o n c e n t r a t i o n s i n p l a s m a a n d whole b l o o d of h u m a n s u b j e c t s a n d e x p e r i m e n t a l a n i m a l s were s t u d i e d before, d u r i n g a n d a f t e r o p e r a t i o n s . I n 6 of 22 p a t i e n t s , e l e v a t e d p l a s m a h i s t a m i n e levels were o b s e r v e d following surgical t r e a t m e n t (Table 2).

T h e p o i n t i n t i m e of m a x i m u m increase in p l a s m a h i s t a m i n e was f o u n d t o v a r y , b u t was w i t h i n t h e first 4 h o u r s a f t e r o p e r a t i o n in 5 of 6 p a t i e n t s . I n all t h e s e 6 i n d i v i d u a l s a n a b d o m i n a l o p e r a t i o n h a d b e e n p e r f o r m e d , w h e r e a s t h e s u b j e c t s being t r e a t e d b y a p u l m o n a r y r e s e c t i o n s h o w e d no increase of p l a s m a h i s t a m i n e c o n c e n t r a t i o n . H i s t a m i n e in t h e whole b l o o d was n o t a l t e r e d s i g n i f i c a n t l y following surgery.

I n t h e s a m e p a t i e n t s as d e s c r i b e d in T a b l e 2, t h e h i s t a m i n e c o n c e n t r a t i o n s before t h e o p e r a t i o n s were 0.086 ± 0.020 Fg/ml, few m i n u t e s a f t e r t h e o p e r a t i o n 0.087 ± 0 . 0 1 9 Fg/ml, 4, 8 a n d 20 h o u r s l a t e r 0.083 ± 0.022, 0.078 =J= 0.014, a n d 0.096 ± 0.026 ~g/ml. So, t h e d e t e r m i n a t i o n of h i s t a m i n e in whole b l o o d was n o t a s u i t a b l e m e t h o d for e v a l u a t i n g h i s t a m i n e release in m a n in t h e course of o p e r a t i o n s .

I n l a b o r a t o r y a n i m a l s e l e v a t e d p l a s m a h i s t a m i n e c o n c e n t r a t i o n s were also f o u n d d u r i n g a n d a f t e r s t a n d a r d i z e d o p e r a t i o n s i n c l u d i n g c a u t i o n s m a n i - p u l a t i o n s on t h e g u t w h i c h were n e c e s s a r y to i n s e r t c a t h e t e r s in t o a m e s e n t e r i c v e i n (dogs a n d pigs) (Table 3). 30 m i n following t h e end of t h e m a n i -

p u l a t i o n s , v a l u e h a d u s u a l l y t u r n e d t o n o r m a l . Thus, in a n i m a l e x p e r i m e n t s , a t l e a s t half a n h o u r a f t e r t h e p r e p a r a t i o n has t o elapse before a p p r o x i m a t e l y b a s a l c o n d i t i o n s are reached. Since, however, t h e h i g h e s t p l a s m a h i s t a m i n e levels were d e t e r m i n e d i m m e d i a t e l y following t h e i n t r o d u c t i o n of a n a e s t h e s i a , studies were p e r f o r m e d on h i s t a m i n e release following t h e a d m i n i s t r a t i o n of n a r c o t i c a n d h y p n o t i c drugs.

Causes/or Histamine Release in Surgery Premedication by Atropine. T h e influence of atro- p i n e (0.01 m g / k g i.v.) on t h e p l a s m a h i s t a m i n e levels in m a n was i n v e s t i g a t e d in 36 p a t i e n t s a n d t e s t persons. 6 s u b j e c t s s h o w e d e l e v a t e d p l a s m a h i s t a m i n e c o n c e n t r a t i o n s 1 a n d 5 r a i n following t h e i n j e c t i o n of t h e d r u g t h e i n c r e a s e b e i n g 150% (from 0 . 6 ± 0 . 5 to 1.5 :L 0.5 n g / m l , p < 0.02 in t h e t - t e s t on p a i r e d d a t a ) . I n t h e o t h e r 30 i n d i v i d u a l s , no s i g n i f i c a n t a l t e r a t i o n s in t h e p l a s m a h i s t a m i n e levels could be o b s e r v e d 1, 5 a n d 10 r a i n a f t e r a t r o p i n e (before: 0 . 5 ~ 0 . 3 ng h i s t a m i n e / m l p l a s m a , 5 r a i n a f t e r t h e i n j e c t i o n : 0.6 :~ 0.5 ng/ml).

