Ethacrynic acid

Ethacrynic acid

Report on Therapy E thacrynic Use in Ambulatory Acid Patients with Resistant Edema* HOWARD H WAYNE, M D , SEYMOURA KOTLER, M D , PAGE S MCGIRR, ...

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Report

on Therapy E thacrynic

Use in Ambulatory

Acid

Patients with Resistant

Edema*

HOWARD H WAYNE, M D , SEYMOURA KOTLER, M D , PAGE S MCGIRR, M D ROGER D STOIKE, M D San Dlego,

R

ECENT reports indicate that ethacrymc acid 1s not only more potent than any presently known dmretlc but 1s effective m edema refractory to conventional dmretlcs 1--6 In addition, It will cause dmresls m alkalotlc patients,lv4 whereas mercurial dmretlcs are relatively meffectlve Figure 1 compares Its formula with several well known dmretlcs, It 1s apparent ethacrymc acid 1s an entirely different structural compound The extreme potency of ethacrymc acid 1s indicated by one patient losing 28 pounds m 24 hours with a single dose of 150 mg ,2 another losing 15 pounds m 24 hours,l and the third excreting 8,590 ml of urme the first day 6 Dmresls 1s mmated wlthm 15 minutes after oral admmlstratlon’ and reaches a peak wlthm two hours3 whereas It 1s well known that dmresls with mercurlals does not begm until about two hours afterward These factors, no doubt, account for its effectiveness in pulmonary edema 7 Its extreme potency, however, introduces a problem not present with the thlazldes, namely, 1s the agent too potent to use on an outpatient basis? If so, Its use will be limited to hospuahzed patients If on the other hand, ethacrymc acid 1s not only effective m the poorly responsive patient who 1s ambulatory but also can be used safely, It will be a remarkable advancement The followmg study was therefore undertaken to test the long term admmlstratlon of ethacrymc acid, mostly m ambulatory,

and

Cahforma

edematous patients reslstant conventional dmretlcs

or refractory

to

MATERIALS AND METHODS Ethacrymc acrd was admnnstered to approximately 40 patients, 25 of whom were subsequently treated for prolonged penods on an ambulatory basis For those panents who did not require hospltahzatlon but were merely becoming more edematous on the usual thlazlde dosage m spite of either stnct or moderate salt restnctlon, ethacrymc acid was substituted, usually m an mltlal dose of 50 to 100 mg twice dally and continued twice dally In many instances these patients had required frequent mercurial mJectlons m addltlon to their thlazldes and m large measure were poorly responsive No attempt was made to adjust the dosage of dlgltahs, restnct the aodmm intake, institute bedrest, or restnct actlvltles m any wav In other words, the patient was allowed to mamtam his previous way of hvmg m order not to influence an) results No other diuretics were administered m conJuncnon with ethacrymc acid Supplementary potassium was not given unless hypokalemla developed Routme hemoglobm, hematocnt, blood count, blood urea nitrogen, serum sodium, potassium, chloride, uric acid, transammase, blhrubm, alkaline phosphatase and blood sugars were obtamed prior to therapy and repeated on one or more occasions thereafter Patient ages ranged from 14 to 95 years The maJonty were m advanced congestive heart failure, a few had clrrhosls with ascltes One had ldlopathlc nephrotlc syndrome A number of the more crltlcally 111 patients were mltlally treated m the hospital and then maintained on an outpatient basis In several instances, ethacrymc acid was used alone without dIgItalis

* From the Stevenson Research Foundation of the San Diego Health Assoclatlon and the Department of Medlcme of the San Dlego County General Hospital, San Dlego, Cahf This study was supported, m part, by grants from the Merck Sharpe & Dohme Research Laboratories, West Point, Pa and the Research Foundation of the San Diego County General Hospital VOLUME

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1965

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RESULTS

H*NstlQ>H

Drurrs~s and I17ezght Loss Table I SUIIIthe earl\ chrncai response 111 22 patients Mho were either resistant or refractor! to thlazldes or mercurlals, or both, and m ct horn it was possible to determine, with some accuracy, the time required to reach dr) weight Weight loss averaged about 12 lb m fi\e daps one third to one half of this usually occurrmg m the first 24 to 48 hr In several instances, dmresls resulted m losses oi 9 to 11 lb m 24 hr and 15 to 20 m 48 to 72 hr LTsually these large weight losses occurred with relatively small doses, e g , 50 to 100 mg twice dally Thus m all hkehhood, greater responses m the first few days could have been readily obtained with higher doses Obvloush, such rapid fluld loss 1s rarelv necessary and potentially In those patients with marked dangerous dmresls, the major side effects were weakness, thirst and urmary frequency Table I shows that several patients with congestive heart failure were not dlgltahzed but treated only with ethacrymc acid In spite of this, they became clmlcally free of edema In 10 patients it was possible to measure the 24 hour weight loss followmg an mJectlon of 2 ml of merallurlde and then, after return to the premercurlal weight, measure the weight loss after 24 hours of ethacrymc acid therapy In several Instances, the merallurlde was given while the patient was already receiving thlazldes Table II compares the responses It may be seen that losses of 5 to 11 5 lb ocmarlzes

