211

Int. J. Biometeor. 1974, vol. 18, number 3, pp. 211-221

Changes in Plasma Cortisol, Blood Antidiuretic Hormone and Urinary Catecholamines in High.Altitude

Pulmonary Oedema

by Inder Singh*, M.S. Malhotra, P.K. Khanna, R.B. Nanda, T. Purshottam,

T.N. Upadhyay, U. Radhakrishnan and H.D. Brahmachari

INTRODUCTION

Because of our commitments in the Himalayan border, our troops shuttle frequently between sea level and 5,500 m. Hence high-altitude pulmonary oedema (HAPO) is a constant problem with us (Singh et a l , , 1965). Its causation is a modt point and several mechanisms have been postulated. There is a shift of blood from the periphery to the lungs (Wood and Roy, 1970) with dilatation of the pulmo- nary a r te r io les (Cross, 1965) which allows capil lary flow to increase . Widespread sludging of RBC and formation of thrombi within the alveolar capi l lar ies and the venules impede the blood flow at the capil lary and venular levels (Singh et a l . , 1965; Singh and Chohan, 1972). There is also an increase in the capi l lary per - meabili ty of a degree which allows even la rger molecules of fibrinogen and RBC to pass through (Viswanathaa et a l . , 1969). Further, in HAPO there is always acute pulmonary hypertension and, experimentally, acute pulmonary hypertension associated with a r te r io la r constriction has been shown to lead to t r ansa r t e r i a l leakage (Severinghaus, 1971). However, of great pract ical significance has been the fact that there is definite t ime-lag, which ranges from 6 to 96 h, between ar r iva l at high altitude and onset of symptoms. During this t ime- lag and during the il lness, predisposed patients suffer f rom ant i-diuresis , whereas res is tant individuals pass urine freely. Improvement is preceded by diuresis which con- tinues for 2-10 days after recovery (Singh et al . , 1965, 1969). Diuresis induced with furosemide very quickly re l ieves the patient of his symptoms and singns, and is highly effective in the prevention of the i l lness as well (Singh, 1967, 1969). We have previously postulated that antidiuresis probably resul ts f rom a disturbed equilibrium between antidiuretic hormone (ADH) and the adrenal steroids or ACTH (Singh et a l . , 1965, 1969). Further, there is a possibil i ty that changes in the cateeholamines secret ion may also affect diuresis (Hayashi, Moss and Yu, 1969). We have now studied this problem as far as ACTH, ADH and cgtechol- amines mgtter and the resul ts are presented and discussed in this paper.

MATERIAL AND METHODS

The maximum incidence of HAPO which we have reported under war conditions was 155%o of soldiers inducted to high altitude (Singh et a l . , 1965). In peace time, however, the incidence seldom exceeds 3.5%o. Observations on HAPO are the re - fore difficult to make on small experimental models. Hence, we selected 10 male volunteers, 20-30 years old, who were known susceptibles, having suffered from HAPO 3 to 4 months pr ior to this t r ia l . They had been suitably treated, evacuated to sea level, and were normal. We hoped that on reinduc:tion to high altitude some of them would get HAPO and provide the requisi te mater ia l for investigation and observation.

*) Defence Institute of Physiology and Allied Sciences, Delhi Cantt. 110010, India. Received 26 October 1973

212

The Obse rva t ions w e r e m a d e at Delhi (200 m) and at Leh (3 ,500 m) u n d e r iden- t i c a l cond i t ions of bed r e s t , diet , and f lu id in take . The da i ly d ie t p rov ided 4000 keal , 2 .90 1 of f luid wh ich inc luded the d i e t a r y w a t e r , and 12 g of NaC1. At Delhi, a f t e r the s u b j e c t s w e r e s t a b i l i s e d on t h i s d ie t fo r 7 days, b a s i c i nves t i ga t i ons which inc luded c h e s t X - r a y s , 2 4 - h u r i n a r y volume, p l a s m a e o r t i s o l and ADH and 24 -h u r i n a r y c a t e c h o l a m i n e s w e r e made. The s u b j e c t s w e r e then f lown to Leh. They lef t Delhi a i r p o r t a t 10 :30 h on 17 N o v e m b e r 1972 and a r r i v e d at Leh at 12:30 h the s a m e day. They r e a c h e d the c e n t r a l l y h e a t e d l a b o r a t o r y at 15 : 00 h. Studies s t a r t e d on 18 N o v e m b e r (day 1) at 06 :00 h and con t inued s u b s e q u e n t l y on day 2, 3, 4 and 5. Venous b lood s a m p l e s w e r e co l l ec t ed fo r e o r t i s o l and ADH a n a l y s i s on days 1, 3 and 5, wh i l e 24 -h u r i n a r y output was r e c o r d e d on a l l days . P l a s m a c o r t i s o l and 24 -h u r i n a r y c a t e c h o l a m i n e s e s t i m a t i o n s w e r e done at the Leh l a b o r a t o r y whi l e d r i e d e x t r a c t s of ADH w e r e t a k e n to Delhi . P l a s m a c o r t i s o l was d e t e r m i n e d by the f l u o r i m e t r i c me thod of Van de Vies (1961), modi f ied to the ex ten t t ha t e o r t i s o l w as e x t r a e t e d f r o m p l a s m a wi th c h l o r o f o r m and the f l u o r e s - c e n c e was deve loped in3 : 7v/V e t h a n o l - s u l p h u r i c ac id m i x t u r e . ADH was a s s a y e d by t he me thod of Yosh ida et a l . (1963). U r i n a r y e a t e c h o l a m i n e s w e r e a d s o r b e d on a c t i v a t e d a l u m i n a by the m e t h o d of Anton and Sayre (1962) and t hen e lu ted into 0 .5 M p e r c h l o r i c ac id . The e lu ted e a t e c h o l a m i n e s w e r e e s t i m a t e d by the me thod of Sobel and Henry (1957). The sub j ec t s w e r e e x a m i n e d c l i n i c a l l y e v e r y m o r n i n g and X - r a y e d for ev idence of HAPO on a l t e r n a t e days .

