Topics in Clinical Nutrition October 1996: 324-328

Enteral Feeding Associated Gastroesophageal Reflux and Aspiration Pneumonia: A Review Nadeem Kazi, M.D. and Sohrab Mobarhan, M.D.

Hospital malnutrition continues to be a serious problem. Although en feral feeding of hospitalized patients is safe and less expensive than paren- feral feeding, it is associated with side effects in- volving the gastrointestinal tract and respiratory systems.

Malnutrition is recognized as a serious concern in the hospitalized patient. Studies show that 40-50% of hospitalized medical and surgical patients suffer significant protein-calorie maln~tri t ion. ' -~ More than 780,000 hospitalized patients receive enteral feeding each year, 50% of whom are above 65 years of age.4 Aside from its lower cost, enteral feeding is preferred to parenteral nutrition support because it is safer and carries a decreased prevalence of sep- s ~ s . ~ . ~ However, enteral feeding is associated with a number of complications, particularly those involv- ing the gastrointestinal tract and the respiratory sys-

Complications of Enteral Feeding

Gastrointestinal Gastroesophageal reflux (GER) occurs in critically ill patients even in the absence of nasogastric (NG) tubes and enteral feedings; up to 30% of patients who are kept in the supine position are estimated to have GER. At least two studies have shown a re- duction of GER when critically ill patients are kept in the semirecumbent p o s i t i ~ n . ~ . ' ~ The upper gastro- intestinal tract of a critically ill patient receiving enteral feedings is additionally challenged by (1) gastrointestinal intubation, (2) rate of feeding, and (3) type of enteral formula.l'J2

Nadeem Kazi, M.D., is a G.I. Nutrition Fellow and Sohrab Mobarhan, M.D., is Professor of Medicine and Co-chairman Department of Gastroenterology and Di- rector of Nutrition, Loyola University Medical Center, Department of Gastroenterology, 21 60 First Avenue, Maywood, IL 60153, USA.

The lower esophageal sphincter (LES) has been recognized for more than three decades as the pri- mary physiologic factor preventing GER.I3 A num- ber of studies in a d ~ l t s ' ~ - l ~ and childrenI9 with or without reflux disease have examined the relation- ship of LES pressure to Occurrence and time of re- flux, using concurrent measurements of esophageal motility and pH. One consistent finding has been that under resting conditions, LES pressure has to be absent for reflux to occur. The NG tube may predispose a patient to reflux by interfering with LES function, as well as prolonging esophageal contact time with refluxed gastric contents.20.21

The majority of enteral feeding tubes remain in the stomach, and even those placed into the duo- denum frequently migrate back into the stomach. Regurgitation occurs even in patients with well- placed NG tubes and less frequently in patients with nasoduodenal (ND) or nasojejunal (NJ) tubes.22 Several studies have shown that NG tubes may in- crease the prevalence of GER in supine patients from 15% to 80% of cases.11J2 Placement of an NG tube may be associated with profound esophagitis within a 24-36-hour period, although it is more commonly observed after a week or more of intu- batiom8

It is commonly accepted that high gastric resid- ual volumes secondary to gastric distention enhance regurgitation and may increase the risk for aspira- tion pneumonia. Fluids that commonly accumulate in the gastrointestinal tract of a tube-fed patient in- clude the tube-feeding formula, swallowed saliva p 0 . 8 L/day), gastric secretion (1.5 Wday), and re- gurgitated small bowel secretion (2.7-3.7 Uday) into the stomach.I0 When gastrointestinal motility is normal, secretions and ingested fluids are propelled forward and absorbed with little difficulty. Signifi- cant gastrointestinal dysmotility, ranging from mod- erate delay in gastric emptying to marked gastric paresis, has been described in patients with a variety of clinical conditions such as bums, sepsis, trauma, surgery, and s h o ~ k . ' ~ . ~ ~ . ~ ~

The type of feeding also influences the preva-

324 Nutrition Reviews, Vol. 54, No. 70

lence of GER and perhaps pulmonary aspiration as well. For example, the placement of a percutaneous endoscopic gastrostomy (PEG) tube does not appear to affect LES pressure. Studies with patients who received enteral feeding via PEG have shown a de- crease in LES pressure with associated reflux when a bolus feeding method was used. No GER was noted when a continuous feeding pump was used.25

Diet composition also influences gastric emp- tying and GER. We have recently shown profound prolongation of gastric emptying with diets that are high in fat (55%) compared with diets that have a moderate fat content.26 The type of fatty acids, pro- teins, and polypeptides also modulate stomach mo- tility and may ultimately delay gastric emptying and increase the prevalence of GER.

