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D.F.P. IN THE TREATMENT OF PARALYTIC ILEU8

By ANTHONY WALSI-I~ F.R.C.S.I.

Jeruis Street Hospital.

p ARALYTIC ileus has been one of the most dreaded complications of abdominal surgery, its evil reputat ion matched only by that of pulmonary embolism. I t commonly proved fatal, and unti l recently

ideas about its etiology were sketchy and confused so tha~ t reatment was empirical and often despairing. Some would belabour the gut with stimulan't drugs, aperients and enemata, while others, pointing out the fut i l i ty of flogging a t i red horse, banned active t reatment and relied on morphine to calm and rest the patient, hoping for natural recovery. Even the merits of morphine were assailed by pharmacologists who in- sis'ted that it must be wrong to exhibit a drug which diminished the tone of a str ip of intestine isolated in the laboratory : nevertheless, more and more surgeons became convinced of the value of morphine, and Chesterman and Sheehan ~ showed that postoperative pain inadequately relieved was a potent fac tor in precipi tat ing paralyt ic ileus.

In the past decade the picture has changed. Increasing knowledge of the importance of fluid and electrolyte balance and of the significance of potassium has led to the general use of intestinal in tubation together with intravenous infusion controlled by biochemical studies in the pre- vention and early t reatment of ileus. The wide spectrum antibiotics and modern anaesthetic techniques have helped to diminish the incidence and the gravi ty of the condition so that established paralyt ic ileus has become rare. Nevertheless, an occasional case is still seen which fails to respond to t reatment along current ly accepted lines and in which D.F.P. may prove valuable.

D.F.P., or di-isopropyl fluorophosphonate, is a by-produc't of research in chemical war fa re : its propert ies were first investigated some ten years ago. I t somewhat resembles physostigmine in that its action is due to a strong inhibition of 'the enzyme cholinesterase, but the inhibition by D.F.P. is irreversible and occurs at much lower concentrations. I t is of some importance that D.F.P. appears to be a more active antagonist of pseudocholinesterase than of t rue cholines'terase. The therapeutic value of the drug rests on its anti-cholinesterase activity, which has been applied in cases of myastheni~ gravis, glaucoma and paralyt ic ileus. The use of D.F.P. in paralyt ic ileus is based on the hypothesis that ileus is due to the product ion of a pseudocholinesterase which blocks the nerve- nmscle junctions in the intestine, thereby inhibit ing normal peristaltic activity. Whereas drugs such as pituitm3" extract and prostigmine used in paralyt ic ileus appear to cause uncoordinated and i r regular contrac- tions of the gut, D.F.P. restores normM peristalsis by counteracting the pseudocholinesterase just as prostigmine will restore the function of voluntary muscle in a curarised patient by direct inactivation of the curare.

D.F.P. is dispensed as a 0-1 per cent. solution in arachis oil and

D.F.P. IN T H E T R E A T M E N T OF P A R A L Y T I C I L E U S 287

adminis tered by in t ramuscular injection of 2 or 3 mls. of the solution. The manufac tu re r s advise that the syr inge and needle and the ampoule should, a f te r use, be immersed in a 2 pe r cent. solution of sodium or potassium hydroxide as the d rug is a dangerous miotic. I feel that these precaut ions are unnecessary as it is a common pract ice among ophthalmologists to dispense an identical p repara t ion of D.F.P. to pat ients for use as eye-drops.

I first obtained D.F.P. ear ly in 1949 through the courtesy of Boots Pure Drug Co., Ltd. The m a n y factors bearing on the development and progress of ileus and the relat ively few cases made a p roper ly con- trolled clinical t r ial out of the question, so I decided to use the drug only in eases of established, progressive ileus which had not responded to t r ea tmen t - -cases which at that t ime seemed to have a hopeless prognosis. This str ict l imitation, for tr ial purposes, of the use of the drug appeared necessary in view of the confusion which had existed about the exact definition of para ly t ic ileus.

