Metoclopramide-stimulated gastric emptying scintigraphy: does it predict symptom response to prokinetic therapy in chronic gastroparesis?

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went a sigmoid colectomy, colostomy with Hartmann’s closure of the rectum, and a hysterectomy with bilateral salpingo-oophorectomy. She made a full recovery. Fistulas account for up to 20% of surgical interventions in the setting of diverticulitis. They most commonly arise from the sigmoid colon. Colovesical fistulas account for 65% of fistulas followed by colovaginal fistulas in 25%, with coloenteric and colouterine fistulas being less common. Colovesical fistulas are more often seen in men than women presumably because of the interposition of the uterus between the bladder and the colon (1). Colouterine fistulas can present with acute or chronic malodorous vaginal discharge (2). In this case, our patient presented with persistent fevers in the setting of diverticulitis. Barium enema may aid in the diagnosis; however, this study is frequently normal (1). It is only useful if it demonstrates a fistulous tract. On the other hand, abdominal CT with oral contrast is very sensitive for detecting the sine qua non of fistulas—the presence of an extraluminal gas collection within the organ involved (3). This study has a low sensitivity for demonstrating the fistulous tract itself (1). Other methods for diagnosing colouterine fistulas have been described, including vaginography (4) and the detection of orally administered activated charcoal flowing through the cervical os (5). In most cases of colouterine fistulas, surgery is the definitive therapy. This can be performed in one en bloc resection of the uterus and the involved segment of colon if conservative therapy succeeds in minimizing inflammation preoperatively. Alternatively, as in this patient, if the inflammation is severe, a resection with colostomy is appropriate, with a plan for reanastomosis once the inflammation has resolved (1). Subodh K. Lal, M.D. Peter D. Clarke, M.D. James M. Becker, M.D. Francis A. Farraye, M.D. M.Sc., F.A.C.P., F.A.C.G. Section of Gastroenterology Departments of Radiology and General Surgery Boston Medical Center Boston University School of Medicine Boston, Massachusetts

REFERENCES 1. Young-Fadok TM, Sarr MG. Diverticular disease of the colon. In: Yamada T, ed. Textbook of gastroenterology. New York: Lippincott Williams & Wilkins, 1999;1936 – 8. 2. Chaikof EL, Cambria RP, Warshaw AL. Colouterine fistula secondary to diverticulitis. Dis Colon Rectum 1985;28:358 – 60. 3. Birnbaum BA, Balthazar EJ. CT of appendicitis and diverticulitis. Radiol Clin North Am 1994;32:885–98. 4. Davis AG, Posniak HV, Cooper RA. Colouterine fistula: Computed tomography and vaginography findings. Can Assoc Radiol J 1996;47:186 – 8. 5. Huettner PC, Finkler NJ, Welch WR. Colouterine fistula com-

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plicating diverticulitis: Charcoal challenge test aids in diagnosis. Obstet Gynecol 1992;80:550 –2. Reprint requests and correspondence: Francis A. Farraye, M.D., M.Sc., F.A.C.P., F.A.C.G., Clinical Director, Section of Gastroenterology, Boston Medical Center, 88 East Newton Street D408, Boston, MA 02118. Received Mar. 13, 2002; accepted Mar. 25, 2002.

Metoclopramide-Stimulated Gastric Emptying Scintigraphy: Does It Predict Symptom Response to Prokinetic Therapy in Chronic Gastroparesis? TO THE EDITOR: The current pharmacological management of gastrointestinal dysmotility remains difficult and, oftentimes, disappointing for both the patient and the clinician. This has led investigators to search for specific predictors of therapeutic response to prokinetic therapy (1–3). As gastric emptying scintigraphy (GES) is the most widely available test used to diagnose gastrointestinal dysmotility syndromes, it would be useful to identify a specific gastric emptying parameter that would allow the clinician to predict which patients would respond to chronic prokinetic therapy. This would be analogous to the use of cholecystokinincholescintigraphy with calculation of a gallbladder ejection fraction to predict those with acalculous gallbladder pain who would benefit from cholecystectomy (4). At our institution, it has been the standard practice of the Nuclear Medicine Department, for over a decade, to administer to those patients found to have gastroparesis on GES, metoclopramide i.v. during the same test session while scintigraphic recordings are continued. On the basis of these measurements, the patients are classified as responders (i.e., normalized emptying half-time) or nonresponders to metoclopramide. Although the origins of this technique are unclear, it seems to be attributable to Domstad et al. who presumably speculated that those patients with gastroparesis who “responded” to metoclopramide were more likely to respond symptomatically to chronic metoclopramide therapy (5). However, the validity of this practice and the extent to which it is performed in other institutions across the nation is unknown. Our aim, therefore, was to determine whether the response to the i.v. administration of metoclopramide during GES is predictive of symptom response to subsequent prolonged oral prokinetic therapy in patients with chronic gastroparesis. Furthermore, we sought to determine the extent of this practice across the country. The results of all GES performed at our institution from January, 1996 to February, 2000 were reviewed. Medical records from those patients who were at least 19 yr of age with at least a 3-month history of gastroparesis symptoms, delayed gastric emptying on GES, absence of mechanical