The duodenum and jejunum remain functional during critical illness and in the postsurgery period and, hence, may be used for early enteral feeding.27 However, there is also significant evidence that the motility of the portion of the gastrointestinal tract is affected by a variety of medications, including anticholinergic agents, hypnotics, narcotic analge- sics, and tricyclic antidepressants." A study con- ducted at Loyola University Medical Center ob- served 18 patients receiving enteral feedings over a period of 2 weeks; results showed that these patients received only 75-78% of their required energy and protein intakes. The primary causes of disruption in enteral feeding were delayed gastric emptying and pulmonary aspiration.

Pulmonary In a carefully conducted population-based cohort of 97 patients receiving enteral feeding via PEG, Tay- lor et a1.28 have shown that the probability of 30-day, 1-3-year, and 4-year survival after referral for PEG was 78%, 35%, and 27%, respectively. The major causes of death within and after 30 days were pneumonia, heart disease, and vascular disease of the central nervous system. The incidence of pneu- monia was 5570, 41%, and 42% in 0-30 days, 31 days to 1 year, and follow-up, respectively.28 The overall contribution of GER and regurgitation to the development of pneumonia noted by Taylor et a1.28 is not yet known. However, it is estimated that at least 50% of the pneumonia cases are due to GER, while the remaining cases are caused by orophar- yngeal aspiration andor are of atelectatic origin.

Preventing GER and Aspiration Pneumonia

Monitoring Gastrointestinal Residual Volume Elevated gastric residual volume (2150 mL) is a frequent cause for cessation of enteral feeding. Even with delivery of tube feedings into the small bowel,

significant pulmonary aspiration can occur if the stomach is distended with gastric secretion^.^^ To prevent gastric distention, gastric decompression by NG tube or surgical gastrostomy is recommended for patients with abnormal gastric motility even when feedings are introduced into the jejunum.30

In one study,3' researchers reviewed the medical records of 50 patients receiving tube feedings via NG tube. They noted that residual volumes were recorded as recommended by hospital protocol only 55-60% of the time. Recommendations vary as to the frequency with which residual volumes should be measured. We (and others) recommend checking residuals every 4 hours in continuously fed pa- t i e n t ~ ~ ~ or immediately before each intermittent feeding.33 In our experience, high gastric residual volume is a common cause of disruption of tube feeding.-In our hospital, 33% of the patients re- ceiving enteral tube feeding did not meet target lev- els of calories and protein, secondary to high gastric residual volumes.

Therapeutic Role of Prokinetic Agents Prokinetic agents, which increase LES tone and stimulate gastric emptying, are appealing for the therapeutic management of GER. These drugs in- fluence gastrointestinal motility through one or more of the following pathways: (1) directly or in- directly promoting cholinergic tone; (2) antagoniz- ing inhibitory neurotransmitters, such as serotonin and dopamine; and (3) mimicking noncholinergic nonadrenergic compounds that increase motility. The most commonly used prokinetic agents are be- thanechol, metoclopramide, erythromycin, and the new prokinetic agent cisapride.

Befhanechol Bethanechol is a direct cholinergic agonist and was the first smooth muscle stimulant used to treat pa- tients with GER. Bethanechol increases LES pres- sure and esophageal clearance34 but has little efect on coordinating contraction, accelerating gastric emptying, or small bowel transit.35 As a cholinergic agent, it has the negative effect of stimulating gas- tric acid secretion. At a therapeutic dose of 25 mg four times a day, bethanechol is often not well tol- erated. Side effects of bethanechol, inc'liding ab- dominal cramps, diarrhea, urinary freqLency, sali- vation, flushing, bradycardia, and blurred vision, de- velop as a result of enhanced parasympathetic tone. The side effects have limited its use as a treatment for GER.