I leus may be par t ia l or complete and may affect pa r t or all of the intestine. At one end of the scale is the t empora ry inhibition and i r regular re turn of peristalsis following any abdominal operation, a syndrome depending as much on lack of movement as on abdominal manipulation, as shown by the considerable meteorism developing in pat ients short ly a f te r immobilisation in a plas ter spinal jacket or on a spinal frame. At the other extreme is the desperately ill pa t ient whose entire gut is completely atonic so tha t there is no progress of the ever- increasing intestinal load of fluid and gas. In any consideration of t rea tment it is obviously essential to define the exact point on the scale at which one considers ileus to be present. Quilliam and Quilliam, ~ wri t ing on the use of D.F.P., considered ileus to be present if on the th i rd post-operat ive day two enemata failed to produce either flatus or faeces. The fa i lure to pass flatus is obviously significant, but in itself is not enough in diagnosis. Jacques ~ considered the presence or absence of bowel sounds unreliable as a criterion of para ly t ic i leus: with this view I would most s t rongly disagree. I have discussed elsewhere 7 the value of abdominal auscultation. The bowel sounds are a most impor tan t guide, especially in differentiat ing para ly t ic f rom mechanical obstruction, a distinction which is by no means easy in every case.

F o r the purpose of the present t r ia l pat ients were considered to have established para ly t ic ileus if they had absolute constipation and pro- gressive abdominal distension with vomit ing or aspirat ion of increasing amounts of dark brown fluid of " faecal " character and if prolonged, repeated auscultation revealed no evidence of actively contract ing gut. but only the high-pitched tinkles and passive sounds characteristic of ileus, and finally if they did not respond to a r6gime including relief of pa in by morphine, continuous gastr ic suction with intravenous fluid the rapy controlled as fa r as possible by labora tory studies, and the ex- hibition of systemic penicillin and su]phonamides. Seven pat ients who fulfilled these cri teria were given D.F.P. by in t ramuscular injection. As recommended by the manufac turers , an enema of plain water was ad- ministered half an hour a f te r the injection of D.F.P. As will be seen in the case reports, this enema is of doubtful value, and I now feel that i~ may be omitted.

2~8 I R I S H JOURNAL OF MEDICAL SCIENCE

CASE R E P O R T S . CASE 1 : R . :McC. A g e d 8. Male. 25th Feb. , 1949. A d m i t t e d w i t h appendic i t i s a n d genera l per i toni t is . G a n g r e n o u s

a p p e n d i x r e m o v e d u n d e r genera l a n a e s t h e s i a ( th iopenteno, gas, oxygen , e ther ) . T h e opera t ing su rgeon cons ide red t h a t pa ra ly t i c i leus was ful ly developed a t t he t i m e of operat ion.

Trea ted pos topera t ive ly b y con t inuous gas t r ic suct ion, i n t r a v e n o u s fluids, penici l l in 100,000 u n i t s 2-hourly, su lpha th iazo le 1 g. 4 -hour ly i n t r avenous ly .

26th Fob. , 1949. Gas t r ic a sp i ra t ion increas ing in a m o u n t . 27th Feb . , 1949. Copious gas t r i c asp i ra t ion increas ing. I n c r e a s i n g a b d o m i n a l

dis tension. :hTo f la tus pas sed . 8 p . m . P u l s e 134. A b d o m e n t ense ly d i s t e n d e d a n d s i l en t excep t for occasional

h igh-p i t ched t inkles . 8.12 p . m . D . F . P . 1,5 m l . in jected in t r amuseu la r i ly . 8.15 p . m . Compla in ing o f p a i n in t h e R . I . F . Occasional bowel sounds p r e s e n t . 8.25 p . m . A b d o m e n aga in silent. 8.35 p . m . R e a p p e a r a n c e of ac t ive sounds w i t h colicky p a i n l a s t ing one m i n u t e . 8.45 p . m . P l a i n w a t e r e n e m a , ½ p in t , r e t u r n e d in t h e n e x t 15 m i n u t e s w i t h o u t f l a tus . 9.15 p . m . F u r t h e r col icky pa in . 11.15 p . m . P a s s e d a l i t t le f la tus . l l . 3 0 p . m . P a s s e d m u c h f l a tus a n d t h e n a solid stool w i th f la tus . A n h o u r l a te r