RESULTS

The g e n e r a l p a r t i c u l a r s and c l in i ca l f e a t u r e s of the s u b j e c t s u n d e r s tudy a r e s u m m a r i s e d in T a b l e 1. Of the ten, 4 s u b j e e t s ( s e r i a l no 1 to 4) d id not su f fe r f r o m any i l l - e f f e c t s of h igh a l t i tude and have b e e n d e s i g n a t e d as c o n t r o l s . Fou r sub j ec t s ( s e r i a l no 5 to 8) su f f e r ed f r o m HAPO, s u b j e c t s 5 and 6 on day 1, and s u b j e c t s 7 and 8 on day 3, and have been d e s i g n a t e d as p a t i e n t s . Two sub j ee t s (9 and 10) su f f e red f r o m acu te moun ta in s i c k n e s s ( A M S ) .

TABLE 1. G e n e r a l da ta and c l in i ca l h i s t o r y of the s u b j e c t s {1972)

Subject no

1 2 3 4 5 6 7 8 9

10

Name Age

{years) Weight

(kg)

P r e v i o u s o c c u r r e n c e of HAPO

R e s p o n s e * on r e - e x p o s u r e to HA on 17 Nov.

Day of d i s e a s e at Leh 3 ,500 m

GST 25 56 .0 25 Aug. U - - SSS 32 75 .0 5 Ju ly U - - GS 32 70 .0 14 Ju ly U - - PS 35 63 .0 14 Aug. U - - RM 26 56 .0 18 Aug. HAPO 1 LPY 23 64 .0 21 Ju ly HAPO 1 KR 23 68 .0 14 Ju ly HAPO 3 CKS 24 66 .0 9 Aug. HAPO 3 VS 33 65 .0 6 Aug. AMS 1 SS 28 80 .0 9 Aug. AMS 1

*) U = HAPO = AMS =

Unaffected, High a l t i tude p u l m o n a r y oedema, Acute m o u n t a i n s i c k n e s s .

A n a l y s e s of da ta in r e s p e c t of eor~trols a r e g iven in Tab le 2. The 24-h u r i n a r y output a t Leh was not s ign i f i can t ly d i f f e ren t f r o m tha t a t Delhi . The m e a n va lues w e r e 1 .55 l a t D e l h i , and 1 .23, 1 .29, 1 .19 and 1 .24 l o n d a y s 1, 2, 3 a n d 4

213

r e s p e c t i v e l y a t Leh . The fluid in take was the s a m e on day 1 at Leh as a t Delh i but , due to d i m i n i s h e d t h i r s t , l e s s by 100 to 300 ml on the fo l lowing days 2-4 at Leh . The p l a s m a e o r t i s o l showed a s ign i f i can t r i s e , wh ich was m a x i m u m on day 1, in a l l c a s e s . The m e a n va lues for p l a s m a e o r t i s o l w e r e 16.4 ~ g / 1 0 0 ml at Delhi and 51 .3 U g /100 m l at Leh on day 1 which d ropped to 29 .5 u g /100 m l on day 4. T h e i r p l a s m a ADH did not show any s ign i f i can t change at Leh; t h e m e a n va lues v a r i e d be tween 1 .95 a t Delhi and 1 . 8 5 - 2 . 5 5 u U / m l at Leh . The u r i n a r y c a t e c h o l a m i n e s a l so did not show any s ign i f i can t change a t Leh and the m e a n v a l u e s v a r i e d be tween 65 .8 at Delhi and 5 1 . 5 - 7 9 . 8 u g / 2 4 h a t Leh.