0

Cl

0

Cl :: CH3-C-NH-C

CH2COOH

C-S02NH2 ‘5’

Ethacrpc

Ac,d

Acekzokmde

Formula for ethacrymc FIG 1 monly used dluretlcs

acid and other com-

Where possible, attempts were made to compare Edematous ethacrymc acid with mercurial dmretlcs patients reslstant to thlazldes here given 2 ml of merallunde, and the 24 hour electrolyte excretions were measured and weight recorded the followmg day After then premercurlal weight was re-estabhshed, ethacrvmc acid was admmlstered usually m a dose of 100 mg twice dally, and the 24 hour urmary electrolyte excretion measured and the weight agam recorded

TABLE I 4mount and Duration of Maxlmal Weight Loss m 22 Patients Reslstant or Refractory to Thlazldes or Mercurlals, or Both Dosage Case

1

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

4ge & Sex

43 M 58 F 66 F 66 F 58 F

65 M 57 71 47 74 73 53 14 68 95 65 62 73 73 57 81 66

M F F F F F M M M M F M M F F M

Dmgnos,s

Cardwqopathy RHD

4SHD ASHD ASHD ASHD 4SHD, HHD RHD

(mg bid)

200 100 100 100

100 50 100

100

Pounds

21 6 6 9 6 11 10

8

Cmrhosls

100

Cxrhasls RHD Nephrotlc avndrome 4\HD ASHD ASHD ASHD RHD ASHD Clrrhasl\ ASHD ASHD

100 200

16 5 12 8 30

200 200 100 100 50 50 100 100 100 100

28 7 9 20 7 9 9 20 5 10

ASHD HHD

5ot

Weqht Loss Duration (days)

8 5 10 4 4* 7 5* 4 3 7 2 9

* Patxnt not dwltabzed Dosage t d ASHD = artermsclerat~ heart disease HHD d~easc and RHD = rheumatlr heart dtaease

Age & +x

5 35

Dmgnow

Loss Followmg Therapy (lb ) M.ZKUlXil> Etha & crvmc Thlandes Aad

MerCUrl& AlOll.?

_

--

:* 2 5 15*

18 20 19 23 24 9 13

73 53 73 83 70 47 14

M F hf F F F M

14 25 12

6R M 64 M 53 F

RHD Ckrrhostr ASHD ASHD ASHD Clrrhoan Nephrotx syndrome ASHD ASHD RHD

0 0 1 4 7

Abbrei

moons

same as ,n Table

THE

AMERICAN

0

1

IO 5 4 5 9

1 2 0 13

heart

0

0

A\erage = h>pertenwe

II

Mt

5 6 7 3 2

12 2

L

TABLE

Response m First 24 Hours m Resistant Patients Followmg a Mercurial InJectlon, With and Wlthout Thlazldes, m Comparison to the Same Response After Ethacrymc 4cld

c s*e

Average

t

Max,mal

I 0

5 > 4 11 5 67

I JOURNAL

OF

CARDIOLOGY

Ethacrynlc ‘O”

Acid

731 700

@

SODIUM POTASSIUM 600

600

CHLORIOE

500

500

400

400

300

300

200

200 .

100 z

MK

Hs URINARY

595

H9

ELECTROLYTE

MK

595 EXCRETION

,

nr

.

ma

5%

MEQ / LITER

MS URINARY

MK

5%

ELECTROLYTE

Ml

MK 595

EXCRETION

H9 MEQ/

24

MK595

0

HOURS

FIG 2 Urmary electrolyte excretion followmg 2 ml of a mercurial compdrrd to 50 to 100 mg twice da111 of ethacrymc acid (MK-595) The left hand side of the figure 1s m mllheqmr alents per liter and represents an average of The 13 patients The right hand side 1s m mllheqmvalents per 24 hours and represents an average of 8 patlent> the aLerage after ethacrymc dcld 4,440 average postmercurlal 24 hour urmary volume for 8 patients was 1,900 ml ml In e\ ery mstance the mercurial was admmlstered first, the ethacrymc acid after the patlent had reqamed his premercurlal uelght curred after ethacrymc acid m patients who or poorly responsible, to were unresponsive, mercurlals or thlazldes, or both Figure 2 shows C&znary Electrolyte Excretzon the average electrolyte excretion m 13 patients m the 24 hour period followmg a single mercurial mJectlon, compared to the first 24 hours of In each instance the ethacrymc acid therapy premercurlal weight was regained before glvmg the new dmretlc When electrolyte excretion m mEq per liter was compared, both mercurlals and ethacrymc acid caused similar excretion patterns When electrolyte excretions were plotted m mEq per 24 hours, m each instance, as a result of Its marked dmretlc effect, ethacrymc acid was two to three times In 8 of as effective as 2 ml of merallurlde the 13 patients for whom this comparison was avallable, mercurlals resulted m average 24 hour urmary excretion of 1,900 ml , while ethacrymc acid yielded 4,440 ml m 24 hours While each patient was his own control, and the measurements were based only on a 24 hour period, the patients were not on a VOLUME