t h e a b d o m e n was v e r y m u c h softer , b u t h e was compla in ing of severe col icky p a i n a n d on a u s c u l t a t i o n the re were a l m o s t c o n t i n u o u s per is ta l t ic sounds of considerable v i o l e n c e - - s o m e a l m o s t explosive in in tens i ty . H e was g iven m o r p h i n e (gr. one- twel f th ) .

28 th Feb . , 1949. Genera l ly v e r y m u c h improved . H e h a d pas sed a l i t t le f u r t h e r f la tus . Bowel sounds aga in d imin i sh ing .

1st March, 1949. 7.45 p . m . H e aga in h a d a n es tab l i shed ileus. Asp i ra t ions increas ing . Pu l se ra te 160. A b d o m e n tense ly d i s t ended . Bowel si lent .

D . F . P . 2 ml . injected in t r amuscu la r i ]y . 7.55 p . m . Occasional per i s ta l t ic sounds heard , a p p r o x i m a t e l y one con t r ac t i on eve ry

two m i n u t e s . 8.5 p . m . S t rong con t inuous per is ta l t ic sounds . 8.15 p . m . P la in w a t e r e n e m a , ½ p in t . 8.30 p . m . E n e m a r e t u r n e d wi th copious f latus. 9 p . m . P u l s e 110, s leeping. H i s progress was t he rea f t e r u n e v e n t f u l . H e c o n t i n ued to pa s s f latus, t he a b d o m i n a l s t ens ion rap id ly decreased a n d his convalescence was i n t e r r u p t e d on ly b y a sub-

phren ic abscess . CASE 2. Mr. N . J . A g e d 35. 14th March, 1949. L ieno . r ena l s h u n t p e r f o r m e d for por ta l hype r t ens ion . Desp i t e

rou t ine m e a s u r e s a l r eady ou t l ined , b y t h e f o u r t h p os t -ope ra t i ve d a y his a b d o m i n a l d i s tens ion was e n o r m o u s ; t he d i a p h r a g m w a s v e r y grea t ly e leva ted so t h a t t h e apex h e a t a p p e a r e d in t h e second left i n t e rcos ta l space. A t th i s s t age 3 ml . D . F . P . were in jec ted i n t r a m u s c u l a r i l y a n d w i t h i n 3 h o u r s t h e p a t i en t pa s sed a ve ry large q u a n t i t y of flatus, followed a n h o u r la ter b y a large l iqu id stool. Convalescence was t he rea f t e r u n e v e n t f u l .

CASE 3. C . B . A g e d 14. Male. 8 th April, 1949. A d m i t t e d w i t h a d iagnos i s of acute pancroa t i t i s . T r e a t e d as above

wi th penicil l in, su lphonamides , gas t r ic suc t ion a n d i n t r a v e n o u s fluids. No per i s ta l t ic sounds were h e a r d in the th ree d a y s following admis s ion and, b y t he even ing o f l l t h April , 1949, t h e a b d o m e n w a s gross ly d i s t ended , only occasional h igh -p i t ched t ink les be ing heard . Gast r ic a sp i ra t ion was increas ing in a m o u n t a n d " faecal " in cha rac t e r .

3 ml . D . F . P . i n j e c t e d i n t r amuscu l a r i l y . F i v e m i n u t e s la ter he h a d m i l d col icky pain , a n d some ac t ive per is ta ls i s was audib le .