TABLE 2. Mean (+SE) v a l u e s of f luid in take, u r i n e v o l u m e and h o r m o n e l e v e l s at s e a l eve l (SL) and on d i f f e r en t days of s t ay at a l t i tude of 3 ,500 m (HA) in control s u b j e c t s

P a r a m e t e r s SL Days at HA

2 3 4

3 .12 2 .95 3 . 0 0 2 .85 + 0 .06 + 0 .05 + 0 .01 + 0 .12

1 .23 1 .29 1 .19 1 .24 + 0 .16 + 0 .14 + 0 .14 + 0 .15

24 -h Flu id in take 3.. 16 (1) + 0 .01

24 -h Ur ine v o l u m e 1 .55 (1) + 0 .27

24-h U r i n e c a t e c h o l a m i n e s 65 .80

(ug) + 8 .50

P l a s m a c o r t i s o l 16 .40 ~g/100 ml) +_ 0 .62

P l a s m a ADH 1 .95 ~U/ml ) + 0 .26

51 .50 77 .30 74 .10 79 .80 +10.38 + 4 . 7 0 + 4 . 7 0 +20.29

5 1 . 3 0 " 38 .30 - - 29 .50* + 7 .46 + 4 .08 + 1 .93

1 .85 1 .92 - - 2 .55 + 0 .30 + 0 .27 + 0 .15

P

HA vs SL

NS

NS

NS

0 .05

NS

To b r i n g out the c o r r e l a t i o n be tween the c l in ica l p i c t u r e and the l a b o r a t o r y f indings , the indiv idual de t a i l s of the 4 pa t i en t s (no 5, 6, 7 and 8) who deve loped HAPO a r e s u m m a r i s e d below and t h e i r l a b o r a t o r y f ind ings at Delhi and at Leh a r e g iven in Tab le 3.

On day 1 morn ing , pa t i en t s no 5 and 6 had no s y m p t o m s . On c l in i ca l e x a m i n a t i o n P2 was loud. X - r a y c h e s t was nega t ive . At 18 : 00 h t hey w e r e s t i l l wel l and c h e e r - ful . At 22 :00 h, m o r e o r l e s s wi th d r a m a t i c suddenness , t hey woke up wi th pain and t i g h t n e s s in the ches t , b r e a t h l e s s n e s s and cough wi th f ro thy e x p e c t o r a t i o n . P u l s e and r e s p i r a t o r y r a t e s i n c r e a s e d , s y s t e m i c blood p r e s s u r e showed a s l i gh t fal l , and P2 was l o u d e r s t i l l . C r e p i t a t i o n s w e r e h e a r d o v e r the ap i ces and m i d d l e zones of both lungs . X - r a y c h e s t showed eot tonwool pa t ches in the s a m e a r e a s and a p r o m i n e n t h o r i z o n t a l f i s s u r e . They w e r e t r e a t e d i m m e d i a t e l y wi th F u r o s e - mide 80 m g and m o r p h i n e su lpha te 15 m g (iv). Subsequent ly , i n t r a v e n o u s f u r o s e - m i d e was r e p e a t e d e v e r y 6 h for 24 h and t hen con t inued e v e r y 12 h by mou th fo r 48 h. Bo th pa t i en t s showed m a r k e d i m p r o v e m e n t on day 2 and c o m p l e t e r e c o v e r y on day 4.

P a t i e n t no 7 c o m p l a i n e d of i n somnia , a n o r e x i a and g idd ines s on day 1. Subse - quent ly , he r e m a i n e d f r e e of s y m p t o m s on day 2 and 3, but P2 was loud. On day 3 h i s c h e s t X - r a y showed e a r l y ev idence of p u l m o n a r y o e d e m a . No e r e p i t a t i o n s w e r e h e a r d . P2 was loude r . No t r e a t m e n t was g iven . On day 4, a t 14 :00 h, he s t a r t e d compla in ing of c h e s t pain, b r e a t h l e s s n e s s and cough. C r e p i t a t i o n s w e r e h e a r d o v e r the h i l a r a r e a s . The X - r a y now showed m o r e m a r k e d co t ton-wool p a t c h e s in the h i l a r a r e a s s p r e a d i n g t o w a r d s the ap i ces and the b a s e s of the lungs . He was g iven a s ing le dose of f u r o s e m i d e 80 m g o r a l l y and r e l i e v e d by day 4.

