Lymphœdema: The case for doubt

LYMPH(EDEMA:

THE CASE FOR DOUBT

By JAMESCALNAN,M.R.C.P., F.R.C.S. Reader in Plastic and Reconstructive Surgery, Royal Postgraduate Medical School (University of London), DuCane Road, London, W. 12 ALTHOUGH the anatomical distribution of the lymphatics had been known since the days of Mascagni (I787), Cruikshank (I79O), Teichmann (I86I) and Poirier (189o), their function and clinical significance were not appreciated. Similarly it was not until the end of the nineteenth century that lymphoedema was distinguished from other forms of swollen leg, such as that due to deep vein thrombosis. Allen (1934) introduced a classification of lymphoedema which is still in current use, dividing it into primary and secondary. Primary lymphoedema was further divided into congenital (Nonne, 1891 ; Milroy, x892), prmcox (the usual time of onset) and tarda (that of late onset). Allen, Barker and Hines (I946) suggested, moreover, that when the cause is found there will " b e some congenital abnormality of the lymphatics " But it was not until 1957 that Kinmonth and his colleagues were able to show the state of the lymphatics in this condition. Using the technique of lymphangiography introduced by Kinmonth in I957, they described the findings in lO7 patients with lymphoedema. They noted that 55 per cent. had hypoplastic, 24 per cent. varicose and I4 per cent. aplastic lymphatics : dermal back-flow was the only abnormality in 6 per cent. and was noted in x2 per cent. of the whole series. They concluded from this that the condition of lymphoedema could be explained by the evidence of abnormal lymphatics that they had demonstrated. Since that time several papers have supported these findings (Crockett, I965; Gough, I966 ; Larson et al., 1966). Indeed it is now tacitly assumed that in l y m p h ~edema the lymphatics are always abnormal and that they are the cause of lymphoedema. This is a most dangerous assumption. The idea that lymphoedema is caused by the abnormal lymphatics, either hypoplastic, varicose or aplastic, I have called the classical concept. In the past three years evidence has accumulated to make one conclude that there are grounds for serious doubt. The real weaknesses of the classical conception arise not from its being untrue, but from its professing to be the whole truth. I shall attempt to show by discussion and analysis of the following nine observations how far it falls short of being true. I. The Age o f O n s e t . - - T h e onset of swelling occurs spontaneously and may affect one leg only as in 7o per cent. of Allen's cases (1934). Lymphoedema pra~cox so often begins during puberty and adolescence that one begins to suspect that fundamental changes in physiology must occur at this time. This is indeed so, but none of them appears pertinent to the lymphatic system. It is therefore difficult to understand why a single hypoplastic lymphatic trunk which has served for the efficient return of lymph for 15 to 20 years begins to fail in its job without any obvious cause. Still more difficult to understand is the case of the much older woman who has successfully passed adolescence, pregnancies, and a very active life of sport before lymphoedema appears.

Case Report.--Mrs P. D., aged 43 (H. H. 288989), always had a tendency to swelling of the ankles after exercise. Three years ago the left ankle suddenly became swollen and slowly increased to involve all the lower leg. It was worse in hot weather but did regress completely 32

LYMPHCEDEMA:

THE

CASE FOR D O U B T

33

Fig. i.--Housewife, 43, with lymphoedema left leg of three years' duration. Fig. 2.--A, Lymphogram of lower legs of Figure i. Note the tortuous hypoplastic lymphatics (arrows). B, Lymphogram of thighs of Figure I. Note the solitary vessels in each leg (arrows).