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1965

rlgldly controlled sodmm diet Thus these electrolyte excretions should be consldered only crudely accurate Blood chemistry values were Szde Effects obtained before and after the patient had been on dally ethacrymc acid for variable periods of time These data are recorded m Table III It may be seen that decreases m sodium, chloride and potassium were not upcommon after prolonged therapy These read111 responded to supplementary potassium chloride and hberahzatlon of the diet In a few patients the new dmretlc was administered m spite of an elevated blood urea nitrogen without an\ further elevation being apparent Patlents with diabetes were not slgmficantlv harder to control No consistent hematologlc abnormahtles were demonstrable In 2 patients to whom the parenteral form of the drug was administered, intense burning developed m the arm and chest, requn-mg dlscontmuance of the drug One mterestmg phenomenon seen was the rapid return of edema when ethacrymc acid

Wayne,

732

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and

Stolke

TABLE III Hematologlc

and Blood Chemical

Platelets

Case

Tome

17

Control 4 mo

11 9 13 1

16,450 14,150

26

Control 4 In0

16 5 15 4

4,000 7,200

13

Control 1 wk 2 wk 1 mo

14 6

6,300

16 8

9,150

15 0

8,450

295,000

16 3

8,450

345,000

14

,g:“,,

Control 3 wk 5 wk 4 mo

NBC

Data after Prolonged

224,000 210,000

BUN (q!

(mts)

09 1 1

11 13

30 20

140 143

43 38

115 102

20 21

101 108

63 80

09 1 6

15 18

12 30

156 142 143 140

67 39 3 1* 41

105 101 96

45 40 16 10

118

10 0

08

20

30

10 7 80

04

8

21

141 150 144 135

45 54 46 51

94 103 93 87

20 20 15

133 111 150

84 84 82

12 09

19 20 10

40 40 40

136 144 146

52 50 42

98 97 106

7,000 7,850 6,900

250,000

135 140

1 Y’

13 5 9 1 13 0

41 52 3 4*

16

Control 1 n-m

18 5 15 0

6,200 7,800

255,000 168,000

140 143

27

COIltrOl 1 mo 4 Ino

13 5 14 6

6,300 5,400

270,000 300,000

Control 1 mo 4 rno

10 8 12 4 13 0

5,600 5,900 6,400

180,000 130,000

22

Control 3 wk

18 0 16 8

6,450 8 600

29

Control 8 mo

15 2 18 5

30

Control 2 mo

24

Control 3 mo 8 mo

15 4 14 8

8,550 6,800

165,000

Control 3 mo

13 6 13 3

9,700 9,150

110,000 135,000

Control 3 wk

16 9 16 3

Control 2 mo 5 mo

75 11 9

Control 3 wk

13 8 13 8

8,700 6,100

Control 2 mo 6 mo

10 8 10 1 85

7,500 9 350 9,100

DOX

100 400 400 400 150 150

24

100

63

13

16

30

27

126

78

1 1

10

30

82 107 86

10 5

132 125

66 64

14 12

14 15

66 48

102 104

32 18

186 118

78 56

140 135 137

42 46 2 7*

110 94 90

115 106

63 76

133

34

108

10

88

31

08

42

32

140

3 1*

104

16

103

40

17

71

47

100 200

138,000 180,000

140 140

49 39

102 96

20 26

102 108

53 85

05 06

7 25

50 40

200

370,000 430,000

141 143

56 33

107 102

15 28

98 132

10

42 18

147 136

45 44

90 107

144 154 134

5 1 49 43

111 110 97

15 11

145 141

46 59

107 81

10 15

6,670 7,420

129 123

54 36

104 84

24 30

10,500 10,450

122 129

32 2 3* 46

85 79 99

6 30

6,600 11,000

*Supplementary potasswn chlonde Hb = hemoglobm, Alk Phos = alkalme

zn Assoczatzon

34 12

200 103

13 9 22

60 60

105 106

50 43

05 06

12 19

50 30

36 34

42

92 70

14 1 75 1 6 1 1 12

122

15 18

108 131

60 72

47 44 40

103 100 99

30 47 15

150

160,000

143 134 138

98 13 6 12 0

14 09 09

= sugar,

SGOT

wzth

Ethacrynzc

In 9 patients, death occurred or followmg ethacrymc acid therapy IV lists the significant clmlcal data had advanced congestive heart failure,

m 2 with rem-

Aczd

during Table Most and m

= blood

100 100 100 300

100 96

doses

200

06 05

46 44

BUN

100 100 200

52 73

145 145

started at thu tune WBC = white blood cells, phosphatase

200 200 400 400

40 1 6

290,000 180,000

was abruptly dlscontmued and maximal of thlazlde substituted This occurred patients with congestive failure and 1 clrrhosls All responded promptly to stltutlon of the new dmretlc