A c t i v e per is ta l t ic s o u n d s c o n t i n u e d to be heard . A p la in wa t e r e n e m a 3 hou r s a f t e r t h e D . F . P . in jec t ion was r e t u r n e d w i t h o u t flatus, b u t 8 h o u r s a f t e r t he in jec t ion he b e g a n to pass f la tus . T h e a b d o m i n a l d i s tens ion a n d gas t r ic a sp i r a t ion decreased a n d his fu r the r recovery was u n e v e n t f u l . A b a r i u m mea l j u s t pr ior to d ischarge sugges t ed t he presence of a duodena l ulcer so t h e case m a y , in fact, h ave been one of pe r fo ra t ed ulcer.

CASE 4. Mrs. G. A g e d 68. 19th May , 1949. O p e r a t i o n for s t r a n g u l a t e d v e n t r a l he rn ia . Pos t -ope ra t i ve

gas t r ic suc t ion , i n t r a v e n o u s dr ip a n d penicil l in. 21st May, 1949. Genera l condi t ion de te r iora t ing . A b d o m i n a l d i s t ens ion increas ing.

A u s c u l t a t i o n revea led occasional v e r y h igh -p i t ched b u b b l e s a n d t ink les b u t no ac t ive sounds . F i v e m i n u t e s a f t e r the in jec t ion of 3 ml . D . F . P . , t h e bubb les a n d t ink les in- creased in f r equency and in add i t ion the re were definite, s t rong , ac t ive per is ta l t ic sounds , each o f a b o u t five s econds d u r a t i o n . Three h o u r s la ter a p l a in w a t e r e n e m a was r e tu rned w i t h a l i t t le f la tus . Ac t ive bowel s o u n d s cont inued , a n d 5 hou r s a f t e r t he inject ion of D . F . P . a considerable a m o u n t of f la tus was passed, fol lowed 3 hou r s l a te r b y a large l iquid stool.

F u r t h e r progress was u n e v e n t f u l .

D.F.P; IN THE TREATMENT OF PARALYTIC ILEUS 289

CASE 5. ) I t s . M . P . Aged 62. 2nd J a n . , 1950. T rans tho rac i c s p l e n e c t o m y (Ban t i s y n d r o m e - - a d v a n c e d cirrhosis) . 5 t h J a n . , 1950. Gross a b d o m i n a l d is tens ion, occasional bowel sounds still p resen t . 6 th J a n . , 1950. Comple te para ly t ic ileus, P ro longed auscu l t a t ion revealed no bowel

sounds . Ox-hi le e n e m a recovered wi th some difficulty a n d no f la tus . 6.20 p . m . 3 ml . D . F , P . in jec ted in t r amuscu la r i ly . 9.30 p.m.. P l a i n w a t e r e n e m a : no resul t .

10.10 p . m . F l a t u s passed . 11,15 p . m , Very large q u a n t i t y o f f la tus pas sed . Per i s ta l t i c sounds easi ly audible .

F l a t u s t h e n p a s s e d a t ha l f -hour ly in te rva ls for the res t o f the n igh t a n d bowel s o u n d s d i s t inc t ly aud ib le f rom t h e foot of t h e bed.

7 th J a n . , 1950. Bowels opened normal ly . 8 th J a n . , 1950. Died. A t p o s t - m o r t e m e x a m i n a t i o n i t considered t h a t de~ th h a d

been d u e to acu te l iver fai lure p rec ip i t a t ed b y por ta l t h rombos i s . CASE 6. Mr. B . T . A g e d 62. 23rd Nov. , 1950. P o l y a g a s t r e c t o m y for duodena l ulcer a n d excision of Meckel ' s

d ive r t i cu lum, 25th Nov. , 1950. I n c r e a s i n g a b d o m i n a l d i s tens ion . On rou t ine gastr ic suc t ion ,

i n t r a v e n o u s fluids, penici l l in a n d s t r e p t o m y c i n . Ox-bile e n e m a r e tu rned w i thou t resul t . 261h Nov. , 1950. 9.30 p . m . Cond i t ion de ter iora t ing . A b d o m e n grossly d i s tended ,

w i t h considerable resp i ra tory e m b a r r a s s m e n t . No ac t ive bowel sounds, b u t occasional b u b b l e s heard , h igh -p i t ched a n d booming .

