Acta Medica Scandinavica. Vol. XCI, fasc. 1-11, 1937.

From theFirs t MedicalClinic of the Seraphimer Hospital (Chief at that time: Professor I. Hclmgren) and the Department of Pharmacology of the

Kamlinska Institute (Chief: Professor G. Liljestrand, Stockholm).

Ventilation in Essential Hypertension and in Anemia.

BY

PER J. WISING.

During the last decade the fundamental morphological papers of Hering (1923) and De Castro (1926, 1928) and especially the numerous experimental investigations of the Heymans school have established the fact that the carotid sinus and the vasosensitive reflex zones in the walls of the heart and the aorta are of profound importance in the normal continuity of the circulatory processes. We know that it is the variation in endarterial pressure which provides the specific stimulus for these reflex zones supplied by terminal branches of the intercarotid (De Castro) and depressor nerves and similarly that the glomus caroticum apparently is an organ reacting specifically to oxygen want and alterations in the H ion concentration of its blood supply, thus exerting a reflex control over the frequency and amplitude of the respiratory move- ments (Bouckaert, Dautrebande & Heymans 1931, Schmidt 1932 Heymans & collaborators 1933, Camus, B6nard & Merklen 1934, Cayet, Bennati & Quivy 1935, Zotterman 1935, Samaan & Stella 1935, Cited from Euler & Liljestrand).

I t was natural t o assume a pathogenetic relation between essential arterial hypertension and a conjectured decreased or suspended sensitivity of the receptor mechanism in these reflex zones

Submitted for publication October 28, 1936.

160 PER J . W I S I N G .

and i t seems as if such an assumption is to a certain extent supported by an investigation of Regnier and Mies who in cases of this disease found a diminution or absence of effect on compression of the cargt id sinus. Up to the present, however, i t would seem as if no support has been brought forward for Bittorf’s postulation that the cause of the blood pressure disease is a decreased sensitivity in the receptor mechanism of the vessels in the reflexogenous zones on the basis of atherosclerotic changes in their walls. A priori however, such an explanation does seem conceivable in regard to the normal hypertension of old age.

Moissejeff (1926), Heymans (1929) and Heymans and Bouckaert (1930) found that an increased endosinusal pressure provoked inhibition, and tha t lowering of the pressure caused stimulation of respiration as long as the sinus nerves were intact, whereas denervation of the sinuses eliminated the effect (Cited from Euler & Liljestrand).

Heymans, Bouckaert & Dautrebande write: ))La sensibilitk rkflexogene respiratoire des zones vasosensibles ii la pression endo- vasculaire peut predominer sur la sensibilite directe du centre respiratoire a la composition chimique du sang: en effet lorsqu’on provoque une hypotension dans les sinus carotidiens, I’hyperpnke rbflexe, qui est ainsi dkclenchke, persiste malgri! l’alcalose sanguine, malgre la diminution de la teneur en CO, du sang produite par cette hyperpnke, e t malgrk l’augmentation de la circulation art& rielle centrale, differente facteurs, qui normalement devraient inhiber l’activitk du centre rkspiratoire)) (Cited from Heymans, Bouckaert & Regniers).

Recently Euler & Liljestrand (1935) and Samaan and Stella (1935) interpreted the respiratory responses of changes in endo- sinusal pressure observed by Heymans and collaborators and others as being due to variations in the oxygen supply. Considering known facts and experiments of their own the above authors attribute the effect on respiration caused by clamping the common carotids to a slight anoxaemia and carbon dioxide accumulation in the glomus.

The diseased conditions mentioned in the title of this paper seemed t o offer an opportunity odissociatedlyo to investigate on clinical material the effect on ventilation of pressure factors and oxygen concentration of the blood.