Deaths Thuapy

(mm)

11 1 99

320,000

Abbrcvmttons transamnase,

%

ML Phos

186 163

335,000

28

(q

SGOT

50 45

6,200

Control 5 mo

(mg 5)

B111rubm

102 111

10,700

18

Unc Acld

45 46

17 4

Control 1 wk 1 mo

Sug (mg “OJ

Acid Therapy

145 143

17 9

19

‘?f:)

Ethacrynlc

160

urea mtrogen,

Sug

50

100 100

8 18

50 50

100

9 14 14

50

200 200

= serum glutamx

oxalacet,c

5 cases ethacrymc acid had been dlscontmued from two days to two weeks before death occurred One had unsuspected metastatlc adenocarcmoma of the stomach found at Three patients were either moribund autopsy or died suddenly wlthm 24 hours after mltlatmg the ethacrymc acid as an emergency procedure In only one instance was there significant dmresls prior to death This occurred m a 77 year old patlent m congestive THE

AMERICAN

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Ethacrk mc Lkld TABLE

I”

Details m 1 hose Patients \t ho Died \%‘hlle on Ethacrymc the Evperunental Dmretlc

hrtment

Duration of Ethacrymc icld Therapy

\cld, or \hortly After Dlscontlnulnq

Dose (“4 1

cd\<

4gr & 5.3

30

80 M

CHF,

,1SHD

2 mo

150 btd

Poorly responsl\e ethacrymc acid

32

86 M

CHF,

XbHD

36 hr

lOObId

CV4 after 36 hr of therapy Urme output m precedmg 24 hr -1,400 cc Died 2 wh after stoppmg ethacrymc acid

4

66 F

CHF,

45HD

5 days

100bld

9 5 lb wt loss m 5 days Died suddenly with chest pam 2 days after ethacrymc acid was dlscontmued

33

65 F

Renal disease

1 wk

50mg

34

77 F

ASHD,

CHF

24 hr

50 mg IV 100mg bid

Urmary output after 24 hr

65 M

CHF,

4SHD

6 wk

50mg bid 2 X weekly

Died of unsuspected wldespread adenocarcmoma of the stomach Therapy dlscontinued 2 days before death

35

70 F

CHF,

4SHD

Less than 24 hr

0 5 mg /kg

36

50 M

CHF,

4SHD

24 hr

100 bid

12

53 F

CHF,

RHD

3 wk

200 mg

Dldqnosls

Circumstances

of Death

--

6

7 lb wt loss m 1 wk Died 2 wk therapy was dlscontmued

bid

IV

Moribund mlsslon

failure Urinary volume m the 24 hours preceding demise was approximately 4,000 ml One of the patients was an 80 year old man with advanced congestive failure who became mcreasmgly edematous m spite of all forms of therapy mcludmg ethacrymc acid, but m submaximal doses He died suddenly after being on the new diuretic for two months, the cause of death was not established ILLUSTRATIVE

CASE REPORTS

Because of the various clmlcal settings m which ethacrymc acid was used, and the dlfferent characterlstlcs it exhibited, the results of therapy are best presented m the form of mdlvldual case histories (Table I) CONGESTIVE

HEART FAILURE

CASE 18 A 73 year old white man with bevere rheumatic heart disease, mural stenosis and msuffiatrIal fibrlllauon, marked cardiac enlargeciency, ment and advanced congestive heart faIlme (Class IV E) with 3-plus tIbIa1 edema, had become comVOLUME

16,

NOVEMBER 1965

4,130

ml

after

Died suddenly

& m pulmonary edema on adDied wlthm 24 hr

In terminal CHF, died wlthm 24 hr , urine output 1,485 ml m precedmg 24 hr b

Id

Died suddenly 2 days after dlscontmumg therapy No slgmhcant wt loss m preceding 10 days

All patients m congestlte heart failure were far advanced CHF = conzestlve heart failure. 4SHD = arterrosclerotlc u accident, and RHD = rheumatic heart disease Abbrevzattons

to submaxIma doses of Died suddenly

heart disease,

CV4

= cardlokascular

pletely refractory to thIazIdes and was mInImally Iesponslve to mercurlals Thlazldes were dIscontmued and 50 mg of ethacrymc acid admInIstered twice dally, weight loss was 9 lb In one day A matrtenance dose of 100 to 150 mg twice dally was required, and for the next SIX months the patient did relatively well He had Increased exercise tolerance, less dvspnea and no evident edema and could be considered Class III D After SIY months, because of generahzed prurms, ethacrymc acid was stopped abruptlv and chlorothlazlde, 1 gm twice dally substituted WIthm one week a weight gam of 10 lb occurred 7 he addIuon of a single InJectIon of 2 ml of merallurlde was totally IneffectIve At this time the patient was again In severe failure with numerous moist rales, dyspnea at rest, and 3-plus tIbIa1 edema ChlorothIazIde and merallurlde were dlscontmued, and ethacrymc acid was restarted at 150 mg twice dally with a resultmg weight loss of 10 lb In three days and concomitant clInIca Improvement Prurms did not reappear For the next two months the patient remained reasonably comfortable, dvspnea occurred only wuh slight to moderate acuvlty An attempt was made to use submamtenance doses of ethacrymc acid with 1