214

TABLE 3. Fluid intake, u r ine output and h o r m o n e l eve l s (during 24 hours )a t s ea level and dur ing 5 days at a l t i tude (3,500 m) in HAPO pa t ien t s

Subject Initial s n o

5 RM

6 L1)Y

7 KR

8 CKS

24-h 24-h 24-h Days Fluid Ur ine Catechol

intake vo lume ami n es I I ~g

SL 3.15 1.22 64.0 1 3 .21 1.80+ 49 .5 2 1.40 1 .10+ 39.9 3 2.09 0.75+ 79.5 4 1.87 0.46 40.5 5 - 0.40 -

SL 3.24 1.67 83.5 1 1.74 2.00+ 65.0 2 1.38 1.40+ 101.8 3 2.25 0.92+ 95.6 4 2.27 0.61 78.1 5 - 0.89

SL 3.25 1.50 123.7 1 3.10 1.95 131.6 2 3 .02 1.00 138.7 3 2.97 0.60 138.8 4 2.84 1.91+ 162.3 5 - 0 .50

SL 3.20 1.68 36.8 1 3 .22 2.02 69.0 2 3.04 1.08 61.3 3 3 .00 1.37+ 38.4 4 2.34 1.05+ 42 .0 5 - 0 .90

P l a s m a

Cor t i so l ADH ~g/100 ml ~U/rn l

13.5 2.4 46 .0 2 .0 22.0 3 .4 19.0 2 .0 21.0 3 .3 26 ..0 2.1

15.0 2 .0 48 .0 2 .1 27.0 5.0 25.0 3 .0 26.0 2.4 26.0

8.5 2.1 47 .0 2 .0

23.0 4 .4 22.0 4 .2 27.0 2.6

17.5 2 .0 57.0 1.7

2 3 . 0 1.5

2 9 . 0 2.5

+) Af t e r a d m i n i s t r a t i o n of I u r o s e m i d e .

Pa t ien t no 8 had no compla in t s on days 1 and 2. On day 3, at 09:00 h, he sudden- ly deve loped headache, g idd iness , t i g h t n e s s and pain in the ches t , b r e a t h l e s s n e s s and cough with expec to ra t ion . Crep i t a t ions w e r e h e a r d all over the lung f i e lds . 1)2 was v e r y loud. X - r a y c h e s t showed w e l l m a r k e d cot ton-wool pa tches over a wide a r e a in both lungs . He was t r e a t ed , as pa t ien ts no 5 and 6 w e r e , and r e l i e v e d by day 5:

Obse rva t ions on the 24-h u r i n a r y output in pa t ien ts no 5 and 6 r e m a i n e d out of cons ide r a t i on as they w e r e t r e a t e d wi th f u r o s e m i d e on day 1 to 3. In pa t ient no 7, the 24-h u r i n a r y output which was 1 .5 1 at Delhi, i n c r e a s e d to 1.95 1 at Leh on day 1, then fel l sha rp ly to 1.0 1 on day 2 and 0.6 1 on day 3, when he showed rad io log ica l ev idence of HA1)O. Pa t ien t no 8 showed a s i m i l a r t r e n d . The 24-h u r i n a r y vo lume which was 1 .68 1 hr at Delhi, i n c r e a s e d to 2.02 1 at Leh on day 1, but fell s ha rp ly to 1 .0 1 on day 2. On day 3, he deve loped s e v e r e HA1)O.

T h e r e was a s h a r p i n c r e a s e in p l a s m a eo r t i so l on a r r i v a l at Leh on day 1. F r o m 13.5, 15.0, 8 .5 and 17.5 ~g/100 ml at Delhi, it i n c r e a s e d to between 46 .0 and 57.0 ~g/100 rnl at Leh in all 4 pa t i en t s . In pa t ien ts no 5 and 6, on day 2, i . e . the day following the at tack of HAPO, i ts level had d ropped to 22.0 and 27.0 ~ g / 100 rnl r e s p e c t i v e l y ; it r e m a i n e d about the s a m e on day 4. Likewise , in both pa t ien ts no 7 and 8, the p l a s m a co r t i so l was 23.0 ~g/100 ml in the mo rn i n g of day 3 and the s a m e day they deve loped HA1)O. On day 5, when they had r e c o v e r e d , the p l a s m a e o r t i s o l showed an i n c r e a s e to 27.0 and 29.0 ~ g/100 rnl r e s p e c t i v e l y .

215

The p l a s m a ADH l e v e l s did not show any s i gn i f i c an t change s t Leh on day 1. Subsequent ly , d u r i n g i l l n e s s pa t i en t no 6 showed a t r e n d t o w a r d s i n c r e a s e f r o m 2 .0 ~ U / m l at Delh i to 5 .0 u U / m l at Leh on day 2. B e f o r e i l l n e s s on day 3, in pa t i en t no 7, the p l a s m a ADH had r i s e n f r o m 2 .1 uU/ml s t Delhi to 4 . 4 u U / m l s t Leh .

