RANDOMISED TRIAL OF JEJUNOILEAL BYPASS VERSUS MEDICAL TREATMENT IN MORBID OBESITY

Saturday 15 December 1979 RANDOMISED TRIAL OF JEJUNOILEAL BYPASS VERSUS MEDICAL TREATMENT IN MORBID OBESITY The Danish

Obesity Project*

In a randomised clinical trial to assess the value of intestinal bypass in the treatment of gross obesity 130 patients who underwent

Summary

end-to-side jejunoileostomy (with either a 1/3 or a 3/1 ratio between jejunum and ileum left in continuity) were compared with 66 non-surgically treated patients. All patients in the study had gross, long-standing, treatment-resistant obesity with resultant somatic, psychic, or social problems; none were alcoholic or had liver disease or other conditions which made them poor surgical risks. Most subjects were observed for more than 3 years. Median weight loss within 24 months was 42·9 kg in the bypass group, compared with 5·9 kg in the control group. No deaths occurred among those who underwent surgery. Patients who underwent intestinal bypass also had a better improvement in quality of life and a higher degree of patient satisfaction. Complications of the operation were, however, common and occasionally severe. Introduction WHENEVER a new therapy is under serious consideration randomisation should begin with the first patient.! Most surgical procedures are, however, used for many years before their value is assessed by randomised clinical trials; such a delay may cause ethical objections to be raised towards the denial, by randomisation, to some patients of what has become more or less the "treatment of choice". Surgical treatment of morbid obesity is an example of a procedure that has not been properly assessed. The first clinical study of jejunocolic anastomosis was published in 1963,2 and by the end of June, 1976, there were 226 articles in English reporting on 6186 patients with intestinal bypass.3 Recent randomised trials have compared either end-to-side with end-to-end jejunoileostomy4.5 or gastric bypass with intestinal bypass, 6. but to our knowledge there have been no randomised compari-

*The

following took part in the project—O. Backer (Bispebjerg HospiGudmand-Høyer (Gentofte Hospital), B. Andersen and H. Baden (Herlev Hospital, University of Copenhagen), P. Martiny (Holstebro Hospital), E. Juhl, F. Quaade, and K. H. Stokholm (Hvidovre Hospital, University of Copenhagen), O. Noring (Nykøbing Falster Hospital), O. Iversen and S. Madsen (Næstved Hospital), C. M. Madsen and E. M. Mogensen (Odense Hospital, University of Odense), K. Gotlieb Jensen (Ribe Hospital), P. Danø, L. Storgaard, and O. Vagn-Nielsen (Rigshospitalet, University of Copenhagen), A. Marckmann (Sønderborg Hospital), K. Emmertsen, K. E. Petersen, and U. Starup (Vejle Hospital), D. Andersen, L. Mosekilde, and N. Schwartz Sørensen (Arhus County Hospital, University of Århus). tal),

E.

between the surgical treatment of morbid obesity and either medical treatment or no treatment. Having completed some initial trials,8 we decided to do a randomised clinical trial, in which patients eligible for jejunoileostomy were allocated to either medical management or end-to-side jejunoileostomy. Here we report our findings obtained when nearly all patients had been followed-up for more than 3 years after randomisation. Mortality, morbidity, weight loss, and quality of life were assessed. sons

Patients and Methods

Subjects consisted of patients who between September, 1973, and September, 1976, were referred to one of the four-

participating institutions because of a history of longstanding obesity resistant to conventional medical treatment (i.e., diet, fasting, exercise, anorectics, &c). Most were referred for intestinal bypass surgery, which they had learned of through the media. After a physical examination patients were given a detailed explanation of the procedure, particular emphasis being given to the risks, side-effects, and uncertainties. If they were eligible-i.e., had been at least 80% overweight for several years, were resistant to medical and dietary treatment, accepted surgery after detailed information, were aged 18-50 years, agreed to all necessary examinations and follow-up, and had no preteen