Wayne,

Kotler,

McGxr

gm of chlorothlazlde a day A prompt increase m u eight and dyspnea occurred, which agam unproved with return to full mamtenance doses of the new At the present time the patlent 1s under farr dmretlc

control, havmg been on ethacrymc acid for a total of 19 months This patlent with advanced conComment gestive heart failure was refractory to thlazldes, poorly responsive to mercurlals, and markedly dyspnelc at rest when etfiacrymc acid was While he obtamed a good reinstituted sponse to only 50 mg twice dally mltlally, later 150 to 200 mg twice dally was requu-ed This does not necessarily imply loss of response since m other patients the mltlal dose was usually Rather It adequate throughout treatment suggests the starting dose was suboptlmal m this particular patlent It should be noted that substltutlon of maxlmal doses of thlazldes for ethacrymc acid resulted m a rapid weight gam and dyspnea at rest, that was also unresponsive to the simultaneous admmlstratlon of merallurlde Responsiveness to ethacrymc acid, however, was retamed A 43 year old Negro

man with a massively enlarged heart, presumably due to alcohohc cardiomyopathy, was admltted to the San Diego County General Hospital for mcreasmg failure which had not responded to mercunals, thlazldes, digitalis, carbonic anhydrase mhlbltors and a strict salt diet At the time of admlsslon, venous pressure was 300 cm of water, and cn-culatlon time (arm to tongue) was 42 set He continued to deteriorate m spite of more mtenslve therapy, and his condltlon was thought to Ethacrymc acid, 200 mg twice dally, be termmal was started, and over a period of eight days a 21 lb weight loss occurred with marked clmlcal lmprovement, enablmg him to be discharged 18 days after ethacrymc acid therapy was mltlated He remained clmlcally free of edema with the use of thlazldes dally and ethacrymc acid mtermlttently on two days of each week He has been on the new druretlc a total of eight months CASE

1

probable This patlent with Comment alcohohc cardiomyopathy was essentially retractory to therapy and m a termmal state when Ordmarlly, it IS started on ethacrymc acid not advisable to use such high doses mmally, even m refractory patients, as massive dluresls may occur CASE

chronic

10 A 74 year old white diabetic woman with congestive heart failure (Class IV E) secondary

to hypertensive, artenosclerotlc,

and valvular heart

disease, had been poorly responsrve to thlazldes and required 2 ml of merallunde twice weekly In spite of this, she continued to have constant pulmonary

and Stolke

rales bilaterally, Jugular venous dlstentlon to 90”. 4plus edema to both knees three-pillow orthopnea and dyspnea at rest Thlazldes uere dlacontmued and ethacrvmc acid therapy, 50 mg three times dally, mltlated with a weight loss of 12 lb m one week without side effects Less than 150 mg /day has not slgmficantly effective but 200 to 300 mg /day permitted her to walk short distances without dyspnea After six months the new diuretic was temporarily dlscontmued when she was hospltahzed for bleeding dlvertlculae Edema and dyspnea returned despite bedrest, low sodium diet, thlazldes, mercurlals and antlaldosterone agents, but she agam responded to ethacrymc acid She continues to remam on 200 to 300 mg /day and, while still severely hmlted, 1s at least ambulatory after 11 months of contmuous therapy

Comment This 74 year old woman with advanced congestive heart fadure was bedridden and pobrly responsive to conventional diuretics prior to mstltutlon of ethacrymc acid After 11 months of ethacrymc acid therapy she IS w&out dyspnea at rest and partially ambulatory CASE 12 A 53 year old nurse was hospltahzed with massive anasarca secondary to right-sided heart fallure due to mitral stenosis and functional tricuspid msufficrency She had falled to respond to mercurlals, thlazldes, antlaldosterone agents, dlgltahs, ammomum chloride, strict salt restriction and bedrest durmg prior hospltahzatlons and was cyanotic, markedly dyspnelc and considered to be m a terminal state The serum sodium, at the mltlatlon of ethacrymc acid

therapy, was 129 mEq /L Other diuretic agents were dlscontmued and ethacrymc acid therapy started m a maximal dose of 200 mg twice dally, and the patient lost 11 5 lb m the first 24 hours Serum potassmm fell from 5 5 to 4 2 mEq /L m this period of time In spite of the hyponatrerma and hypochloremla of 84 mEq , on 300 to 400 mg every two to three days she lost an addltlonal 16 lb m the next two weeks, a total weight loss of 2.7 5 lb On several occasions, acetazolamlde was admmlstered alternately with ethacrymc acid with a somewhat better response to the latter drug At the end of two weeks, hepatomegaly had receded re-

markably, cyanosis was gone and she was near drv weight Nausea was associated with each admmlstratton of the drug The patlent died suddenly four days after her last dose of ethacrvmc acid Autopsy revealed a massively enlarged heart with mitral stenosis and a recent pulmonary embohsm