T h e r e was a wide r a n g e of v a r i a t i o n be tween 3 6 . 8 - 1 0 1 . 8 ug in the 2 4 - h u r i n a r y c a t e c h o l a m i n e s in a l l the p a t i e n t s .

Individual d e t a i l s of sub j ec t s no 9 and 10 who su f f e r ed f r o m AMS a r e s u m m a r i s - ed in Tab le 4. Both s u b j e c t s deve loped AMS on a r r i v a l a t Leh on day 1. P a t i e n t no 9 had mi ld headache , g idd iness , b r e a t h l e s s n e s s and pain in the c h e s t . His b lood p r e s s u r e (BP) was 170/90 m m Hg. He r e c o v e r e d f r o m his s y m p t o m s and h is B P r e t u r n e d to 135/90 m m Hg on day 2. P a t i e n t no 10 had s e v e r e t h r o b b i n g headache , i n somnia , t i g h t n e s s and pa in in the c h e s t and m a r k e d a n o r e x i a . The B P was 160/110 m m Hg. He fe l t s o m e w h s t b e t t e r on day 2 and r e c o v e r e d c o m - p l e t e ly on day 4. His B P then was 150/80 m m Hg. In both s u b j e c t s X - r a y ch es t s , in sp i t e of pa in in the c h e s t and b r e a t h l e s s n e s s , d id not show any ev idence of HAPO.

TABLE 4. Values of l eve l and

Subject Name n o

9 VS

10 SS

du r ing 5 days a t altitud~ 24 -h u r i n e vo lume, f luid in take and h o r m o n e l e v e l s a t s e a

(3 ,500 m) in AMS p s t i e u t s

24 -h U r i n e C a t e c h o l - a m i n e s

ug

58 .20 85 .50 59 .10 63 .40 4 6 . 1 0

83 .40 26 .50 57 .60 59 .40 4 2 . 2 0

2 4 - h 2 4 - h Days Flu id U r i n e

in take Volume 1 1

SL 3 .22 1 .38 1 3 .14 0 .90 2 3 .03 0 .93 3 2 .97 0 .96 4 2 .22 0 .97 5 - 1 .70

SL 3 .21 1 .24 1 2 .50 1 .06 2 3 .02 1 .40 3 3 .01 1 .35 4 3 .01 1 .30 5 - 1 .77

P l a s m a

C o r t i s o l u g / 1 0 0 ml

16 .00 53 .00

31 .00

33 .00

17 .00 37 .00

33. O0

30 .00

ADH U/ml

1 .67 1 .80

2 .40

4 . 0 0

1 .80 2 .50

3 . 0 0

3 . 0 0

In p a t i e n t no 9, the 24 -h u r i n a r y output wh ich was 1 .38 i a t Delhi, r a n g e d f r o m 0 .9 to 1 .7 1 at Leh . The p l a s m a c o r t i s o l showed a s h a r p i n c r e a s e f r o m 16 .0 u g / 100 ml at Delhi to 53 .0 u g / 1 0 0 ml at Leh on day 1. T h e r e a f t e r , i t d ropped to 31 .0 u g /100 ml on day 3 and 33 .0 u g /100 m l on day 5. The p l a s m a ADH showed a p r o g r e s s i v e t r e n d t o w a r d s a r i s e f r o m 1 .67 u U / m l at Delhi to 4 . 0 ~ U / m [ a t Leh on day 5. U r i n a r y c a t e c h o l a m i n e s wh ich w e r e 58 .2 u g / 2 4 h a t Delhi, r a n g e d be tween 85.5 and 46 .1 ~ g /24 h at Leh f r o m days 1 to 4.

P a t i e n t no 10 did not show any d rop in the u r i n a r y output at Leh . Bo th p l a s m a e o r t i s o l and b lood ADH showed s o m e w h a t s m a l l e r r i s e t han of pa t i en t no 9. P l a s m a e o r t i s o l was 17.0 ug /100 m l at Delh i and r a n g e d be tween 37 .0 and 30 .0 u g /100 ml a t Leh . ADH was 1 .8 ~ U / m l a t Delhi and i n c r e a s e d to 3 . 0 ~ U / m l at Leh.

216

DISCUSSION

As al l t he s u b j e c t s w e r e known s u s c e p t i b l e s to HAPO, we fee l t h a t d i f f e r e n c e s be tween changes in the h o r m o n a l l eve l s in c o n t r o l s and p a t i e n t s could have p r e - d i sposed to the d i s e a s e .