Metoclopramide Metoclopramide is a dopamine receptor antagonist. Blockade of dopamine receptors by metoclopramide

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allows the cholinergic arm, which is stimulatory, to gain ascendancy. Thus, the gastrointestinal actions of metoclopramide are described as cholinergic or as enhancing acetylcholine action and resembling the actions of bethanechol. Metoclopramide increas- es LES pressure and the amplitude of esophageal contraction^,^^ but in contrast to bethanechol, it also accelerates gastric emptying in retention states as well as normal emptying rates.37

Metoclopramide is well absorbed after oral ad- ministration. The onset of pharmacologic action is apparent in 30-60 minutes and persist for 2 hours. The half-life of metoclopramide is 3-6 hours, but impairment of renal function proportionally extends the half-life to as much as 24 hours. Removal of the drug by dialysis is feasible in patients with renal failure.38 Metoclopramide crosses the blood-brain barrier and has antiemetic actions as a dopamine receptor antagonist. The recommended dose of me- toclopramide is 10 mg before meals and at bedtime.

The limiting factors in metoclopramide use are its side effects. The incidence of side effects is com- monly reported to be between 10% and 20%, but some reports note side effects in more than 30% of patient^.^^-^' The most common side effect results from central nervous system effects, secondary to intracerebral dopamine antagonism. These side ef- fects vary in severity from mild anxiety, nervous- ness, insomnia, and depression to the more dis- abling symptoms of confusion, disorientation, and hallucinations. The most troublesome are the extra- pyramidal side effects of tremor, akathisia, tardive dyskinesia, and other dystonic reactions that mimic Parkinson's disease.42-+' Metroclopramide-induced elevation of the prolactin level and peripheral anti- dopamine effect may cause reversible amenorrhea and galactorrhea in women and nipple tenderness and gynecomastia in men.4s.46

Erythromycin Erythromycin is a macrolide antibiotic with a mo- tilin-like effect.47 Like motilin, erythromycin induc- es phase 3 activity of gastrointestinal migrating mo- tor complex. Erythromycin is used primarily as a prokinetic agent in diabetic gastroparesis, given at a dose of 250 mg 15-30 minutes before meals. Pa- tients with postvagotomy gastroparesis who had not responded to bethanechol or metoclopramide treat- ment did respond to 250 mg of oral erythromycin taken 30 minutes before meals.48 Erythromycin in- creases the LES pressure in the fasted49 and in the fed state.50 The effects of erythromycin on esopha- geal motility and on gastric emptying indicate that it may be useful in the treatment of GER; one study noted that the GER caused by white wine was re- versed by infusion of 3.5 m g k g erythromycin be-

fore inge~t ion .~ ' More recently, Pennathur et al. showed that erythromycin significantly increased the defective LES pressure in patients with GER disease.52

The common side effects of erythromycin are epigastric pain, nausea, vomiting, abdominal cramps, bloating, diarrhea, and fungal infections. Tanis et al. investigated the long-term effects of oral erythromycin on gastric emptying and intestinal motility, but they had to discontinue the study be- cause of the side effectss3 In our experience, pa- tients recieving erythromycin for gastroparesis de- veloped resistance to erythromycin in 2-3 weeks.

Cisapride Cisapride is an oral gastrointestinal prokinetic agent that is rapidly absorbed after oral administration. Plasma concentration reaches its peak in 1-1.5 hours, with a mean half-life of 6-12 hours. The on- set of its pharmacologic action is approximately 30-60 minutes after oral administration. The mech- anism of action of cisapride is thought primarily to be an enhancement of acetylcholine release at the myenteric plexus. Cisapride does not induce mus- carinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity.

Cisapride increases LES pressure in both normal volunteers and patients with reflux. After a 10-mg dose, the LES pressure in patients with reflux in- creases and reaches the values achieved by normal

Cisapride also increases gastric emptying in healthy subjects,55 patients with GER and patients with gas t r~pa res i s .~~ Rajendran et al. have shown that the administration of cisapride sig- nificantly decreases the mouth-to-cecum transit time.58 A recent well-controlled study of 21 patients on enteral feeding and mechanical ventilation showed a significant increase in gastric emptying in those patients receiving cisapride as compared with a placebo group over a period of 1 week's obser- ~ a t i o n . ~ ~ However, this study was done only on pa- tients on mechanical ventilation; GER and aspira- tion pneumonia were not evaluated.