Intravenous Short-acting Anaesthetics. F o l l o w i n g t h e i n j e c t i o n of m e t h o h e x i t o n e , p r o p a n i d i d a n d A l t h e s i n CT 1341 ® h i s t a m i n e was r e l e a s e d in some t e s t persons (Fig. 1). O n l y E t o m i d a t e ® n e v e r a l t e r e d t h e p l a s m a h i s t a m i n e levels. C r e m o p h o r ® alone, t h e solubilizer b o t h of p r o p a n i d i d a n d A l t h e s i n CT 1341 ®, as well as p h y s i o l o g i c a l saline as a c o n t r o l s o l u t i o n for m e t h o h e x i t o n e , d i d n o t increase t h e p l a s m a h i s t a m i n e c o n c e n t r a t i o n s i n t h e s a m e t e s t persons as u s e d for t h e i n j e c t i o n of t h e h y p n o t i c s .

Acute Blood Losses and In/usion o] Plasma Sub- stitutes. N e i t h e r in t e s t persons n o r i n e x p e r i m e n t a l a n i m a l s d i d a c u t e loss of b l o o d cause a release of h i s t a m i n e w i t h i n t h e t i m e i n v e s t i g a t e d . I n h u m a n s u b j e c t s , o n l y a b o u t 1/10 of t h e c i r c u l a t i n g b l o o d

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=* ^_

=* _

o n = 6 1.5

1.0

0 5

15 ng/ml 10 2.5 ng/m[

2.0

• reacting subjects o non reacting subjects

2.0 ng/mt 15

1.0

0 5

~m • n = 4

o n = h

I I I I I I

l 0 2 0 r a i n 3 0

If m e

I i i i I ; 1 I 1 I 0

-10 0 10 20 min 30

Time

- ~ ~ ~

2 2 _. _. _. _. ₂ ~g/r~l~ ~ ° E

I t [ l . I [ [ I 1 I 0 [ II [ ] [ I [ ] I

-10 0 10 20 rain 30 -10 0 10 20 min 30

Time Time

Fig. 1. Histamine release in several test persons following the injection of anaesthetic drugs. Mean values :~ S.E.M. The values from reacting and non reacting subjects were shown separately. The evidence for histamine release in a single test person was delivered by showing a type of climination curve for the plasma histamine concentration following the injection of the histamine liberator Bateman function. Statistical significance: Methohexitone 0/1 min p < 0.025; 0/5 min p < 0.01 ; 0/10 rain 29 < 0.05. Althesin CT 1341 ® 0/5 min < 0.001, T-test for paired data. For further conditions see Materials

and Methods

Table 4. Incidence of histamine release and maximum increase of plasma histamine levels in man and several animals following rapid infusion of plasma substitutes

Species Plasma Incidence Plasma histamine concentration Increase Signifi-

substitute [ni/n2] (ng/ml] [%] cance

Before 1-10 rain

infusion after infusion

Man Dextran 6/15 0 . 4 ± 0.4 2.0~: 0.6 400 p<0.01

Gelatin 10/12 0.8 ~ 0.3 1.9 ~: 0.3 140 p<0.001

Ringer 0/12 0.8 =L 0.3 0 . 6 ~ 0.3 - - - -

Monkey Gelatin 2/6 0.2 3.0 1400 - -

Pig Dextran 0/9 16:[: 7 17 :t: 5 - - - -

Dog Dextran 0/10 0.24- 0.2 0.1~: 0.2 - - - -

Gelatin 9/23 0.2 41 0.3 20.5 ~ 18.5 10100 p < 0.02

Mean values :ix S.D.. incidence of histamine release given in number of individuals reacting to the substances [ni] per number of subjects tested In2]. The plasma histamine concentration is given only for reacting individuals. Non-reacting subjects showed only insignificant changes in plasma histamine following infusion. The preinfusion levels of plasma histamine were not significantly different in reacting and non-reacting subjects. For comments, definition of the batches, and further conditions see Materials and Methods.