A loud 1)2 on a r r i v a l a t h igh a l t i tude , b e c o m i n g loude r s u g g e s t i n g an i n c r e a s i n g p u l m o n a r y a r t e r i a l p r e s s u r e , was a p r e - r u n n e r of s y m p t o m s and s igns of HAPO to follow. It had t h e r e f o r e a p r e d i e t o r y s i gn i f i c ance .

As a l l t h e s u b j e c t s w e r e s u s c e p t i b l e s , t hey w e r e not expec ted to have a d i u r e s i s on a r r i v a l a t h igh a l t i tude . Thus , in 8 out of the 10 s u b j e c t s in whom the 2 4 - h u r i n a r y output was r e c o r d e d , 4 c o n t r o l s and one AMS s u b j ec t showed a t r e n d t o - w a r d s d e c r e a s e , 2 pa t i en t s showed a t r e n d t owards i n c r e a s e , and one AMS sub - j e c t showed no change . None of t h e s e d i f f e r e n c e s w e r e s ign i f i can t . However , in pa t i en t s no 7 and 8 who deve loped HAPO on day 3 and in whom we got the oppor tu - n i ty to m e a s u r e 24 -h u r i n a r y v o l u m e on days 1, 2 and 3, ag a i n s t the u r i n a r y v o l u m e of 1 .50 and 1 .68 1 r e s p e c t i v e l y a t Delhi, i t was found to be 1.95 and 2 .02 1 on day 1, 1 .0 and 1 .08 I on day 2 r e s p e c t i v e l y , and only 0 .6 1 in pa t i en t no 7 on day 3 at Leh. P a t i e n t no 7 had no s y m p t o m s and s igns on day 3 m o r n i n g but X - r a y c h e s t showed i n c r e a s e d v a s c u l a r [ s a t [ o n , p r o m i n e n t i n t e r l o b a r f i s s u r e and a few co t ton-wool pa t ches o v e r the lung f i e lds . Su b -c l i n i ca l HAPO had t h e r e - fo re a l r e a d y o c c u r r e d be fo re the fu l l - f l edged c l in ica l p i c t u r e of the d i s e a s e deve loped l a t e r in t he day. It would, thus, s e e m o l i g u r i a is a p r e c u r s o r of the d i s e a s e r a t h e r than i t s ef fect .

No s ign i f i can t changes in the u r i n a r y e a t e e h o l a m i n e s w e r e o b s e r v e d e i t h e r in c o n t r o l s o r in p a t i e n t s . Th i s is in c o n f o r m i t y wi th the Obse rva t ions made by Sir[, C leve land and B l a n c h e (1969) in E v e r e s t c l i m b e r s . T h e r e w e r e v a r i a t i o n s wi th in wide r a n g e s in al l pa t i en t s and t he s i gn i f i c ance of t h e s e v a r i a t i o n s r e m a i n e d in- conc lus ive . The p l a s m a ADH l e v e l s at Leh on day 1 w e r e a l m o s t the s a m e as at Delhi . Subsequent ly , t h e r e was a t r e n d t o w a r d s i n c r e a s e b e f o r e / d u r i n g i l l n e s s in p a t i e n t s . Thus , in pa t i en t s no 6 and 7 t he ADH l e v e l s w e r e 2 . 0 and 2 .1 u U / m l r e s p e c t i v e l y at Delhi . In Leh, d u r i n g i l l ne s s , in pa t i en t no 6 the l eve l r o s e to 5 .0 ~ U / m l on day 2, and in pa t i en t no 7 i t r o s e to 4 . 4 ~ U / m l on day 3. T h e s e changes , however , w e r e wi th in n o r m a l v a r i a t i o n s . Unl ike the u r i n a r y c a t e e h o l - a m i n e s and blood ADH leve l s , t he p l a s m a c o r t i s o l showed significar~tly d i f f e ren t r e s p o n s e s be tween c o n t r o l s and p a t i e n t s . Al though the p l a s m a c o r t i s o l va lues at Leh w e r e about the s a m e in c o n t r o l s and pa t i en t s on day 1, t h e r e was a s h a r p d rop be fo re i l l n e s s only in the p a t i e n t s . The drop in p l a s m a c o r t i s o l to about hal f i t s p r e v i o u s day v a l u e w a s no t i ced in the m o r n i n g s a m p l e of t h e blood, and the s a m e night pa t i en t s no 5 and 6 deve loped HAPO. S imi l a r ly , in pa t i en t s no 7 and 8, the p l a s m a c o r t i s o l d ropped when HAPO m a n i f e s t e d i t se l f . So s t r i k i n g s e e m e d to be t h i s d rop in P l a s m a c o r t i s o l l eve l in r e l a t i o n to the onse t of the d i s e a s e that , in the a b s e n c e of s y m p t o m s and phys i ca l s igns , pa t i en t no 7 was s u s p e c t e d to be a c a s e of HAPO on day 3 and c o n f i r m e d to be as such on r a d i o l o g i c a l ev idence . It t h u s a p p e a r s t ha t a sudden d rop in p l a s m a c o r t i s o l l eve l is a s s o c i a t e d wi th fa l l in u r i n a r y output and the o c c u r r e n c e of HAPO. Th i s is a l so in c o n f o r m i t y wi th the f indings in pa t i en t no 9 who was a c a s e of AMS. F u r o s e m i d e had a m i r a c u l o u s c l in ica l ef fec t on t he r e c o v e r y of the p a t i e n t s . The p l a s m a c o r t i s o l l eve l s , how- eve~, r e m a i n e d low t i l l r e c o v e r y was c o m p l e t e r ad i o l o g i ea l l y .