This patient who was m totally Comment refractory congestive failure experienced a 27 5 pound weight loss over a period of two weeks of treatment with ethacrymc acid, over half of which was wlthm the first 48 hours THE

AMERICAN

JOURNAL

OF CARDIOLOGY

Ethacr\ She died sudden11 of a pulmonarv embohsm tour dabs after the last dose of ethacrymc acid There was no e\ldence to suggest her deml\e was related to the diuretic agent PUI,\IO\

4Rk

EDEM

\

16 A 65 year old white man with dlabete\ melhtu\ diabetic trlopathy and arterlosclerotlc heart dlaeaae experienced rapldly increasing dyspnea over a pellod of \everal days m the absence of chest pam, despite previous dlgltahs maintenance therapy It hen been he was m acute distress with marked dyspned CTanosls, Jugular venous distention to 90°, dlastohc gallop, hepatomegaly of 8 cm, 4-plus edema of both 10% er limbs, and signs of pulmonary edema An electlocardlogram showed dlgltahs effect somewhat less than demonstrated on previous electrocardlograms The patient refused hospltahzatlon and was treated at home with morphme, lanatoslde C and ethacrymc acid 35 mg , all mtravenously In addition, 100 mg of ethacry mc acid twice dally was started orally In 24 hours he had lost 8 lb, m 48 hours 16, and m 72 hours 20 At this time venous distention had dlsappeared, the lung fields were clear, the liver was not palpable and there was no evident edema The patient was weak and thirsty, but blood chemistry values revealed no significant electrolyte abnormahties He has continued to take 50 to 100 mg twice da111 for SIX months and has remained m a Class III D status C~>E

Comment Pulmonary edema developed m this 65 year old white man while he was taking dqltahs, and he refused hospltahzatlon While the addition of lanatoslde C undoubtedly helped, the use of both oral and intravenous ethacrymc acid was felt to be the maJor factor m his 20 lb weight loss m three days and dlsappearance of almost all signs of congestive failure 4SCIlES

AND

EDEMA

DUE

CASE 9

TO

CIRRHOSIS

A 47 year old white woman was admitted to the hospital m hepatlc pre-coma as manifested by profound lethargy, fluctuatmg neurologlc signs and a serum blhrubm of 14 mg Physical exammatlon revealed numerous spider anglomata, weight loss, ascites and marked hepatomegaly Admmlstratlon of chlorothlazlde, 1 gm twice dally, repeated mercurial mJectlons, splronolactone, a 500 mg sodium diet with water restriction, and steroids failed to effect any weight loss during the first week These agents were dlscontmued and ethacrymc acid started, at 100 mg twice dally Nme pounds were lost m 24 hr , 12 lb m 48, and a total of 16 5 lb m 72 hours Ascltes and edema disappeared, and the patient improved sufficiently to be discharged from the hospital Supplementary potassium was VOL UUE

16,

NOVEMBER

1965

nlc Ac Id

735

not given at thla time but !+ds required two months later Ethacrcmc acid was stopped after five month\ and chlorothlazlde, 1 gm twice ddil\ substituted, but a rapid gam m \Lelght required remstltutlon 01 ethacrymc acid The patient has remained on ethacrymc acid therapv for 13 months thu\ fal ltlthout jaundice OI ascltes

Comment This patient m heptatlc pre-coma with ascltes and Jaundice was refractor\ to maximal doses of thlazldes, repeated qectlons of mercurlals, antlaldosterone agents, steroids, a strict sodium diet and water restrlctlon She experienced a 16 5 lb weight loss with three davs of ethacrymc acid therapy and had concomitant climcal improvement For the past 13 months she has been maintained on ethacq mc acid, 100 mg twice da&, with no return of ascltes, and like other patients became edematous when maximal doses of thlazldes were abruptly substltutvd for ethacre mc acid NEPHROTIC

SYNDROME

13 A 14 year old Mexican boy with advanced nephrotlc syndrome of unknown etlologb was hospltahzed with massive anasarca that had not responded to thlazldes or maximal doses of ethacrymc acid (400 mg /day) Intravenous ethacrymc acid 35 mg admmlstered on two successive days was ineffective Predmsone, 60 mg /day was begun, and m 48 hours oral ethacrymc acid, 200 mg twice dally, restarted as the onlv diuretic In three days the patient lost 12 lb Ethacrymc acid was dlscontmued and merallunde. 2 ml , substituted No additional weight loss occurred m the next 24 hr Chlorothlazlde, 1 gm twice dallv, administered next for 24 hours resulted m a 1 5 lb weight loss The latter two dmretlc agents were dlscontinued and ethacrymc acid restarted with an additional weight loss of 16 lb m 48 hr Thus with five days of combined ethacrymc acid and steroids, the patient sustained a weight loss of 28 lb Blood urea nitrogen fell from an admlsslon level of 45 mg to normal The patient was discharged clmlcallv free of edema on predmsone and no dmretlcs but agam became edematous with a 12 lb weight gam within the next few weeks Ethacrymc acid 200 mg twice dally, was therefore remstltuted with a weight loss of 10 lb m three days After three months of dallv therapy with the new dmretlc, chlorothlazlde was substituted without return of edema Steroids have been continued CASE