v o l u m e -was w i t h d r a w n , w h i c h m a y h a v e b e e n t o o w e a k a s t i m u l u s for i n d u c i n g h i s t a m i n e release f r o m t h e tissues, b u t in all of t h e a n i m a l s s t u d i e d as m u c h as a b o u t 1/3 of t h e b l o o d v o l u m e was r a p i d l y r e m o v e d . I n 16 t e s t persons, t h e p l a s m a h i s t a m i n e c o n c e n t r a t i o n before t h e b l o o d d o n a t i o n was 0.2 =t=0.2 n g / m l , a f t e r

t h e w i t h d r a w a l of b l o o d 0 . 1 4 - 0 . 1 n g / m l b e i n g n o t s i g n i f i c a n t l y d i f f e r e n t f r o m zero in m o s t of t h e cases.

T h e i n f u s i o n of p l a s m a s u b s t i t u t e s i n d u c e d hista- m i n e release b o t h in h u m a n s u b j e c t s a n d in a n i m a l s (Table 4). I n t e s t persons, d e x t r a n a n d g e l a t i n b o t h showed t h e effect, b u t R i n g e r ' s s o l u t i o n d i d not. As

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O,30- rneq

0 . 2 5 .

0 . 2 0 _

0.15

O.10

0 . 0 5

I I k

Haemaccel ~) batch No 2551

II--,lll n= s

D , , - V I n= 2

A ~ / ~ n = l O (Ringer)

Bleeding Infusion

o ~ _¢ _t _r _r _~ _f

B.B.B.I. El. 5 10 20 3 0

• ,me Em,n]

Fig. 2. Gastric acid secretion in test persons following r a p i d infusion of gelatin (batch 2551) and Ringer's solution. Mean values :~ S.E.M. The values from reacting and nonreacting subjects were shown separately. The same test persons as for the plasma histamine determinations were used (Table 4), gastric acid secretion and plasma histamine were determined.

simultaneously. However, in two test persons gastric acid secretion could not be measured for technical reasons, but only the plasma histamine levels. Statistical significance: Gelatin, reacting subjects BI/5 rain p < 0.005, BI/30 min p < 0.02.

B. B = before bleeding, B. I ~ before infusion, E. I = end of infusion. For further conditions see Methods and Materials

in the case of the anaesthetics, the colloid and the control solution were administered in random order (digits of the Random Corporation, England). I n dogs, gelatin was a very potent releaser of histamine in 9 of 23 animals, but dextran was without effect.

Furthermore, gelatin elicited a small increase of the plasma histamine levels in 2 of 6 monkeys. Dextran was without effect in pigs. Thus, a relatively strong species specificity was observed regarding the histamine releasing activity of plasma substitutes, which has to be considered in the clinical evaluation of our results.

Clinical Symptoms and Biological Reactions in the Course o/ Histamine Release

during Operations

At the time of elevated plasma histamine concentrations, no significant arterial hypotension could be observed in patients undergoing abdominal ope-

rations. The injection of the narcotics, with the exception of Etomidate ® sometimes caused a con- siderable hypotension lasting for 2-3 minutes, but the reaction of the circulatory system neither quanti- tatively nor regarding to the course of time showed correlations with the plasma histamine levels (see also Lorenz et al., 1972). The infusion of plasma substitutes in test persons also did not alter the arterial blood pressure significantly.

I n the 22 patients investigated no correlation could be demonstrated between alterations of the heart rate and changes in the plasma histamine concentrations. The tachycardia occurring regularly after the injection of the anaesthetics did not last longer than about 3 rain being therefore not related to the histamine release. No changes in heart rate could be observed following the infusion of the plasma substitutes. However, in two test persons who showed an increase of the plasma histamine concentration up to 4 ng/ml following the infusion of gelatin, a slight tachycardia occurred which reached its maximum exactly at the time of the maximum increase of the plasma histamine concentration (increase in heart rate b y 17 and 20 beats/rain). These two test subjects also showed a ocdematous swelling behind the ear and on the eye-lids as well as single wheals on the neck.