VENTILATION I N E S S E N T I i L HYPERTENSION A N D I N ANEMIA. 161

Thus according to the hypothesis of Heymans, Bouckaert & Dautrebande, a hypoventilation could possibly be expected in cases of hypertension and an anoxemic hyperventilation due to low hemoglobin content in patients with anemia. The justification of such a presumption in regard to anemia is suggested clinically by the known tendency toward dyspnea in this disease, by the constant finding of emphysema in cases of more advanced anemia of some duration (I. Holmgren), by the hyperventilation of the ))anoxic anoxia, of high altitudes (Peters and van Slyke) as well as of experimental animals kept in air with lowered oxygen tension.

Means, Bock & Woodwell, Peters, Barr & Peters (1921) found that the blood showed a flatter CO, absorption curve and an alkalosis in severe primary and secondary anemia and the latter two authors ascribe this condition to an excessive pulmonary ventilation, without however submitting any figures in support of their contention (Cited from Dautrebande).

Evans (1921) found an elevated alkali reserve in experimental anemia produced by bleeding otherwise healthy rabbits and cats.

Dautrebande (1925) observed considerable alkalosis and low C O , alveolar tension in two cases of pernicious anemia but he ascribed this to the disease itself rather than to hyperventilation.

In anemias of various origin Kraus and others found that the gaseous exchange of 0, and CO, lay practically at the upper border of the normal.

Haldane, Kellas and Kennaway (1919), Henderson (1919, 1920) Haggard and Henderson (1920,1924) have shown that even a com- paratively slight diminution of the oxygen pressure of the inspired air causes hyperventilation with decreasing alveolar CO, pressure and alkalosis, and that on removal of the anoxaemia, there is a quite appreciable immediate rise in alveolar C0,-pressure. (Cited from Haldane & Priestley.) Maferial and methods.

Simultaneous gasometric determination of ventilation and CO, alveolar tension while breathing almost pure oxygen was performed in 12 cases of grave anemia of varying etiology. The CO, alveolar tension was also studied in 10 cases of essential hypertension. The controls were 8 patients with normal blood values and a systolic blood pressure below 130 mm Hg. The information is summarized in Tables I t o 111. All experiments were carried out under basal 11 - A d a med. scandinau. Vol . X C I .

162 PER J . WISING.

Tabel I. (Controls.)

(8 sub). with normal blood counts and blood pressure below 130 mm Hg systolic)

Condition

€ealthy sub1

. _ - - - - - - - lealthy subj

iealthy subj

- - - - - - - -

lemirrania

Veurasthenii

- - - - - - - -

Erythema nodosum

. - - - - - - - -

Myasthenia gravis

- _ - - - - - - - Mb. Raynar

70 68

62 62

_ _ _ -

68 68

- _ - -

69 69

11.0-8.5 .LO-9.0

12.0-8.5 12.0-8.5

. - - - - - -

10.5-8.0 11.0-8.5

12.0-9.0 11.5-8.5

_ _ _ _ _ _

12.5-9.0 12.5-9.0

- - - - - -.

13.0-9.a 13.0-9.C

12.5-9.( 12.0-8.5

Average ven- tilation in lit.

to OO.760 mm, dry air

- ' a Per min. red. 3 Alveolar t X CO,-tension I. L. i n m m H g

32

36 34 34 Medium:34

43 96 45 8.97

45 46 46 Medium:44

41 91 40 9.04

40 41 41 Medium:41

36 93 38 4.87

38 39 39 Medium:38

37

97 36 8.07

- - - . - - - - - - - - - . - - - -

_ _ _ _ _ _ _ _ _ - .----

- - - -. - - _ - _ - _ - - - - - - -

. - - - - - - - - - - - - - - - - - 6.40

100

39 Medium:38 37 38 6.86 40 39 38 37 Medium:38 37

. - - _ - - - - - - . _ - - -

----

38 Mediurn:37

104 136 36 1 6.7C

I 37 137

1;; Medium:36 I

- Per

sq.m.

4.29

_ _ _ _

5.13

4.61

_ _ _ _

3.19

4.48

4.24

----

4.20

----

4.59

-

VENTILATION I N ESSENTIAL HYPERTENSION AND I N ANEMIA. 163

Tabel 11. (Alveolar GO,-tension in 10 cases of essential hypertonia.)