FIG. I

A

IC

FIG. 2

B

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on rest in bed. During both pregnancies there was no increase in the swelling and she had played tennis several times a week until recently (Fig. i). For the last year there had also been some swelling of the right leg. When she had influenza and was in bed for three weeks, both legs became normal. On examination the ~edema was pitting to above the knee. The plasma proteins were 6"9 g. per cent. (albumin 3"4 g. per cent., globulin 3"5 g. per cent.). A left femoral venogram showed no obstruction to the great veins, but lymphography demonstrated a single large lymphatic trunk in both thighs. Pelvic lymph nodes appeared normal (Fig. 2, n and B). II. F e m a l e D o m i n a n c e . - - I n all published series the dominance of female patients is particularly striking. Table I summarises the findings from four series in which details of sex were recorded. Admittedly there are diseases for which the sexes are not evenly distributed, but few show such a marked difference. The classical concept of lymphoedema does not account for this difference. III. S i d e . - - N o t all publications include the detail of which leg was affected, but in those which do there is a notably high proportion in which the left leg is affected (Table I). In our own series, in 80 per cent. of patients the left leg was lymphoedematous (which includes those that were bilateral) and in 66 per cent. one leg only was affected, the majority being of the left side.

TABLE I Lymphoedema Prdcox Total Cases

Females

Only one Side affected

len, Barker and Hines (I946)

93

87%

70%

6 5 % a t 9-25 years

inmonth, Taylor, Trace and Marsh (I957)

95

74%

47%

80% less than 35 years

firger, Harrison and Janes (I962)

I23

9i%

tlnan and Pentecost (I965)

52

88%

Authors

66%

Left Side affected

Age of onset

50%

90% less than 3 ° years

80%

I9"6 years

Intrigued by the high proportion of patients with lymphoedema of the left leg, the great veins in the pelvis were examined. The left common iliac vein is crossed by the right common iliac artery opposite the body of the fifth lumbar vertebra. It is therefore possible that the vein, which drains virtually all the blood from a leg, could be compressed between artery and bone. This indeed seemed to be the case (Calnan et al., I962). In a series of z 3 consecutive patients examined, evidence of obstruction to the left common iliac vein was found in II (Calnan et al., I964). Obstruction was assessed by femoral venography (Fig. 3, A and B) pressure gradient in the common iliac vein at the site of obstruction, and by laparotomy with direct observation in three patients (Fig. 4, A and B). These observations, while unexpected and of great interest, may explain the increased incidence of lymphoedema of the left leg, but they offer no explanation for swelling of the right leg, and hence do not define the cause of lymphoedema.

LYMPH(XDEMA: THE CASE FOR DOUBT

A FIG. 3 B A, Left femoral venogram in 25-year-old female, with lymphoedema of the left leg of seven years' duration. Note the catheter (arrow) and good outline of the left common iliac vein which is cut off sharply at the site of crossing of the right common iliac artery (double arrows). B, Venogram as in Figure 3, A but view during valsalva manoeuvre. The contrast material has filled the right common iliac vein (arrow) from the multiple collaterals in the pelvis (double arrows).

A Fla. 4 B A, Condition of left common iliac vein in patient in Figure 3, A and B at laparotomy. The right common iliac artery (A) is compressing the left common iliac vein (V) near its junction with the inferior vena cava (I.V.C.). B, Depression in left common iliac vein (V) due to right common iliac artery (A) now seen, from Figure 4, A, when artery is distracted.

35

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Fig. 5---Female, 25, with seven-year history of left leg lymphoedema. Note general swelling of the calf and ankle. This patient's 7enograms are seen in Figure 3, a and B, and the condition of the left common iliac vein at laparotomy in Figure 4, A and B. Fig. 6.--A, Left leg lymphogram of patient in Figure 5. Note numerous lymphatic trunks which are not tortuous. B, Lymphogram of left thigh. C, Lymphogram of pelvis. Note normal arrangement of lymph nodes.