vious resectional surgery on stomach or intestines, no manifest no abnormalities in the liver besides fatty metamorphosis, no cardiac, pulmonary, or renal disease, no history of alcohol abuse, and no substantial weight loss in the pretrial period, and showed themselves to be cooperative throughout a pretrial period of at least 2 months-they were randomly allocated to either a medical management or to an end-to-side jejunoileostomy group; the anastomosis was done with either a 3/1 or 1/3 ratio between segments of jejunum and ileum left in continuity. We did not ask for informed consent for randomisation. Patients allocated to medical treatment were told that surgery had to be postponed for an undetermined period primarily because liver-biopsy findings showed fatty infiltration. The shunt was 50 cm except in persons who were more than 120% overweight according to a Scandinavian height and sex adjusted standard.9 They had a shunt of 47.5 cm. All measurements were taken on the mesentery adjacent to the intestine, and the average of three independent measurements was used. After randomisation all patients were seen frequently for 36 months; thereafter the individual departments were free to choose type of treatment. 202 patients were randomised, but 3 from the medical group never turned up again, and from the surgical group 1 refused surgery and 2 had surgery outside the participating institutions. The age, weight, and height of the 196 patients (36 males, 160 females) available for assessment were:

psychosis,

Variable

Age

Weight (W) Height (H) W/IF

Median 32-2 yr

125.3 166.4 45.1

Range 18-50 yr 90-213 kg 145-190 cm 39.5-70.7

kg cm

were similar with regard to age, sex, height, weight, degree to which they were overweight, presence of con-

The three groups

8155

1256 comitant diseases, liver-biopsy findings, and results of biochemical and other hospital investigations. In the medical group 14 patients were lost to follow-up after a median of 9 months (range 1-26 months). The remaining 52 patients have now been observed for a median of 42 months

(range 26-70 months). In the surgical group intestinal continuity has been re-established in 1 patient because of a duodenal ulcer. 2 patients defaulted from follow-up during the second postoperative year. The 130 patients operated on were observed for 2 to 69 months (median 45 months). All patients withdrawn from study or lost to follow-up are known to be alive by July, 1979. A cross-sectional evaluation of quality of life was done in 1977 in most of the participating hospitals. A questionnaire with 177 questions pertaining to social circumstances as well as to somatic and psychic symptoms was sent to 111 patients in the surgical group and to 55in the medical group at least 15 months after randomisation. The response-rate was 98%. The changes in symptoms and circumstances brought about by the operation were also assessed by a retrospective interview of 83 patients 18-24 months after surgery.

Results

By July, 1979 (the closing date for this assessment), there have been no deaths among patients allocated to surgery (95% confidence limits of fatality-rate, 00-2-7%). 2 patients in the medical group died. 1 had fatty metamorphosis in the initial liver biopsy specimen and normal liver chemistry. Raised liver enzyme levels 1 year later led to a repeat biopsy. He died from a succession of unusual complications of the biopsy. Necropsy showed cirrhosis of the liver. The other patient had bypass surgery after 4 years of medical treatment. He acquired cirrhosis of the liver and bleeding duodenal ulcer and died after restoration of intestinal continuity. There have been no anastomotic leaks and no major pulmonary emboli, but 3% of the patients operated on had other pulmonary complications and 6% had either wound infection or dehiscence. 2 patients had severe but transient hepatic dysfunction. Other complications, early and late, that we encountered did not differ substantially from those reported in large surveys of patients who had undergone jejunoileostomy.3.10 During the first 24 months after randomisation statistically significant (p<0’01) weight losses occurred in the medical as well as in the surgical group, but the median weight loss 24 months after randomisation was only 5 - 9 kg in the medical group (range from -11-9 to 40.4 kg). Weight loss 24 months after jejunoileal bypass ranged from 20.5to 108.5kg with a median of 42.9 kg, but 25% of the patients lost less than 35.1kg. Beyond 24 months only minor weight changes were observed. The differences in weight loss between medical and surgical treatment were highly significant (p<0-001). Late gains in weight have been observed in the surgical group but, perhaps because of the limited duration of observation, they have so far been minor and infrequent. Most of the patients operated on are still obese. Although 54% are less than 30% overweight, only 11% have reached a normal weight. Although 68% of the surgical group considered their present weight too high, 83% were satisfied with the operation. 78% declared their willingness to go through it all over again, if necessary. A substantially greater weight loss was observed after the 47-5 cm shunt (median 60.3 kg) than after the 50