Al though a l a r g e n u m b e r of r e p o r t s c o n f i r m i n c r e a s e d a d r e n o e o r t i e a l ac t iv i ty at h igh a l t i tudes (Cunningham, B e c k e r and Kreuze r , 1965; D a r r o w and Sarason , 1944; Ha lhuber and Gabl, 1964; Hornbe in , 1962; Lang ley and Clarke , 1942; Mackinnon, M o n k - J o n e s and Fo the rby , 1963; Moneloa et a l . , 1965; Singh e t a l . , 1969; Sir[, C leve land and Blanche , 1969; T i m i r a s , Pace and Hwang, 1 9 5 7 ) a n d i ts r e t u r n to s e a - l e v e l va lues wi th in 3-21 days of a c c l i m a t i z a t i o n (Halhuber and Gabl, 1964; Hornbe in , 1962; Mackinnon, M o n k - J o n e s and Fo the rby , 1963; Mon- e loa and P r e t e l l , 1964; Moncloa, P r e t e l l and C o r r e a , 1961; Moneloa et aI., 1965;

217

Singh et a l . , 1969; T i m i r a s , Pace and Hwang, 1957), no w o r k ha s c o m e to ou r no t i ce so f a r d i r e c t l y connec t ing the l e v e l s of p l a s m a c o r t i s o l wi th o l i gu r i a and o c c u r r e n c e of HAPO. Since i n c r e a s e d a d r e n o c o r t i e a l ac t iv i ty p r o m o t e s d i u r e s i s de sp i t e m a r k e d i n c r e a s e of ADH (Wil l iams, 1955), i t would be r e a s o n a b l e to sugges t t ha t the s h a r p d rop in p l a s m a c o r t i s o l l eve l was r e s p o n s i b l e for o l i g u r i a and o c c u r r e n c e of HAPO in ou r p a t i e n t s . When the p l a s m a c o r t i s o l l e v e l s w e r e low, the i n s ign i f i c an t i n c r e a s e s in p l a s m a ADH and the f a i l u r e of u r i n a r y c a t e e h o l - a m i n e s to r i s e migh t have played an i m p o r t a n t r o l e . U n d e r a s t r e s s f u l s i tua t ion w h e t h e r a p e r s o n wil l have a n t i d i u r e s i s o r po lyu r i a a p p a r e n t l y depends on the e q u i l i b r i u m be tween the ADH, the a d r e n a l s t e r o i d s and t he c a t e e h o l a m i n e s , r a t h e r than on the abso lu t e ind iv idua l h o r m o n a l c o n c e n t r a t i o n s .

A fa l l in p l a s m a c o r t i s o l has been c o n s i s t e n t l y r e l a t e d to a fa l l in the u r i n a r y output, w h e r e a s changes in t he p l a s m a ADH and u r i n a r y e a t e c h o l a m i n e s have been inconsis terxt . In pa t i en t no 7 the a n t i d i u r e t l c e f fec t of fa l l in p l a s m a c o r t i s o l l eve l has been a u g m e n t e d by a r i s e in b lood ADH, w h e r e a s in pa t i en t no 8 i t h a s been a u g m e n t e d by fa l l in u r i n a r y c ~ t e c h o l a m i n e s (Fig : 1).

The m e c h a n i s m u n d e r l y i n g the d rop in p l a s m a e o r t i s o l l eve l in pa t i en t s is not c l e a r . It s e e m s hypoxia can b lun t the s e n s i t i v i t y of a d r e n o c o r t i e a l r e s p o n s e to the ACTt I s t i m u l u s . Thus , a l though on a r r i v a l a t h igh a l t i tude d u r i n g the e a r l y s t a g e s the a d r e n a l c o r t i c a l ac t iv i ty is i n c r e a s e d and i t r e t u r n s to n o r m a l when a c c l i m a t i z a t i o n is we l l advanced, a h i g h e r t f t r e of ACTH is n e c e s s a r y to m a i n - r a in th i s ac t iv i ty (Sir i et a l . , 1966). In ind iv idua l s p r e d i s p o s e d to HAPO the d rop in p l a s m a c o r t i s o l m a y t h e r e f o r e be r e l a t e d to a h i g h e r d e g r e e of h y p o x a e m i a wh ich is found in t h e m than in t hose who a r e i m m u n e ( P e n a l o z a and Sime, 1969; Singh et a l . , 1967).