Fro. 5

FIG. 6

LYMPH(EDEMA:

THE CASE FOR DOUBT

37

IV. Normal Lymphatics in Clinical Lymphcedema. Case Report.--B. P., a female aged 25, had a seven-year history of swelling of the left leg only. The onset was slow and at first only affected the ankle. Six years ago she had an operation on the left knee for removal of a torn cartilage : the swelling disappeared on rest in bed but recurred as soon as walking was started. At this time she was told that the other leg would also swell later and was given an elastic stocking, which did not help. Five years ago the swelling had extended almost to the groin (Fig. 5) and in I962 venous flow studies using an indicator dilution technique (ShiUingford, Bruce and Gabe, x962) were carried out. The blood flow in the inferior vena cava low down was 900 ml./minute and the flow from the right common iliac vein was 80o ml./minute. It was not possible to cannulate the left common iliac vein from above and so confirm the deduction that only ioo ml./min, of blood came from that side, but at laparotomy the right common iliac vein was found to be compressing the vein very effectively. Venography demonstrated collateral vessels in the pelvis, emptying into the right common iliac vein (Fig. 3). More importantly, lymphography showed a normal pattern of lymphatics of the left leg (Fig. 6, A, S and c). She was married three years ago and has had one child and is expecting another. The right leg shows no swelling and the left leg has become no worse. Now, one may argue that because the lymphatics were normal this was not lymphcedema, but this is a specious argument because clinically the condition was lymphoedema. In other patients with normal lymphatics there has been no evidence of venous obstruction, and in several with hypoplastic lymphatics there has been evidence of venous obstruction. T h e relationship of the various states of these vessels do not therefore correlate well. V. Abnormal Lymphatics in Normal L i m b . - - I n a service which carries out lymphography for a variety of diseases, patients with hypoplastic lymphatics are seen occasionally who have never suffered from swelling of the leg. Figure 7 (A, B and c) includes a clinical photograph of a 69-year-old man with extremely thin legs. He had a carcinoma of the prostate and the lymphogram shows a few hypoplastic lymphatic trunks travelling the length of the limb, which can also be seen in the clinical photograph. Now if hypoplasia of a lymphatic is the cause of lymphcedema, the classical concept is unable to explain why this patient did not suffer from clinical lymph~edema. VI. The Post-mastectomy A r m . - - A t the time of radical mastectomy, when all the lymphatic trunks from the arm and the axillary nodes are on view, it is very unusual for a surgeon to leave lymphatic tissue behind. There is therefore complete destruction of the lymphatic pathways in the axilla, and one would perhaps expect lymphoedema to follow. Yet in more than 8o per cent. of patients there is minimal or no swelling. Table II summarises the findings from several publications representing the assessment of over I,OOO operations. In those patients who do suffer oedema of the arm, the onset occurs more often after a lapse of years rather than immediately after operation. Indeed, in the older literature it is frequently stated that the onset of late oedema indicates recurrent turnout in the axilla, but modern experience would not agree. T h e interest is not so m u c h in those who suffer ~edema but in those who do not, after loss of the total lymphatic pathway from the arm. VII. Experimental Production of L y m p h o e d e m a . - - W h e n the condition of obstruction of the common iliac vein seen in some patients with lymphcedema (Calnan

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A

13

C FIG. 7 A, Clinical photograph of left lower leg of 69-year-old male with carcinoma of prostate. Note lack of oedema, and the outline of a lymphatic filled with oil during lymphography and easily seen through the skin. B, Lymphogram of lower legs. Lymphatics are tortuous and hypoplastic. C, Lymphogram of thighs. Note fewer than normal lymphatic trunks.