cm

shunt

however,

(median 40.1kg) (p< 0-01). Shunt length was, not decided by allocation, but by degree of

weight excess. No significant

differences in weight loss were found between those who had shunts with 3/1 and those who had shunts with 1/3 ratio between jejunum and ileum left in continuity. Replies to the questionnaire on quality of life revealed many differences between the medical and the surgical group which were probably attributable to the operation and which taken together suggest considerable improvement in quality of life in patients with a steady postoperative weight. The accompanying table summarises replies to 52 questions with statistically significant differences between patients operated on and those not

operated on. The retrospective

evaluation of quality of life by interview revealed the same findings. Dissatisfaction with the outcome of surgery was almost exclusively due to insufficient weight loss. The major benefits were increased capacity for work, improved social contacts, and increased self-esteem. Neither method of assessing quality of life showed statistically significant differences in urogenital symptoms, sleep patterns, employment, absence from work, disability pension, marital status, housing, or economic circumstances.

(52 PATIENTS) AND (110 PATIENTS) IN REPLIES TO

DIFFERENCE BETWEEN MEDICAL GROUP -

SURGICAL GROUP

QUESTIONNAIRES

*x2 test, df= 1.

ON

QUALITY

OF LIFE

1257 Discussion

Massive obesity is a severe social, physical, and psychological handicap, and failures are common with all non-surgical treatments, including therapeutic starva-

tionll.12 and behavioural treatment.13 This is of

one of the has become

obesity why surgical widely practised. With jaw wiring most patients regain weight after removal of the wires. 14 Gastric bypass limits food intake without interfering seriously with digestion and absorption, 15 and it produces an acceptable weight loss with substantially less serious side-effects than intestinal bypass.6,7.16 Vagotomy is still in the pilot trial stages. 17 Although the merits of jejunoileostomy have yet to be definitely proven, it is the yardstick by which new surgical treatments are compared. There are only minor difreasons

treatment

ferences between end-to-side and end-to-end anastoMoses, 4,5 and within the range of shunt lengths in the literature, the reported number of centimetres in continuity may be less important than the method of measurement. In a survey based upon 2500 patients with a varying, but generally limited, duration of observation, overall mortality after jejunoileostomy was 3.1%.10 From the report by DeWind and Payne18 we have estimated, by the life-table method, that their 230 patients had an 11.1% 5-year mortality-rate. Unfortunately mortality rates in matched cases of untreated, extreme obesity are not available, but they are likely to be substantially better’9 since the typical shunt patient is in her/his thirties. The important early complications are wound infection, dehiscence, thromboembolic and pulmonary complications, and anastomotic leaks. Other side-effects are diarrhoea, lassitude, hypokalxmia, hair loss, vomiting, and foul-smelling flatus.1O Many patients require readmission and surgery for incisional hernias, anal fissures and haemorrhoids, abdominal aprons, or revisions of the bypass. Among 101 bypass patients 58% either had life-threatening complications, had to be reanastomosed, or died.2O Serious complications of jejunoileostomy3,1O include biliary calculi, hyperoxaluria and urinary-tract calculi, nephrocalcinosis, acute reversible renal failure, acidosis, transient mild impairment of liver function, cirrhosis and fatal liver failure, arthritis, magnesium and calcium malabsorption, osteomalacia and metabolic bone disease,21 copper and zinc malabsorption,22 disturbed immunological function,23 portal venous occlusion,24 colonic pseudo-obstruction, atrophic beriberi,zs intestinal pneumatosis,26 and tuberculosis. Most of these complications are reversible, but they may require reconstitution of gastrointestinal continuity. Drug absorption and hepatic drug metabolism with regard to phenazone were unaffected 12-57 months after bypass.27 Pregnancy and normal delivery is possible after shunting. 28 The main beneficial effect of jejunoileostomy is a weight loss of 35-50 kg, or 30-50% of initial bodyweight.10 The rate of weight loss depends primarily on length of functioning intestine and on initial bodyweight.10 Weight loss is due partly to malabsorption and partly to a reduced calorie intake and improved eating