Cisapride is contraindicated for patients in whom an enhancement of gastrointestinal motility could be harmful, such as in the presence of gastro- intestinal hemorrhage, mechanical obstruction, or perforation. It is also contraindicated in patients with known sensitivity and/or intolerance to this drug. In the past year there have been some reports of QT interval prolongation and ventricular arrhyth- mia, including torsades de pointes, in patients re- ceiving other medications in conjunction with cis- apride. The reported rate of serious ventricular ar- rhythmia is estimated to be 1 per 120,000 cases. It appears that agents that inhibit P450 enzyme sys-

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tems (3A4), such as ketoconazole, may cause a marked elevation of plasma concentrations of cisa- pride. The manufacturer of cisapride suggests that the coadministration of antifungal agents such as ketoconazole with cisapride has been the cause of the cardiac arrhythmias. Accordingly, it is recom- mended that cisapride should not be given with ke- toconazole or other antifungals, including itracona- zole, miconazole, and troleandomycin.

Summary

It appears that there are many factors influencing the prevalence of aspiration in patients receiving en- teral nutrition. Although the position of the tube and the supine position of the patient may be contribu- tory factors, the most important factor is probably altered coordination of the delicate motility of the esophagus, stomach, duodenum, and jejunum in de- bilitated patients.

Bethanechol, metoclopramide, and erythromy- cin have been used extensively in the past but are not very effective in reducing reflux. They also have significant clinical side effects; most significant of which are the extrapyramidal neurologic complica- tions seen with metoclopramide. Although the ef- fectiveness of cisapride, which has fewer side ef- fects, has been shown in patients with GER, its use- fulness in preventing reflux and aspiration pneu- monia has not been effectively evaluated in tube-fed patients.

1.

2.

3.

4.

5.

6.

7.

8.

9.

Bistrian BR, Blackburn GL, Hallowell E, Heddle R. Protein status of general surgical patients. JAMA 1974;230:858-60 Hill GL, Blackett RL, Pickford I, et al. Malnutrition in surgical patients. An unrecognized problem. Lancet 1977; 1 :689-92 Bistrian BR, Blackburn GL, Vitale J, Cochran D, Nay- lor J. Prevalence of malnutrition in general medical patients. JAMA 1976;235: 1567-70 Maslow K. Total parenteral nutrition and tube feeding for elderly patients: finding of an OTA study. JPEN 1988;12:425-32 Jones KW, Seltzer MH, Slocum BA, Cataldi-Betcher EL, Goldberger DR, Wright FR. Parenteral nutrition complication in a voluntary hospital. J Parenter En- teral Nutr 1984;8:385-91 Cataldo-Betcher EL, Seltzer MH, Slocum BA, Jones KW. Complication occurring during enteral nutrition support: a prospective study. J Parenter Enteral Nutr 1983;7:546-52 Bastow MD. Complication of enteral nutrition. Gut

Blackstone MO. Endoscopic Interpretation: Normal and Pathological Appearances of the Gastrointestinal Tract. New York, NY: Raven Press, 1984 Elpern EH, Jacobs ER, Bone RC. Incidence of as-

1986;27:51-5

piration in tracheally intubated adults. Heart Lung

10. lbanez J, Penafiel A, Raurich J, Marse P, Jorda R, Mata F. Gastroesophageal reflux in intubated pa- tients receiving enteral nutrition: effect of supine and semirecumbent positions. J Prenter Enteral Nutr 1992; 16:419-22

11. Melnik G. Pharmacologic aspects of enteral nutrition. In: Rombeau JL, Caldwell MD, eds. Clinical Nutrition: Enteral and Tube Feeding. Philadelphia, PA: WB Saunders, 1990 472

12. Zaloga G. Enteral nutrition in hospitalized patients: a summary. In: Enteral Nutrition Support for the 7990s: lnnovations in Nutrition, Technology, and Tech- niques. Report of the Twelfth Ross Roundtable on Medical Issues. Columbus, OH: Ross Laboratories, 1992

13. Atkinson M, Edwards DAW, Honour AJ, Rowlands EN. The esophogogastric sphincter in hiatus hernia. Lancet 1957;2: 1 138

14. Dent J, Dodds WJ, Friedman RD, et al. Mechanism of gastroesophageal reflux in recumbent asympto- matic human subjects. J Clin Invest 1980;65:256-67

15. Mittal RK, McCallum RW. Characteristics of transient lower esophageal sphincter relaxation in humans. Am J Physiol 1987;252:G636-41