LYMPH(EDEMA: THE CASE FOR DOUBT

39

TABLE II Gross Swelling o f the A r m after Radical M a s t e c t o m y

Authors

Year

Patients

Gross Swelling noted

Holman, McSwain and Seal Nicolson and Grady Daland Fitts, Keuhnelian, Ravdin and Schorr Villasor and Lewison West and Ellison Nias Tracy, Reeves, FitzSimons and Rundle

z944 I948 z95o I954

IO0

II

23O 90 130

7 7 7

z955 I959 z96o

79

25

I04

Io

253

I96I

Z06

20 I2

No. of

et al., x964) was duplicated experimentally in dogs, chronic cedema did not occur (Calnan and Kountz, z965). After complete obstruction of lymphatics by ligature in dogs, chronic 0edema did not occur although the obstruction could be demonstrated by lymphography (Burn et al., I966) and by the failure to clear albumin from a peripheral lymphatic trunk. Later, however, there was good evidence that spontaneous artificial lympho-venous anastomoses had occurred and these perhaps maintained the return from the limb (Pentecost et al., I966). The earlier experiments of Homans, Drinker and Field (I934) in which particles of silica were injected repeatedly into lymphatic trunks did produce limb oedema in some dogs but it took a long time to appear and the amount of trauma was considerable. Such chronic oedema is sometimes seen in patients who have had repeated attacks of thrombophlebitis over a number of years, and this condition is clearly different from that of lymphoedema prmcox.

VIH. Evidence for an Acquired Origin.--In many of the reported series of cases of lymphoedema the suggestion is made that the condition is congenital in origin (Allen, Barker and Hines, I946). In the series reported by Kinmonth et al. (I957) I8 (I7 per cent.) gave a family history and eight of them knew of two or more members of their family affected, but these were not examined. In addition to the low incidence of a family history in this condition, there is other evidence against the idea that it may be of congenital origin : I. It is eight times more common in women than men, yet if congenital one would expect the sex incidence to be nearly equal. 2. In lymphoedema prmcox the highest incidence of onset occurs at about z5 years whereas if congenital one would expect the onset to occur earlier and have a much wider range. 3- There is rarely more than one person in a family affected, whereas if of congenital origin more than one in a large family could be expected to suffer from lymphoedema in a fair percentage of instances. 4. It rarely occurs with other congenital defects. Although Boyd (I95O) and Aird (I95O) both recorded other vascular defects in patients with lymphoedema, these have not been noted by others and certainly are not a feature of the condition.

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IX. S o m e Unexplained Curiosities.--1. Watson (I953) noted that when a lymphoedematous limb was emptied--by a combination of compression, elevation and rest in bed--this was a slow process which often took several weeks. When however the patient resumed normal activities the limb could fill up again with oedema fluid within a matter of hours. The difference between the rate of emptying and refilling could not easily be explained by a purely lymphatic pathology. Conversely, in one of our own patients investigated by pelvic venography, 1,5oo ml. of fluid (measured by water displacement tank) were lost from the swollen right leg overnight. Next morning the exhausted patient was able to pick up the skin of the leg in folds, but the limb resumed its former firm contours over a period of three days. 2. In our own series (Calnan and Pentecost, I965) of patients with lymph~edema we have three who have maintained their legs completely free from swelling for IO to I4 years on intermittent courses of diuretics. In all, the lymphograms showed a single lymphatic trunk in the lower leg and thigh (similar to Fig. 2), and all had troublesome oedema of the feet for several months after oil contrast lymphography. It would seem that in some patients diuretics may have a true lymphogogue effect since removal of water without its protein from swollen tissues can only produce temporary benefit (Cattel, Taylor and Aitken, I965). 3. If, as Taylor, Kinmonth and Dangerfield (I958) suggest, it is the high protein content of the oedematous tissue fluid which maintains the oedema, then some simple calculations raise further issues. The volume of a swollen leg is commonly 2,ooo ml. in excess of its fellow and the oedema fluid may contain 5 per cent. of protein, so that we may presume that there are IOO g. plasma protein stored in that limb. But we also know that the total plasma albumin leaves the circulation every z4 hours to be returned by the lymphatic system (Mayerson, I963), and that a leg contains about one-sixth of the total blood volume. Hence the loss of albumin from the circulation in the capillaries of the leg in 24 hours , --6--!×5,000 (blood volume)×1~o (plasma protein per cent. grams=58. 3 g., which is about half of what the limb contains after perhaps one year ] Hence it must be obvious that while the transfer of protein from blood capillary to lymphatic is going on the whole time only a minute percentage of this remains in a lymphoedematous leg, the vast majority being returned to the circulation either by lymphatics or by some other mechanism. What are the Possible Causes o f Lymphoedema ?--Before answering this question, it is necessary to examine critically our knowledge of the physiology of lymph. At the end of the last century Starling (I894, I895, I896, I9O9) published the results of his extensive studies on the exchange of fluid between plasma and lymph. A fundamental assumption of his concept was that large protein molecules do not pass readily through the capillary membrane. Starling's hypothesis stated that the exchange of fluid between capillaries and interstitial space was governed by the relation between the oncotic pressure of the plasma proteins (which held fluid within the capillary) and the blood pressure. The difference between the two he called t h e " filtration pressure ", and this is shown diagrammatically in Figure 8. In his concept, Starling looked upon the lymphatics as an overflow conduit system which acted as a safety valve when the circulation was overloaded. Drinker (I946) challenged the assumption of Starling and believed that protein was continuously filtering out of the blood, and that the plasma protein level was maintained solely by an efficient return of lymph. Unfortunately Drinker was unable to show that the protein in lymph did not originate from the tissue spaces. But in I95I Wasserman and Mayerson using albumin labelled with I TM were finally able to demonstrate quite dearly