patterns.30 Associated with weight loss are psychosocial improvements, the most important being a loss of self-dislike, in-

security, and sense of failure." Despite improvement in work capacity, interpersonal relationship, leisure-time activity, and adjustment to daily life,31 marital discord may occur.32 In most diabetic patients normal fasting blood sugar and normal glucose-tolerance test are restored.33 Approximately half of very obese persons have hyperlipoproteinsemia and hypercholesterolsemia, which usually revert to normal or subnormal levels.34.35 Whether these changes will favourably influence the long-term morbidity and mortality associated with

obesity has yet to be proven. Kral and Bondjers36 found that arterial cholesterol content increased after severe

shunting. So little is known about the prognosis of persistent obesity that the justification for surgery is still in doubt. Our trial may have served to clarify some of the issues. The short-term findings favour jejunoileostomy ; however, because the weight loss is often insufficient shunt length should be less than 50 cm, or the bypass should be revised whenever necessary. The obvious limitation in our study is the short duration of observation. Late weight gains, osteomalacia, and liver damage are some of the factors which may lead us to revise our conclusions. Another limitation is the fact that although surgical treatment was fairly uniform, controls received different medical treatments carried through with varying degrees of dedication. A factor that could have produced bias in our assessment of quality of life is that the control patients were the ones who hoped most for bypass eligibility while at the same time being given the least effective conservative help; their dissatisfaction with their obesity could be overstressed. Another possible source- of bias in our assessments based upon patient satisfaction may be the belief that entry into the trial indicated that what was previously considered despicable consequences of a weak character has become a serious disease necessitating drastic surgery. A problem shared by all studies on jejunoileostomy is the self-selected nature of the surgical patients. Reports such as ours expressing cautious optimism about this surgical treatment for obesity may lead to more patients wanting and obtaining surgery. Such new cases may have fewer or less serious consequences of obesity, and accordingly less tolerance towards the sideeffects of jejunoileal bypass. extreme

Requests for reprints should be addressed to: Bjam Andersen, department of surgical gastroenterology, Herlev University Hospital, DK 2730 Herlev, Denmark. REFERENCES 1. Chalmers TC. When should randomisation begin? Lancet 1968; i: 858. 2. Payne JH, DeWind LT, Commons RR. Metabolic considerations in patients with jejunocolic shunts. Am J Surg 1963; 106: 273-89. 3. Philips RB. Small intestinal bypass for the treatment of morbid obesity. Surg Gynecol Obstet 1978; 146: 455-68. 4. Baddeley M. The results of two techniques of jejuno-ileostomy. Br J Surg

1976; 63: 149. Jewell WR, Hermreck AS, Hardin CA. Complications of jejunoileal bypass for morbid obesity. Arch Surg 1975; 110: 1039-42. 6. Buckwalter JA. A prospective comparison of the jejunoileal and gastric bypass operations for morbid obesity. World JSurg 1977; 1: 757-68. 7. Griffen WO Jr, Young VL, Stevenson CC. A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity. Ann Surg 1977; 5.

186: 500-07. 8.

9.

Juhl E, Quaade F, Baden H. Weight loss in relation to the length of small intestine left in continuity after jejunoileal shunt operation for obesity. Scand J Gastroenterol 1974; 9: 219-21. Lindberg W, Natvig H, Rygh A, Svendsen K. Høyde- og vekt-undersøkelser hos voksne menn og kvinner. Tidskr norske Lægeforen 1956; 76: 361-68.

1258 DOUBLE-BLIND TRIAL OF ANTIHYPERTENSIVE EFFECT OF CHLOROTHIAZIDE IN SEVERE RENAL FAILURE

failure. To

knowledge previously reported. our

no

such

study

has been

Patients and Methods B.