Blood pressuri efore and aft1 period of regie

tration (in cm Hg)

24.0-15.0 24.5-15.0

_ - _ _ _ _ _ _ _ _

18.5-1 0.5 18.5-10.5

21.0-11.0 20.5-10.5

22.0-13.5 22.0-14.0

20.0-11.0 20.0-11.0

. - - - - - - - - -.

23.5-13.0 22.0-14.0

20.0-12 0 19.0-12.0

_ _ _ _ _ - _ - _ _

19.5-11.0 20.5-12.0

111

Alveolar GO,-tension in mm Hg

34 34 33 34 Medium:34

41 43 40 43 41 41 Medium:42

41 41 41 42 42 42 Medium:42 40 30 49 39 40 41 Medium:40

_ - - - - - - - - - - - - - - - -

35 35 36 36 Medium:35

42 42 42 43 43 44 Medium:43 38 37 36 3z 37 Medium:37

36 37 38 37 37 Medium:37

164 P E R J . WISING.

Blood pressure before and afte period of regis.

tration (in cm Hg)

22.0-12.0 22.0-12.0

~ _ _ _ _ ~

23.0-14.5 22.5-14.5

Alveolar GO,-tension in mm Hg

39 38 40 40 40 40 Medium:40 46 45 44 46 46 48 Medium:46

and as identical experimental conditions as possible. Alveolar air samples were removed simultaneously with the spirometer experi- ments. The procedure was as follows: Between the LovCn-valve of the Krogh-spirometer (Kifa) and the mouth piece (Knipping No. 111) a short glass T-tube was inserted through which a thin rubber tube about 25 cm in length could be connected with the gas pipettes of which 3 to 6 were used for each test. All the patients were kept in bed the days before the investigations. After a preli- minary further hour of rest the blood pressure was measured immediately before each experiment (Riva-Rocci Hg manometer, the lowest value of three readings). After a preparatory period of 6 4 minutes during which the patient breathed through the appa- ratus, the radial pulse was counted for one-half minute and then followed the main experiment of 10 to 15 minutes duration. At the height of every expiration during this period a few cubic centimeters of the expired gas were let into the gas pipette (Lindhard) which had first been washed out two or three times with 15-20 cm3 of such air.

The CO, analyses were done according to Haldane. Immediately after each registration period the pulse was again counted to control whether it had remained constant during the experiment. The gasometer was a carefully controlled model.

VENTILATION I N ESSENTIAL HYPERTENSION A N D I N A N E M I A .

Tabel 111. (12 cases of anemia with systolic blood pressure below 130 mm Hg.)

165

re i 3 L g q

g I. ED 3s

115

_ _ _ _

105

_ _ _ _

- - 3

8 " a G 89

B

m m

m

- 19 66 d

20 48 ?

_ _ _ _

21 41 ?

_ _ - _

22 60 ?

_ - _ _ 23 44 ?

24 67 d

_ _ _ _

25 69 ?

Alveolar CO,-tension i n m m H g

33 31 33 31 31 32

M = 32 35 37 38 38 37

M = 37

_ _ _ _ _ _ _ _ -

Condition

- - - -

135

_ _ _ _

107

Pernicious anemia

33 34 35

M = 33 31

32 30

M = 31 32 33 33 34

- - - _ - - _ _ _

-

_ _ _ _ _ _ _ _ -

Pernicious anemia

Pernicious anemia

Pernicious anemia

Pernicious anemia

:ancer recti Anem. sec.

. - - - - - - - -

Icterus haemolyt.

55 3.7 mill.

_ _ _ _ _ _

10 1.85 mill

30 1.03 mill

35 1.28 mill

15 3.2 mill.

- _ - - - -.

55 3.1 mill.

74 76

_ _ _ -

90 90

72 76

88 88

46 48

68 .72

31 129 I 32

32 I 31

37 M = 37

Average venti lation in lit.

per min. red. to OO.760 mm

dry air.