Comment This 14 year old boy with massive anasarca secondary to ldlopathlc nephrotlc syndrome was mltlally refractory to all dmretlcs, mcludmg ethacrymc acid, but then had massive dmresls when the new dmretlc was com-

736

Wayne,

Kotler,

Ordmarlly predmaone bmed with predmsone does not induce spontaneous dmresls m the In this nephrotlc syndrome for 10 to 21 davs particular instance, the lag m the predmsone effect was evident on the forth and fifth davs when ethacrymc acid was dlsof therapy, contmued and mercurlals and thlazldes subThis stituted wlthout significant weight loss eliminated predmsone as bemg prlmarlly reAddltlonally, edema sponslble for the dmresls returned while he was on predmsone when all The patient dmretlc agents were dlscontmued lost a total of 28 lb after five days of ethacrymc acid therapy and suffered no significant side effects DISCUSSION These studies demonstrate not only the efficacy of ethacrymc acid but also that It can be used dally on an outpattent basis for It exhlblts a prolonged periods of time number of dlstmct characterlstlcs, the most dramatlc of which 1s Its extreme potency Six patients demonstrated 9 to 11 5 lb weight losses wlthm the first 24 hours and three of these were ambulatory at the time It 1s to be emphasized, however, that such rapld and massive dmresls might well cause severe metabohc changes, electrolyte deficlencles, enhanced dlgltahs toxlclty, marked dehydration, hepatlc coma and even mcreased susceptlblhty to thromboembohsm It 1s advisable to admmlster relatively small doses of 25 to 50 mg two to three times per day mmally, regardless of whether the patient 1s m the hospital or ambulatory Larger doses should be reserved for the crmcally 111, resistant or refractory patlent with marked respiratory embarrassment at rest, even these patients may exhlblt satisfactory dmresls on only 100 mg per day In 6 patients with congestive failure, the diuretic was sufficiently effective to permit omlsslon of dlgltahs for many weeks and m 1 If this can be further case for four months documented, ethacrymc acid will be useful m first, m patients with rapld onset two areas of congestive heart failure m the absence of Serum chest pam or other apparent cause enzymes are frequently elevated m these mdlvlduals due to hepatlc congestion Silent myocardlal mfarctlon always has to be excluded m such mstances Unfortunately, it 1s usually necessary to dlgltahze such patients, and the resulting electrocardlographlc changes

McGnr

and

Stolke

are often confused with lschemla Secondly, It 1s not uncommon to see patients with mcreasmg congestive heart failure while on Often it 1s difficult to decide whether dlgltahs such symptoms as the accompanymg weakness, nausea and anorexia are secondary to the failure or to dlgltahs toxlclty Decreasing or increasing the dlgltahs may mtenslfy the symptoms, fatal toxlclty IS not rare m the latter instance Ethacrymc acid may better permit the temporary reduction of dlgltahs dosage m these cucumstances Another Important characterlstlc of ethacrymc acid 1s its ability to cause slgmficant dmresls even m the presence of marked hyThis might ponatremla and hypochloremla partially account for its effectiveness in patients unresponsive to mercurlals and thlazldes It is, of course, known that mercurlals become mcreasmgly meffectlve as hypochloremla develops While thlazldes are somewhat more successful durmg electrolyte and pH imbalance, the more severely 111 patlent eventually beNo comes refractory to both groups of drugs patlent, once responsive to ethacrymc acid, has lost that responsiveness to date In the present series of patients, dmresls did tend to decrease as weight loss contmued, however, this lessening of response was mdependent of electrolyte changes This would suggest that less edema flmd was avallable to moblhze The ablhty to cause dmresls m spite of hyponatremla and hypochloremla would suggest that either the locus of actlon m the proximal tubule was different, or the drug mhlblts a different set of enzymes 8 Furthermore, Its mechamsm or site of action m the distal tubule may be different When one examines the urinary electrolyte excretions m terms of mllhequlvalents per liter, both mercurlals and ethacrymc acid are very slmllar m effect The difference lies m the marked urinary output followmg use of the new diuretic For example, one patlent excreted 6,800 ml and lost 10 lb m 24 hours after ethacrymc acid Forty-eight hours previously, mercurial mIn spite of Jectlon resulted m no weight loss this, urmary outputs for both drugs, m terms of mllheqmvalents per liter, were essentially the same Of extreme mterest 1s the rapidity of onset dmresls beginning m about 15 of actlon, minutes One 95 year old patient, with an mdwelhng catheter attached to a reservon bag, could not take the dmretlc on the mornings THE