JONES

R. S. NANRA

Department of Nephrology, Royal Newcastle Hospital, Newcastle, NSW 2300, Australia

Summary

A randomised double-blind trial was done to assess the

crossover

efficacy of chlorothiazide as an antihypertensive drug in patients with severe renal failure. There was a significant reduction in standing (mean drop 13/6 mm Hg) and supine (mean drop 13/5 mm Hg) blood-pressure, without postural hypotension. Chlorothiazide has a place in the management of hypertension in patients with severe renal failure and its antihypertensive effect is probably due to a change in peripheral vascular resistance and not to volume contraction. Introduction ALTHOUGH thiazide diuretics have been widely used in the treatment of essential hypertension for almost two decades, their value in the management of hypertension associated with severe renal failure has been much less certain. The natriuretic response associated with thiazide therapy progressively diminishes with a decline in glomerular filtration rate (GFR) and is virtually absent when the GFR is less than 20 ml/min.1 Thiazide diuretics have therefore been assumed to have no antihypertensive activity in advanced renal insufficiency. There is, however, evidence to suggest that thiazides may have an antihypertensive effect independent of their diuretic action and that this may be mediated by a direct effect on vessels.2.3 To test this hypothesis a study was undertaken to evaluate the efficacy of chlorothiazide in the management of hypertension in patients with severe renal

Bray GA, Greenway FL, Barry RE, et al. Surgical treatment of obesity: a review of our experience and an analysis of published reports. Int J Obesity 1977; 1: 331-67. 11. Johnson D, Drenick EJ. Therapeutic fasting in morbid obesity. Arch Intern

10.

Med 1977; 137: 1381-82. JA, Campbell IW, Campbell CJ, Needle AI, Munro JF. Long-term follow-up of therapeutic starvation. Br Med J 1974; ii: 356-59. 13. Currey H, Malcolm R, Riddle E, Schachte M. Behavioral treatment of obesity. JAMA 1977; 237: 2829-31. 14. Rodgers S, Burnet R, Goss A, Phillips P, Goldney R, Kimber C, Thomas D, Harding P, Wise P. Jaw-wiring in treatment of obesity. Lancet 1977; i:

12. Innes

1221-22. 15. Mason EE, Printen

KJ, Hartford CE, Boyd WC. Optimizing results of gastric bypass. Ann Surg 1975; 182: 405-13. 16. Alden JF. Gastric and jejunoileal bypass. Arch Surg 1977; 112: 799-804. 17. Kral JG: Vagotomy for treatment of severe obesity. Lancet 1978; i: 307-08. 18. DeWind LT, Payne JH. Intestinal bypass surgery for morbid obesity. JAMA 1976; 236: 2298-301. 19. Sørensen TIA, Sonne-Holm S. Mortality in extremely overweight young men. J Chron Dis 1977; 30: 359-67. 20. Halverson JD, Gentry K, Wise L, Ballinger WF. Reanastomosis after jejunoileal bypass. Surgery 1978; 84: 241-49. 21. Parfitt AM, Miller MJ, Frame B, et al. Metabolic bone disease after intestinal bypass for treatment of obesity. Ann Intern Med 1978; 89: 193-99. 22. Faber J, Randolph JG, Robbins S, et al. Zinc and copper status in young patients following jejunoileal bypass. J Surg Res 1978; 24: 83-86. 23. Hallberg D, Nilsson BS, Backman L. Immunological function in patients operated on with small intestinal shunts for morbid obesity. Scand J

Gastroent 1976; 11: 41-48. R, Gray R, Goldstein L. Portal venous occlusion. Digest Dis 1978; 23 (suppl): 59-61.