Gastric acid secretion was studied only in test persons receiving infusions of gelatin and Ringer's solution. Subjects who did not react to gelatin by a histamine release or were treated only by Ringer's solution showed no significant changes in gastric secretion (Fig. 2). However, the individuals, who reacted to gelatin b y a histamine release, showed a stimulation of acid secretion parallel to the elevation of the plasma histamine levels. This reached half the maximal rate of acid secretion in some cases (Fig. 2).

I n laboratory animals, no arterial hypotension following the infusion of plasma substitutes could be observed in monkeys and pigs. I n dogs, however, a severe and in 2 cases letal hypotension occurred following infusion of gelatin in 9 of 23 animals. These dogs showed also an increase of the plasma histamine concentration.

Discussion

Histamine is known as a pharmacologically highly active substance: I n human subjects, it stimulates gastric and salivary secretion, lowers the arterial blood pressure, causes tachycardia, increases the permeability of the vessels in the microcireulation and contracts the smooth muscles of the bronchi and the gastro-intestinal tract. The release of endogenous histamine, mainly from mast cells, induces the same biological reactions and subsequently the same clinical symptoms as being observed after the parentera]

application of histamine. Only certain modifications in the pathophysiological reactions elicited by histamine can occur which must be taken into consideration, such as by the simultaneous release of other vaso~ctive

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W. Lorenz et al. : Histamine in Surgery 425 substances from amine containing cells, especially the

catecholamines, or b y the region where the histamine release takes place (e.g. histamine from the gut does not or only partially overcome the liver's barrier).

Very different threshold doses or threshold concentrations of histamine in plasma are necessary to elicit different effects in the body. According to Lorenz el al. (1972), who produced increasing plasma histamine levels b y infusion of increasing doses of histamine, the most sensitive reaction to histamine in m a n is the stimulation of gastric secretion (1 ng/ml), the second one tachycardia (4-6 ng/ml plasma), whereas a significant hypotension can be measured only at plasma histamine concentrations of 6-10 ng/ml. These findings explain, w h y the increase of the plasma histamine levels observed during the operations in this s t u d y only induced a stimulation of gastric acid secretion [see also Lorenz et al. (1969); Lorenz el al.

(1972)].

Through severe or life-threatening clinical reactions to histamine release are not represented in this communication, the demonstration of histamine release during surgical operations seems to be clinically significant :

1. Normal h u m a n subjects react to anaesthesia and to the other t r e a t m e n t s investigated in this s t u d y only b y a small histamine release. However, in single cases and under various pathophysiological conditions such as sepsis, disturbances of the blood coagulation and fibrinolysis including the release of phosphatidyl serine, activation of the com- plement system b y immunoglobulin aggregates or b y the C3-activator system as well as sensitization, a massive histamine release occurred in patients (Lorenz et al., 1972), with the clinical s y m p t o m s of a severe anaphylactic or anaphylactoid reaction. Furthermore, such incidents have been repeatedly observed before, during and after operations, following the administration of atropine, propanidid, thiopentone, muscle relaxants and analgetics (for a survey see Lorenz et al., 1972) and also following the infusion of plasma substitutes (Lorenz el al., in preparation). Finally, severe clinical reactions (hypotension, cardiac arrest) com- plicated the course of liver transplantations which in certain phases of the operation could be attributed mainly to the occurrence of histamine in the circulation (Lorenz et al., 1973). I t has not been suffi- ciently recognized t h a t histamine release from the gastro-intestinal t r a c t or from the liver is often not accompanied b y skin reactions or b y bronchospasm.

So acute arterial hypotension in operations has seldom been attributed to histamine release.