Total

- 9.56

8.01

7.39

5.27

-----

7.72

6.70

6.84

-

Per sq. m

- 5.43

5.49

4.83

4.72

- - . - -

4.95

-_--

4.32

5.14

PER J . WISING.

; ~1 :: 1 a,.,

i F =gJ;

27 35 ?

Average venti- lation in lit. per min. red.

Alveolar t o OO.760 mm CO,-tension dry air in mm Hg -

Tota

28 33 ?

Hepatome- galia

Anaemia sec.

29 69 ?

30 88 2.2 mill. 84

30 43 ?

-

Neoplasma coli asc. c.

Anaemia sec.

Achylia

145 1 70 gastrica, 3.2 mill. 86

Anaemia sec.

30 88 2.8 mill. 92

Hepatome- 1 25 1 104 galia 1.16 mill. 102

Anaemia sec.

Myomata uteri c.

Anaemia sec.

45 58 3.8 miII. 58

113 32 35 34 35

7.61

I I

122 29 29 29

M = 29

119

123 123

_ - _ _

103

_ - _ _

103

9.05

34 35 I 6.65 35

M = 35 35 I 25 26

25 M = 26

26

27 28 29

M = 28

-

- - - - _ - - - - -

25 26

25 M = 26

26

27 28 29

M = 28

-

. - - - _ - - - - -

5.89 5.89

7.81 7.81

- Per

rq. m. - 4.70

6.16

_---

5.00

4.27

4.57

Results. The tables below give the results of these experiments. In

Table IV the anemia cases show a somewhat higher ventilation than the control material. The difference is 2.7 times the mean error. The CO, alveolar tension, which Haldane maintains is a more sensitive indicator of the degree of ventilation, is considerably lower in the anemia patients than in the controls. The difference is equal t o about 9 times the mean error. This decrease can be demonstrated in each case of anemia independetly of the genesis and seems to be roughly proportional t o the degree of the anemia.

VENTILATION I N ESSENTIAL HYPERTENSION A N D I N A N E M I A . 167

Controls: (Cases 1-8) .....................

Tabel IV. Average ventilation per sq.m. per min. of the present material.

Medium (M) Stand. Deviation (d)