LYMPH(EDEMA:

41

THE CASE FOR DOUBT

that plasma proteins do leak from capillaries and that the daily turn-over is more than 5o per cent. of the total plasma blood volume (Fig. 9). Mayerson (1963) later accurately measured this loss of albumin from the circulation in dogs and found that onethousandth part of the total leaked from capillaries each minute, and that this figure increased significantly in hmmorrhage and after large saline infusions.

I]RINKER'SVIEW

STARLING'S VIEW

CAPILLARY

LYMPHATIC

Arteria[ ! ~ end B.P

CAPILLARY

LYMPHATIC

Arteria[ ~ e n d

e~-I

'

Protein' I Venous end

Protein •

! Venous end FIG. 8

CAPILLARY Arteriat end

FIG. 9

LYMPHATIC

•

/~

•

/X

Fig. 8.--Diagram to illustrate Starling's theory of capillary protein loss and recovery. Fig. 9.~Diagram to illustrate Drinker's theory of capillary protein loss and recovery. Fig. Io.--Diagram to illustrate possible causes of lymph~edema (see text).

o_ Venous end

BP- . ~ O ~

L .. FIG. IO

We may conclude then from this evidence that albumin does leak continuously and in large amounts from the circulation. Since it cannot be re-adsorbed by the capillaries it must depend entirely on the lymphatic system for its return. We may now consider the possible causes of failure to return lymph efficiently. They are, as shown diagrammatically in Figure IO : I. Higher pressure in the capillary bed due either to increased arterial pressure or to high venous back pressure. There is no evidence to suggest that patients with lymph~edema are hypertensive and in our series none were. However, there were an appreciable number with venous obstruction in the pelvis so that there could have been venous back pressure in the capillary bed, if not at rest then certainly during exercise. This venous effect may account for a proportion of patients with idiopathic lymphoedema. 2. Excessive leakage through the capillary wall, or increased capillary permeability.

42

BRITISH

JOURNAL

OF

PLASTIC

SURGERY

Kirk (I964) measured the capillary filtration rates in normal and lymphmdematous legs, and concluded that there was no difference. 3. Albumin may be slow to cross the tissue space between capillary and lymphatic. 4. Albumin adsorption by the lymphatic may be slower than normal. 5. Albumin once it is in the lymphatic may leak out again. There is no evidence to confirm or refute 3, 4 or 5. 6. The lymphatic valves are incompetent.

..-* M.FI. ., ,°°° c

E

Injection I m H S A 8# C.