2. E v e n in normal h u m a n subjects, the release of relatively small amounts of histamine, as determined in this study, m a y be of clinical significance. In- creased gastric acid secretion desp~'Lte of the injection of atropine (Lorenz et al. 1972) m a y be a cause of vo- miting and aspiration as observed in one of our patients receiving propanidid (Doenicke, personal corn-

31 Klin. Wschr., 52. J a h r g .

munication). Histamine release could have an importance in the development of postoperative stress ulcers (Seidel et al., 1973). According to K a t z and Siegel (1968) a dose of exogenous histamine which elicites a nearly h a l f - m a x i m u m gastric secretion is capable of causing haemorrhagic erosions in the h u m a n gastric mucosa. The plasma histamine levels, however, reached b y such a dose of exogenous histamine (Lorenz el al., 1972), are v e r y similar to those measured in the 6 patients included in Table 2. These results show t h a t one cannot exclude the possibility endogenous histamine is involved in the formation of acute gastro-duodenal ulcers in h u m a n subjects.

Considering histamine release in surgery it is striking t h a t medical t r e a t m e n t s were responsible for increases of the plasma histamine concentration. The operation itself seemed usually to have m u c h less effect. Also, extracorporeal blood circulation can cause histamine release as an undesired side-effect (Meyer- Burgdorff el al., 1973).

References

Erspamer, V.: Participation of 5-hydroxytryptaminc in physiopathological processes. Handbook of experimental pharmacology, p. 360. Berlin-Heidelberg-New York:

Springer (1966)

Holtz, P., Palm, D.: Brenzkatechinamine and andere sym- pathicomimetische Amine. Reviews of physiology, biochemistry and experimental pharmacology, p. 263. Berlin- Heidelberg-New York: Springer (1966)

Katz, D., Siegel, H. J. : Progr. Gastroenterol. 1, 67 (1968) Lorenz, W., Barth, H., Kusche, g., Reimann, H.-J., Schmal,

A., Matejka, E., Mathias, Chr., Hutzcl, M., Werle, E.:

Europ. J. Pharmacol. 14, 155 (1971)

Lorenz, W., Doenicke, A., Halbach, S., Krumey, I., Werle, E. : Klin. Wschr. 47, 154 (1969)

Lorenz, W., Doenieke, A., Meyer, R., Reimann, It.-J., Kusche, J., Barth, H., Geesing, H., Hutzel, M., Weissenbaeher, B.:

Europ. J. Pharmacol. 19, 180 (1972)

Lorenz, W., Doenieke, A., Meyer, R., Reimarm, H.-J., Kusche, J., Barth, H., Geesing, H., Hutzel, M., Weissenbaeher, B. : Brit. J. Anaesth. 44, 355 (1972a)

Lorenz, W., Hell, E., Boeckl, O., Reimann, H.-J., Zimmer- mann, G., Seidel, W., Laszcz, M., Uhlig, R., Europ. Surg.

Res. 5, 11 (1973)

Lorenz, W., Matejka, E., Schmal, A., Seidel, W., Reimann, H.-J., Uhlig, R., Mann, G.: Comp. General Pharmaeol.

4, 229 (1973)

Lorenz, W., Reimann, H.-J., Barth, H., Kusche, J., Meyer, R., Doenicke, A., Hutzel, M. : Hoppe-Seylers Z. physiol. Chem.

858, 911 (1972b)

Messmer, K., Lorenz, W., Sunder-Plassmann, L., Kloevekorn, W.-P., Hutzel, M.: I~aunyn-Schmiedebergs Arch. Phar- macol. 267,433 (1970)

Meyer-Burgdorff, C., Seidel, G., Schliiter, F. g. : Anaesthesist 22, 212 (1973)

Rocha e Silva, M. : Histamine. Its role in anaphylaxis and allergy. Springfield: Ch. C. Thomas

Schayer, R.W. : Chemotherapia 3, 129 (1961)

Seidel, W., Lorenz, W , Doenicke, A., Mann, G., Uhlig, R.:

Brit. J. Surg. 60, 320 (1973)

Prof. Dr. W. Lorenz Chirurg. Universit/itsklinik Abt. fiir Exper. Chirurgie und Pathologische Biochemie D-3550 Marburg a.d. Lahn Robert-Koch-Strafe 8 Federal Republic of Germany