3 ml . D .F .P . injected in t r amuscu la r i ly . 9.40 p . m . W e a k , ac t ive sounds clearly audible in t he a b d o m e n .

11.30 p . m , A fair q u a n t i t y of f la tus passed . 27th Nov. , 1950. 12,30 a . m . P la in wa te r e n e m a , ½ p in t , r e t u rned w i th a ve ry large

q u a n t i t y of f la tus . There was a n i m m e d i a t e i m p r o v e m e n t in his genera l condi t ion and considerable rel ief of t h e resp i ra to ry e m b a r r a s s m e n t .

5.30 p . m . S p o n t a n e o u s bowel ac t ion--- large l iquid stool wi th considerabl6 f la tus . F u r t h e r progress u n e v e n t f u l , CASE 7. Mr. J . P . Aged 26. 291h J a n . , 1951. R i g h t n e p h r o - u r e t e r e c t o m y for h a g m a t u r i a of r igh t rena l origin. 3Oth J a n . , 1951. Bowel s o u n d s present , b u t v o m i t i n g b rown mate r i a l . 31st J a n . , 1951. No fu r the r vomi t ing . 1st Feb . , 1951. V o m i t i n g re turned , g radua l ly becoming " faecal ." 2nd Feb. , 1951. No f la tus p a s s e d since opera t ion. A b d o m e n d i s t ended a n d t y m p a n i t i c .

O n auscu l t a t ion h e a r t sounds were clearly aud ib le low in bo th iliac fossae. Occas ional s l igh t g u t con t rac t ions heard , b u t no t rue per is ta ls is .

11.30 p . m . 2 ml . D . F . P . in jec ted in t ramuscu la r i ly . 3rd Feb , , 1951. 1.40 a . m . Smal l a m o u n t of f la tus passed . 2.30 a . m . P la in w a t e r e n e m a , ½ pint , r e tu rned wi th considerable a m o u n t o f f l a t u s The rea f t e r he c o n t i n u e d to pass f la tus a n d fu r the r progress was u n e v e n t f u l .

The results of uncontrolled clinical trials are notoriously fallacious, but it will be noted that all seven cases appeared relieved of their ileus shortly after the exhibition of D.F.P. and six of the seven recovered, the one death occmTing from portal thrombosis. Without D.F.P. the out- look for these cases seemed hopeless. Abdominal auseult~:tion revealed sounds of active peristalsis very soon (3-10 minutes) after the injection of D.F.P., but the passage of flatus was delayed up to eight hours and usually followed a few hours later by a copious, watery stool

The most important treatment of paralytic ileus is prophylactic. When ileus does occur, gastric (or, if possible, intestinal) suction, careful main- tainance of fluid and electrolyte balance and control of infection by antibiotics are essential in treatment and usually effective. The results presented in this paper suggest that D.F.P. is a valuable auxiliary.

~eferences :

1. C h e s t e r m a n , J . T . and Sheehan , W . J. , (1945), Brit . Med. J . , ii ; 528. 2. C h e s t e r m a n , J . T. , (1946), Brit . Med. J . , i ; 830. 3. Jacques , J . E. , (195I), Lancet, ii, 861. 4. Qui l l iam, J . P. , (1947), Post Grad. Med. J , , 23, 280. 5. Qui l l iam, J . P. , a n d Quil l iam, T. A., (1947), Med. Press ; 218, 378. 6. St reeten, D. H . P. , a n d Ward -McQua id , J . ~ . , (1953), Bri t . 1Fled. J . , ii, 587. 7. Welsh , A., (1955) ; J . I r i sh Med. Assn . , 36, 48.