AMERICAN

JOURNAI

OF

CARDIOLOGY

Ethacrynlc he was scheduled to be seen, masmuch as the bag; would be overflowmg before he arrived 20 to 30 minutes later Undoubtedly the rapldlty of effect will have some usefulness m the treatment of pulmonary edema H\ pochloremla and h) pokalemla were noted prmlarlly with higher dosages, or with smaller doses with prolonged therapy Supplementary potassium chloride usually averted the electroll te imbalance Evcesslve thirst, urinary frequency, nocturla and nausea were not uncommon and occasionally required dlscontmumg the drug The development of dlarrhea usually necessitated complete withdrawal since even small doses could rarely be tolerated -4 more serious development was noted m 3 patients when ethacrymc acid was dlscontmued and maximal doses of thlazldes subIn each instance there was a ngmfistituted cant and rapid increase m edema \Yhen death occurred during or followmg ethacrvmc acid therapy, the patient was either m a terminal state or had been off therapy for two days to two weeks when death occurred In four instances death was sudden, presumably due to a new myocardlal infarction or pulmonary In only 1 patient was death embolism preceded by significant dmresls, a 77 year old man m terminal failure who had been on ethacrymc acid therapy for only 24 hours Thus there 1s little evidence to suggest that death m these patients was prlmarlly related to ethacrvmc acid therapy SUMMARY Ethacrymc acid, an unusually potent and entirely new class of diuretic unrelated to thlazldes and their derivatives, was admmlstered to 40 patients Twenty-five patients with marked edema secondary to congestive heart failure, cn-rhosls and the nephrotlc syndrome were resistant or refractory to thlazldes or mercurlals, or both, and received the new diuretic dally on an ambulatory basis for 3 to 19 months (average G mo ) Most showed moderate to marked improvement The average weight loss m these resistant patients was 12 lb m five days, with one third to one half of this occurring m the first 24 to 48 hours Ina number of instances, weight losses of 9 to 11 lb m 24 hours, and 15 to 20 lb m 48 to 72 resulted, usually with submaximal doses SlX patients with congestive failure were reasonably

VOLUME

16, NOVEMBER1965

Acid

737

compensated on ethacrymc acid alone without dlgltahs Dmresls was not slqmficanth lmpaired b\ either h\ pochloremla or hbponatremia In patients once responsne to ethacrvmc acid resistance did not develop Hematologlc abnormahtles were not noted Hypochloremla and hypokalemla were seen on occasion when higher dosages were used or when low doses were administered for long periods of time and were corrected with supplementary potassmm chloride Side effects rarely necessitated dlscontmumg the drug The marked potency of ethacrymc acid, Its ablhty to cause dmresls m patients poorly responsor e or refractory to conventional dmretlcs, Its effectiveness m spite of hyponatremla and hypochloremla, and its extremely rapid onset of action will provide a slgmficant therapeutic advance m all types of edema Fmally, Its ablhty to allow the temporary omlsslon of dlgltahs, If this observation can be confirmed, will lessen the dilemma deciding whether a patient 1s under- or overdlgltahzed ACKNOWLEDGMENT The authors wash to thank Douglas Mooney, M n for allowmg them to use the data m Case 4, and W&am H Wrlkmson M D , of Merck Sharp & Dohme Research Laboratories for supplymg the ethacrymc actd

REFERENCES 1 CANNON, P J , AMES, R

2

3

4

5

6

7

8

P and LARACH J H Methylenebutyryl phenoxyacettc acid Novel and potent natrmrettc and dmrettc agent JA M A , 185 854, 1963 DALEY, D and EVANS, B Dmrettc actron of ethacrymc acrd m congestive heart failure Brzt M J. 2 1169, 1963 DOLLERY, C T , PARRY E H D and YOUNG, D S Dmrettc and hypotenslre propertres of ethacrymc actd A comparrson wrth hydrochlorothrazrde Lancet, 1 947, 1964 CANNON, P J, HEINEMANN,H 0, STASON, W B and LARAGH, J H Ethacrymc acrd EffectI\ eness and mode of dmretlc actron m man Czrculatzon,31 5, 1965 MAHER, J F and SCHREINER, G E Studies on ethacrymc acid m patients wrth refractory edema Ann Int Med, 62 15, 1965 MELVIN, K E LY FARRELL>, R 0 and NORTH, J D K Ethacrymc acid i new oral dmretrc Bnt M J, 1 1521, 1963 LEDINGHAM,J G G Ethacrymc acrd parenterally m the treatment and prevention of pulmonary edema Lancet, 1 952, 1964 KOMORN, R M and CAFRUNY, E J Ethacrymc acid Dmretrc property coupled to reactron with sulfhydrvl groups of renal cells Sctence, 143 133 1964