," ..,"

i

..'""

•

'"'"

. . . . . . . . . . ,o'"

o" ' " ' " " " ' ' " " " g o20 ',o

30

""'so ;o'

i

130 I

TIME in minutes FIG. II~ A

'

G r a p h i n t w o p a t i e n t s o f increase in s y s t e m i c b l o o d r a d i o a c t i v i t y after i n f u s i o n o f o. 3 m l . o f 1131 h u m a n s e r u m a l b u m i n into foot l y m p h a t i c t r u n k f o l l o w e d b y saline at o'5 rnl. p e r m i n u t e for IO m i n u t e s . N o t e t h e increase in r a d i o a c t i v i t y w h i c h starts xo to 2o m i n u t e s after infusion~ d u e to t h e p a s s i n g o f t h e a l b u m i n f r o m t h e t h o r a c i c d u c t to the b l o o d stream.

E

Injection li31 H SA 5# C.

E F-z 0

I

0

I

I

1

I

i

I0

I

i

I

i

I

i

I

I

I

20

I

i

I

30

I

1

I HI I

40"

60

I

I

80

I

I

I00

I

I

I

120

TIME in minutes FIG. II~ B

R e s u l t s o f the s a m e p r o c e d u r e as i n F i g u r e IZ, A i n a p a t i e n t w i t h l y m p h o e d e m a o f t h e leg. N o t e t h e v e r y s m a l l radioactivity w h i c h b e g i n s a b o u t 9 ° m i n u t e s later.

This has been suggested by several authors in the past (Malek, Belan and Kocandrle, I964) on the analogy that incompetent valves in veins lead to local stagnation of blood, but the two systems are by no means comparable. It is still not clear why lymph moves in lymphatic trunks of the limb. The multiplicity of valves in any one segment suggests that an oncotic mechanism could move lymph : if albumin was selectively taken into a lymphatic its presence would tend to draw water into that section, thereby increasing its volume, which could then only be accommodated by moving proximally (the valves preventing it from flowing distally). 7. The flow in lymphatic trunks is slow.

LYMPH(EDEMA:

THE CASE FOR DOUBT

43

If one places a bolus of I131-albumin of about o.2 5 ml. into a lymphatic trunk on the dorsum of the foot, and infuses saline at o'5 ml./minute to push the bolus proximally, one can expect to find radioactivity in blood (due to the albumin being emptied from

Injection

I i3i H S A

~.W

8# C

E t/3 l-Z 0 (J

I 0

10

I

i

t

20

I 30

i

I

t

I

i I~

40

1 50

] 60

TIME in minutes FIG. I I , C Compare the graph of the same procedure as in Figure I I , A in a patient with metastatic carcinoma in the lymph nodes of the pelvis. T h e increase in radioactivity in systemic blood occurs almost immediately after intralymphatic infusion, indicating a lymphovenous communication. There was no clinical oedema of the limb.

the thoracic duct into the circulation) after 20 minutes (Fig. I I). In a dozen patients with lymphoedema there was always a gross delay and in several radioactivity did not appear in blood for some hours. This is fair evidence of a defect in the transport of lymph. SUMMARY In a philosophical manner, the current concept of the mtiology of lymphoedema has been examined and its weaknesses enumerated and discussed. Alternative proposals have been presented and lines for future research indicated. REFERENCES AIRD, I. (1950). Proc. R. Soc. Med., 43, 1052ALLEN, E. V. (1934). Archs intern. Med., 54, 606. ALLEN, E. V., BARKER, N. W., and HINES, R. A. (1946). " Peripheral Vascular Diseases." Philadephia : Saunders. BOYD, A. M. (195o). Proc. R. Soc. Med., 43, lO45. BURN, J. I., RIVERO, O. R., PENTECOST, B. L., and CALNAN, J. S. (1966). Br.ff. Surg., 53, 634. CALNAN, J. S., MENZlES, T., PENTECOST, B. L., SHILLINGFORD, J. P., and STEINER, R. E. (1962). Lancet, 2, 537-