16. Baldi F, Ferrarini F, Balestra R, et al. Oesophageal motor events at the occurrence of acid reflux and during endogenous acid exposure in healthy subjects and in patients with esophagitis. Gut 1985;26:33&41

17. Dent J, Holloway RH, Touli J, Dodds WJ. Mechanism of lower oesophageal sphincter incompetence in pa- tients with symptomatic gastroesophageal reflux. Gut 1988;29:1020-8

18. Mittal RK, McCallum RW. Characteristics and fre- quency of transient relaxation of the lower esopha- geal sphincter in patients with reflux esophagitis. Gastroenterology 1 988;95:593-9

19. Cucchiara S, Staiano A, DiLorenzo C, Deluca G, del- la Rocca A, Auricchio S. Pathophysiology of gastro- esophageal reflux and distal esophageal motility in children with gastroesophageal disease. J Pediatr Gastroenterol Nutr 1988;7:830-6

20. Nagler R, Spiro HM. Persistent gastroesophageal re- flux induced during prolonged gastric intubation. N Engl J Med 1963;269:495-500

21. lbanez J, Penafiel A, Raurich JM, Marse P, Mata F. Gastroesophageal reflux in intubated patients receiv- ing enteral nutrition: effect of supine and semirecum- bent positions. J Parenter Enteral Nutr 1 !3!32;16:41 S22

22. Strong RM, Condon SC, Solinger MR, Namihas BN, Ito-Wong LA, Leuty JE. Equal aspiration rates from postpylorus and intragastric-placed small-bore na- soenteric feeding tubes: a randomized prospective study. J Parenter Enteral Nutr 1992;16:59-63

23. Norton J, Ott L, McClain C, et al. Intolerance to en- teral feeding in the brain-injured patient. J Neurosurg 1988;68:62-6

24. Silk D, Payne-James J. Complications of enteral nu- trition. In: Rombeau JL, Caldwell MD, eds. Clinical Nutrition: Enteral and Tube Feeding. Philadelphia, PA: WB Saunders, 1990

1987;16:527-31

Nutrition Reviews, Vol. 54, No. 10 327

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

Coben RM, Weintraub A, DiMarino AJ Jr, Cohen S. Gastroesophageal reflux during gastrostomy feeding. Gastroenterology 1994;106:13-8 Konturek JW, Thor P, Maczka M, Stoll R, Domschke W, Konturek SJ. Role of chollcystokinin in the control of gastric emptying and secretory response to a fatty meal in normal subjects and duodenal ulcer patients. Scand J Gastroenterol 1994;29:583-90 Bowling TE. Does disorder of gastrointestinal motility affect food intake in the postsurgical patient? Proc Nutr SOC 1994;53:151-7 Taylor C, Larson D, Ballard DJ, et al. Predictor of outcome after percutaneous gastrostomy: a com- munity based study. Mayo Clin Proc 1992;67:1042-9 Methany NA, Eisenberg P, Spies M. Aspiration pneu- monia in patients fed through nasoenteral tubes. Heart Lung 1986;15:256-61 Grant JP, Curtas MS, Kelvin FM. Fluoroscopic place- ment of nasojejunal feeding tubes with immediate feeding using a nonelemental diet. J Parenter Enteral Nutr 1983;7:299-303 Breach C, Saldanha L. Tube feedings: a survey of compliance to procedures and complications. Nutr Clin Prac 1988;3L230-3 Beare P, Myers J. Principles and Practice of Adult Health Nursing. St Louis, MO; CV Mosby, 1990 Levin M. Nutrition therapy. In: Woodley M, Whelan A, eds. Manual of Medical Therapeutics. Boston, MA; Little Brown, 1992 Cohen S, Green F. Force-velocity characteristics of esophageal muscle: effect of acetylcholine and nor- epinephrine. Am J Physiol 1974;226:1250-5 McCallum RW, Fink SM, Lerner E. Effects of meto- clopramide and bethanecol on delayed gastric emp- tying present in gastroesophageal reflux patients. Gastroenterology 1983;84:1573-7 Fink SM, Barwick K, Deluca V. The association of histologic gastritis with gastroesophageal reflux and delayed gastric emptying. J Clin Gastroenterol