24. Metz

16 female patients with analgesic nephropathy and creatinine clearances below 25 ml/min/115873 m2 were studied in a randomised double-blind crossover study. The mean age of those included in data analysis was 54 years (range 43 to 65), and the creatinine clearance (ml/min/1-73 m2) ranged from 5 to 24 with a mean of 14+2 (SEM). All patients were taking chlorothiazide 0-5 g twice a day before entry into the trial; other antihypertensive drugs being taken were methyldopa (6 patients, mean dose 860 mg daily), hydrallazine (2 patients, mean dose 130 mg daily), frusemide (2 patients, mean dose 160 mg daily) propranolol (7 patients, mean dose 110 mg daily), clonidine (3 patients, mean dose 650 ;’.g daily), and debrisoquine (1 patients, 20 mg daily). Either placebo or active drug (chlorothiazide 0.5 g) was given twice daily for 6 weeks, followed by 6 weeks of the alternative tablet. No formal dietary analysis was made, but each patient was encouraged to keep dietary habits constant, and sodium intake was monitored by urinary sodium excretion levels. Blood-pressure was measured supine after 5 min of rest, and then after 2 min of standing, by the one observer who used the same mercury sphygmomanometer for each case. Phase I and phase iv Korotkoff sounds were taken as systolic and diastolic blood-pressures, respectively. Blood-pressure was recorded weekly, and antihypertensive drugs were altered only if the diastolic blood-pressure exceeded 120 mm Hg on two successive weeks, or if hypotension with symptoms occurred. Body-weight, 24 h urinary sodium and potassium excretion, 24 h creatinine clearance, and serum electrolytes, creatinine, urea, and uric acid were also measured weekly. Hxmoglobin was measured twice during each 6-week period. Plasma-renm activity from peripheral venous blood was measured under standardised conditions within 2 weeks of the end of the trial; sodium and potassium supplements and diuretics were stopped for 3 days and the patients were ambulant for at least 4 h before blood collection. Criteria for withdrawal from the trial were alteration in antihypertensive medication, change in body-weight greater than 1 kg, or intercurrent illness.

25. Glad BW, Hodges RE, Mechas CA, et al. Atrophic berberi. A complication of jejunoileal bypass surgery for morbid obesity. Am J Med 1978; 65: 69-74. 26. Clements JL, Jr. Intestinal pneumotosis-a complication of the jejunoileal bypass procedure. Gastrointest Radiol 1977; 2: 267-71. 27. Andreasen PB, Danø P, Kirk H, Greisen G. Drug absorption and hepatic drug metabolism in patients with different types of intestinal shunt oper-

28.

ation for obesity. Scand J Gastroenterol 1977; 12: 531-35. Ingardia CJ, Fischer JR. Pregnancy after jejunoileal bypass and the SGA in-

fant. Obstet Gynecol 1978; 52: 215-18. Bray GA, Barry RE, Benfield JR, Castelnuovo-Tedesco P, Rodin J. Intestinal bypass surgery for obesity decreases food intake and taste preferences. Am J Clin Nutr 1976; 29: 779-83. 30. Solow C, Silberfarb PM, Swift K. Psychosocial effects of intestinal bypass surgery for severe obesity. N Engl J Med 1974; 290: 300-04. 31. Danø P, Hahn-Pedersen J. Improvement in quality of life following jejunoileal bypass surgery for obesity. Scand J Gastroenterol 1977; 12: 769-74. 32. Neill JR, Marshall JR, Yale CE. Marital changes after intestinal surgery. JAMA 1978; 240: 447-50. 33. Fielding JWL, Baddeley RM. The effect of small bowel bypass on diabetes mellitus. Br J Surg 1978; 65: 30-32. 34. Scott HW Jr, Dean RH, Younger RK, Butts WH. Changes in hyperlipidemia and hyperlipoproteinemia in morbidly obese patients treated by jejunoileal bypass. Surg Gynecol Obstet 1974; 138: 353-58. 35. Scott HW Jr, Dean RH, LeQuire V, Swift LL, Younger RK, Butts WH. Alterations in plasma lipid concentrations in normal and hyperlipidemic patients with morbid obesity before and after jejunoileal bypass. Am J Surg 1978; 135: 341-47. 36. Kral JG, Bondjers G. Increased arterial-tissue cholesterol after intestinal bypass in severe obesity. Lancet 1978; ii: 288-89.

29.