44

BRITISH JOURNAL OF PLASTIC SURGERY CALNAN, J. S., KOUNTZ, S., PENTECOST, B. L., SHILLINGFORD,J. P., and STEINER, R. E. (1964). Br. reed. J., 2, 221. CALNAN, J. S., and PENTECOST,B. L. (I965). Personal series, to be published. CALNAN, J. S., and KOUNTZ, S. L. (1965). Br. J. Surg., 52, 800. CATTELL, W. R., TAYLOR, G. W., and AITKEN, D. (1965). Lancet, 2, 312. CROCKETT, D. J. (1965). Br. J. plast. Surg., 18, 12. DALAND, E. M. (1950). New Engl. J. Med.. 242, 497. DRINKER, C. K. (1946). Ann. N . Y . Acad. Sci., 46, 8o7. FITTS, W. T., KEUHNELIAN,J. G., RAVDIN, I. S., and SCHORR,S. (1954). Surgery, 351,460. GOUGH, M. H. (1966). Br. 37. Surg., 53, 917 • HOLMAN, C., McSwAIN, B., and BEAL, J. M. (1944). Surgery, 15, 757. HOMANS, J., DRINKER, C. K., and FIELD, i . (1934). Ann. Surg., IOO, 182. HUGHES, J. H., and PATEL, A. R. (1966). Br. 37. Surg., 53, 4. KINMONTH, J. B., TAYLOR, G. W., TRACY, G. D., and MARSH, J. D. (1957). Br. 37. Surg., 45, I. KIRK, R. M. (1964). Clin. Sci., 27, 363 • LARSON, D. L., COERS, C. R., DOYLE, J. E., RAPPERPORT, A. S., KLOEHN, R., and LEwIs, S. R. (1966). Plastic reconstr, surg., 38, 293. MALEK, P., BELAN, A., and KOCANDRLE,V. L. (1964). 37. Cardiovasc. Surg., 5, 686. MAYERSON, S . S. (1963). Surgery Gynec. Obstet., I I 6 , 259. MILROY, W. F. (1892). N . Y . Med. 37., 56, 5o5. ~IIAS, A. H. W. (196o). Br. med. 37., I, lOO5. NICOLSON, W. P., and GRADY, E. D. (1948). Ann. Surg., 127, 992. NONNE, M. (1891). Virchows Arch. path. Anat. Physiol., 125, 189. PENTECOST,B. L., BURN, J. I., DAVIES,A. J., and CALNAN,J. S. (1966). Br.37. Surg., 53, 63 o. SHILLINGFORD,J., BRUCE, T., and GABE, I. (1962). Br. Heart 37., 24, 157. SHIRGER, A., HARRISON,E. G., and JANES, J. M. (1962)2 37. Am. med. Ass., 182, 14. STARLING, E. H. (1894). 37. Physiol. (Lond.), 16, 224. -(1895). 37. Physiol. (Lond.), 17, 30. (1896). dT. Physiol. (Lond.)., I9, 312. -(19o9). " Fluids of the Body." London : Constable. TRACY, G. D., REEVE,T. S., FITZSIMONS,E., and RUNDLE,E. F. (1961). Aust. N.Z. 37. Surg.j 3o, 2o4. TAYLOR, G. W., KINMONTH, J. B., and DANGERFIELD,W. G. (1958). Br. Med. 37., 2, 1159. VILLASOR,R. P., and LEWlSON, E. F. (1955)- Surgery, Gynec. Obstet., ROD,743. WASSERMAN,K., and MAYERSON,H. S. (1951). Am. J. Physiol., I65, 15. WATSON, J. (1953). Br. 37. Surg., 4 I, 31. WEST, J. P., and ELLISON, J. B. (1959). Surgery Gynec. Obstet., 1o9, 359.