Fink SM, Lange RC, McCallum RW. Effect of meto- clopramide on normal and delayed gastric emptying in gastroesophageal reflux patients. Dig Dis Sci 1983;28:1057-61 Albibi R, McCallum RW. Metoclopramide: pharma- cology and clinical application. Ann Intern Med 1983;98:86-95 Harrington PR, Hamilton CW, Brogden RN, Linkwich JA, Romankiewicz JA, Heel RC. Metoclopramide: an updated review of its pharmacological properties and clinical use. Drugs 1983;25:451-94 Perkel MS, Moore C, Hersh R, Davidson ED. Meto- clopramide therapy in patients with delayed gastric emptying: a randomized, double-blind study. Dig Dis Sci 1979;24:662-6 Temple JG, Bradby GV, OConnor FO, et al. Cimet- idine and metoclopramide in gastroesophageal reflux disease. Br Med J (Clin Res) 1983;286:1863-4 Albibi R, McCallum RW. Metoclopramide: pharma- cology and clinical application. Ann Intern Med 1983;98:86-95

1984;6:301-5

43. Putnam PE, Orenstein SR, Wessel HB, Stowe RM. Tardive dyskinesia associated with use of metoclo- pramide in a child. J Pediatr 1992;121:983-5

44. Grimes JD, Hassan MN, Preston DN. Adverse neu- rologic effects of metoclopramide. Can Med Assoc J 19823 26:23-5

45. McCallum RW, Sowers JR, Hershman JM, Sturde- vant RA. Metaclopramide stimulates prolactin secre- tion in man. J Clin Endocrinol Metab 1976;42:1148-52

46. Harrington PR, Hamilton CW, Brogden RN, Linkwich JA, Romankiewicz JA, Heel RC. Metoclopramide: an updated review of its pharmacologcal properties and clinical use. Drugs 1983;25:451-94

47. ltoh 2, Nakaya M, Suzuki T, Arai H, Wakauayashi K. Erythromycin mimics exogenous motilin in gastroin- testinal contractile activity in the dog. Am J Physiol 1984;247:G688-94

48. Mozwecz H, Pael D, Pitrak D, Orellana P, Schlesing- er PK, Layden TJ. Erythromycin stearate as proki- netic agent in postvagotomy gastroparesis. Dig Dis Sci 1990;33:902-5

49. Janssens J, Vantrappen G, Annese V, et al. Effect of erythromycin on LES function and esophageal body contractility. [Abstract] Gastroenterology 1990;98: A342

50. Dalton CB, Devore MS, Smouth AJPM, et al. The effect of erythromycin on lower esophageal sphincter pressure and esophageal motility. [Abstract] Gastro- enterology 1990;98:A342

51. Pfeiffer A, Wendl B, Pehl C, Kaess H. Effect of eryth- romycin on gastroesophageal reflux. Gastroenterol Clin Biol 1991;15:561-2

52. Pennathur A, Tran A, Cioppi M, Fayad J, Sieren GL, Little AG. Erythromycin strengthens the defective lower esophageal sphincter in patients with gastro- esophageal reflux disease. Am J Surg 1994;167: 169-73

53. Tanis AA, Baggen MGA, Wiggers RH, Ouwendijk RJ. Side-effects of oral erythromycin for treatment of di- abetic gastroparesis. Lancet 1993;342: 1431

54. Corazziari E, Bontempo I, Anzinl F. Effects of cisa- pride on distal esophageal motility in humans. Dig Dis Sci 1989;34:1600-5

55. Madsen JL. Effects of cisapride on gastrointestinal transit in healthy humans. Dig Dis Sci 1990;35:1500-4

56. Maddern GH, Jamieson GC, Meyers JC, Collins PJ. Effects of cisapride on delayed gastric emptying in gastroesophageal reflux disease. Gut 1991 ;32:47W

57. Rothstein RD, Alavi A, Reynolds JC. Electrogastog- raphy in patients with gastroparesis and effect of long term cisapride. Dig Dis Sci 1993;38:1518-24

58. Rajendran SK, Reiser JR, Bauman W, Zhang RL, Gordon SK, Korsten MA. Gastrointestinal transit after spinal cord injury: effect of cisapride. Am J Gastroen- terol 1992;87:1614-7

59. Spapen HD, Duinslaeger L, Diltoer M, Gillet R, Bos- suyt A, Huyghens LP. Gastric emptying in critically ill patients is accelerated by adding cisapride to a stan- dard enteral feeding protocol: results of a prospec- tive, randomized controlled trial. Crit Care Med 1995;23:481-5

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