Changes in the lef t a t r i a l p r e s s u r e m a y d e t e r m i n e the blood ADH leve l . D i u r e s i s deve lop ing in m i l d hypoxia is a p p a r e n t l y due to d i m i n u t i o n of c i r c u l a t i n g ADH (Silvet te , 1943, 1944), r e s u l t i n g f r o m i n h i b i t o r y i m p u l s e s o r i g i n a t i n g f r o m the d e f o r m a t i o n r e c e p t o r s in the lef t ~ t r i u m when i t is d i s t e n d e d by l a r g e v o l u m e of blood d u r i n g hypox ie - induced h y p e r v e n t i l a t i o n . And o l i g u r i a a s s o c i a t e d wi th s e v e r e anoxia s e e m s to be the cons equence of sudden d i s c h a r g e of ADH (Brun, Knudsen and Raaschou , 1945; Noble and Tay lo r , 1953). The a v a i l a b i l i t y of e a t e e h o l a m i n e s i s a l so l ike ly to be d e c r e a s e d in s e v e r e d e g r e e s of hypoxaemia . Al though hypoxie s t r e s s i s u sua l ly a s s o c i a t e d wi th i n c r e a s e d s y m p a t h e t i c ac t iv i ty

(Cunningham, B e c k e r and K r e u z e r , 1965; Pace , Gr i swo ld and Grunbaum, 1964; Surks , Beckwi t t and Chidsey, 1967), t h e r e is a p o s s i b i l i t y t h a t e p i n e p h r i n e in s o m e c a s e s is i nac t i va t ed by hypoxia be fo re i t s full a c t ion t a k e s p lace , o r t h a t hypoxic t i s s u e s a r e l e s s s e n s i t i v e to e p i n e p h r i n e (Sur t sh in , Rodba rd and K~tz, 1948; Van Loo, S u r t s h i n and Katz, 1948). When such i nac t i va t i on does not o c c u r c ~ t e c h o l a m i n e s m a y p r o m o t e d i u r e s i s . T h e r e f o r e , [t r e m a i n s to be shown w h e t h e r is m o r e s e v e r e c a s e s of HAPO t h a n we a r e r e c o r d i n g now, the p l a s m a ADH l e v e l s would be h i g h e r and the u r i n a r y c a t e c h o l a m i n e s l o w e r or h i g h e r .

Cl in ica l ly , AMS and HAPO have m u c h in c o m m o n (Singh et a l . , 1969). Among p a t i e n t s no 9 and 10 who deve loped AMS, unl ike in HAPO pa t i en t s , t h e r e was no d r o p in p l a s m a c o r t i s o l l eve l be fore the onse t of t he d i s e a s e in sub jec t 10. The n u m b e r s , t h e r e f o r e , do not allow us to draw any c o n c l u s i o n r e g a r d i n g d i f f e r e n t i a - t i on of the two d i s e a s e s on t h i s b a s i s .

218

- I

o u

,< Z

,< _J o.

6 O

. j 5 0

g ~ o ~ 3 0

~ 2 0

I 0

4.0 "1"

< 3.0

o q .~2.o 1-0

1 7 0

1 6 0

1 5 0

v~ 1 4 0

z 1 3 0

. o

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Fig . 1. Inf luence of fall in p l a s m a c o r t i s o l and r i s e in ADH on u r i n a r y output in HAPO pa t ieu ts 7 and 8.

219

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221

ABSTRACT.- In 10 subjects susceptible to high altitude pulmonary oedema (HAPO) plasma eort isol and antidiuretic hormone (ADH) and ur inary catechol- amines were estimated both at sea level and dally during their stay at 3,500 m (Leh). At high altitude 4 of the subjects developed HAPO, 2 got acute mountain sickness (AMS) and 4 remained unaffected. P lasma cort isol showed a sharp r i se on the f i rs t day ~t high altitude in all the subjects. Thereafter , it declined gradually in the unaffected subjects. In the HAPO p~tients there was a sharp fall in the plasma cort isol level combined with ar~tidiuresis. Changes in plasma ADH and ur inary cateeholamines were not consistent, tt appears that fai lure in the nor- mal adrenocortical response to altitude s t ress in susceptible subjects is a factor in precipitating HAPO.