4.34 f 0.19 0.51 f 0.13

(Cases 19-30). Anaemias: I ' 4.97 f 0.15 .................

~~~

Dtfterence: MAnaemias - Mcontrols =0.63 f 0.24

0.51 & 0.11

Controls: (43 determin. in 8 pat.) ........ Essential Hypertonia:

---

(54 determin. in 10 pat.). .......

(51 determin. in 12 pat.). ....... Anaemias:

A remarkable feature on the spirometer curves of two anemia cases (Nr. 21 and 28) was the occurrence of periodic breathing, in one case mild, and in the other rather pronounced in type, in spite of the fact that a high percentage of oxygen was being administered The phenomenon of periodic breathing was first described by Hal- dane and Priestley as a characteristic of diminished oxygen supply.

This series of experiments thus shows that patients with anemia have a hyperventilation, demonstrable even on the administration of a high percentage of oxygen, and accompanied by a corresponding fall in the CO, alveolar tension. This hyperventilation explains the well known alkalosis of the blood in anemia as being of the same type as that of other b)anoxics conditions. Its persistence

Medium ( M ) Stand. Deviation (d)

38.4 f 0.5 3.0 f 0.3

39.8 f 0.5 1 - 3.3 f 0.3

32.4 f 0.5 3.59 f 0.4

168 PER .I. WISING.

in spite of the alkalosis, when taken along with the observation of Heymans, Euler, Liljestrand and others that sthe stimulating effect of oxygen want on respiration was found to disappear after denervation of both carotid sinuses,, makes it probable that the anemic hyperventilation arises through a carotid sinus reflex on the basis of the relative oxygen want in the anemic blood (the ,anemic anoxia)) of Peters and van Slyke). The tendency of anemic patients toward emphysema thus acquires a natural explanation.

The blood pressure in cases with hypertension showed no influence on the respiration as far as a change in the CO, alveolar tension was concerned (Tables 11 and V). The difference between the CO, alveolar tension in the 10 hypertensive patients and the controls was only twice the mean error and therefore not statisti- cally significant. The assumption of Moissejeff, Heymans and Bouckaert and others of the endosinusal pressure per se eliciting a reflex control of the respiration does not get any further support by the above results. They are, however, quite in harmony with the opinion of Euler and Liljestrand, attributing the action of decreasing endosinusal pressure to local anoxaemia and carbon dioxide accumulation in the glomus.

The tendency to tachycardia in essential hypertension, as pointed out by Mannaberg and Mies, is also shown very well in Table I1 as is the proneness toward elevated basal metabolism in a number of such cases.

Summary :

1) Ventilation and alveolar carbon dioxide tension have been investigated in 12 cases of anemia of various origin, as well as in 8 control cases. In addition 10 cases of essential hypertension were investigated with respect to alveolar carbon dioxide.

2) The average ventilation of the 12 cases of anemia (5.0 lit. per sq.m. per min.) was somewhat higher than that of the 8 controls (4.3 lit. per sq.m. per min.). The difference equalled to 2.7 times the mean error. The alveolar carbon dioxide tension of the anemic patients was found to be lower than that of the control cases (32.4 and 38.4 mm Hg, respectively), the difference being nearly 9 times the mean error.

VENTILATION I N ESSENTIAL H Y P E R T E N S I O N A N D IN A N E M I A . 169

3) Though in all experiments a high percentage of oxygen was administered one of the anemic patients showed a slight, another a pronounced periodical breathing, a phenomenon described by Haldane and Priestley as characteristic of oxygen lack.

4) The hyperventilation observed in anemic subjects seems to be undependarit of the origin of the anemic condition. I t is in harmony with that observed in other oanoxic, conditions. Most certainly it accounts for the alkalosis of these patients. Con- sidering known facts, i t may be assumed to be due to an ,anoxemic$ carotid sinus (glomus) reflex.

5) The alveolar carbon dioxide tension of 10 cases of essential1 hypertension showed no significative difference from tha t of the control material (1.4 f. 0.7). The assumption of Moissejeff, Heymans and Bouckaert and others of the endosinusal pressure per se eliciting a reflex control of the respiration does not get any further support by the authors results. These are, however, quite in harmony with the opinion of Euler and Liljestrand, attributing the action of decreasing endosinusal pressure to local anoxemia and carbon dioxide accumulation in the glomus.

References.

Barr, D. P. & Peters, J. P.: J. Biol. Chem.; 45: 571, 1920-21. Bie- ling, R.: Biochem. Zschr., 60: 421, 1914. Dautrebande, L.: Cpt R. de la SOC. de Biol., 93: 1031, 1925. Evans, C. L.: Brit. J. Exp. Path., 2: 105, 1921. v. Euler, U. S. & Liljestrand, G.: Skand. Arch. Physiol., 1936. Haldane, J. S. & Priestley, J. G.: Respiration, Oxford 1935 (Clarendon). Heymans, C. & Bouckaert, J. J.: J. Physiol. 69: 254, 1930. Heymans, C., Bouckaert, J. J. & Regniers, P.: Le Sinus Carotidien. Paris 1933 (G. Doin & Ce) . Holmgren, I.: Personal communication. Kylin, E.: Die Hyper-, tonikrankheiten, Berlin, Springer, 1926. Kraus: Ztschr. f. klin. Med., 22, 449. Liljestrand, G.: Handbuch der normalen und pathologischen Phy- siologi. Means, J. H., Bock, A. V. & Woodwell, M. N.: J. Experim. Med., 33: 201, 1921. Peters, J. P. Jr: cit. Means, Bock & Woodwell, J. Experim. Med. 33: 201, 1921. Peters, J. P. &van Slyke, D. D.: Quantitative Clinical Chemistry, London, 1931. (Baillibre, Tindall & Cox). Zotterman, Y.: Skand. Arch. Physiol. 72: 73, 1935.

Band 11, 1925, Abt. ,Physiologi der Blutgase,.