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gastric outlet obstruction, clinical follow-up of at least 3 months, and absence of an untreated systemic disorder were reviewed in detail. We also reviewed the records of an ageand sex-matched group of individuals who had similar symptoms but normal results on GES and who subsequently received treatment with a prokinetic agent. All medical records were retrospectively reviewed using both subjective and objective criteria to assess short- (1-month) and longerterm (12-month) clinical response to prokinetic therapy. Those with gastroparesis were further classified as either responders or nonresponders to i.v. metoclopramide administered during GES (see below). Subjective response to treatment with prokinetic therapy was assessed by a global symptom scale as determined by information found in clinic visit notes (6): 0 ⫽ no improvement or worse, 1 ⫽ slight improvement, 2 ⫽ moderate improvement, and 3 ⫽ clinical remission. A value ⱖ2 was considered to represent significant clinical improvement. Response to prokinetic treatment before and after GES was also assessed on the basis of changes in weight and frequency of outpatient clinic visits for gastroparesis complaints. Finally, a questionnaire was mailed to 68 academic Nuclear Medicine Departments across the United States asking whether they used a similar GES practice with respect to metoclopramide stimulation. Fisher’s exact test was used to compare categorical data, whereas the Wilcoxon rank sum test was used to compare continuous data. The Mantel-Haenszel ␹2 procedure (test for trend) was used to compare the global symptom scale at 1 and 12 months. This study was approved by the Institutional Review Board at the University of Nebraska Medical Center. Solid-phase gastric emptying scintigraphy was performed as follows: after an overnight fast, the patient ingested a single scrambled egg that had previously been radiolabeled with 1.0 millicurie 99mTechnetium. Within 5 min of ingesting the test meal, the subject lay supine before a large, three-headed gamma camera furnished with a low-energy collimator, and dynamic images were obtained for 1 h (60 s/frame). A left anterior oblique projection was used during the gastric-emptying phase. The geometric mean was used to plot the time-activity curve from which the emptying half-time (T1/2) was calculated. If the T1/2 was ⬎90 min, 10 mg of metoclopramide was injected i.v., and additional images (60 s/frame) were obtained for another 30 min. Delayed gastric emptying was defined as a T1/2 ⬎90 min. A responder to metoclopramide was arbitrarily defined as a T1/2 ⬍90 min. Of 549 GES performed, 157 (28.6%) had delayed gastric emptying, 123 (78.3%) were classified as responders, whereas 34 (21.7%) were nonresponders. Thirty-five (22.3%) fulfilled our criteria for further review—28 responders (24 women, mean age 51.6 ⫾ 3.2 yr) and seven nonresponders (seven women, mean age 50.3 ⫾ 4.6 yr). The vast majority was excluded because of insufficient duration of symptoms. Our control group (i.e., normal GES) consisted of nine patients (seven women, mean age 49.7 ⫾ 6.2

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yr). T1/2 did not differ significantly before administration of metoclopramide between responders and nonresponders (240.9 ⫾ 31.6 min vs 187.3 ⫾ 30.3 min). In contrast, after metoclopramide, the median T1/2 was 42.6 ⫾ 7.3 min for the responders, whereas the T1/2 was unchanged for nonresponders (167 min, p ⬍ 0.05, responder vs nonresponder). We found no difference in weight gain or number of clinic visits between the two groups and our control group at 1 or 12 months after GES after initiation of prokinetic therapy. Similarly, we identified no difference among the three groups with respect to symptom outcome (Fig. 1). Interestingly, our control group did appear to have a worse symptom response to subsequent prokinetic therapy, although this was not statistically significant. Lastly, 35 of 68 (51%) Nuclear Medicine Departments responded to our survey: only two used a similar GES practice. In summary, most patients found to have gastroparesis on GES will subsequently “respond” to an i.v. injection of metoclopramide. Nevertheless, we did not demonstrate utility of metoclopramide-stimulated GES in predicting outcome to prolonged prokinetic therapy in patients with chronic gastroparesis, further questioning a link between improved gastric emptying and symptom relief (7–10). However, our findings are limited by the study’s retrospective design, the subjective nature of symptom scoring system, the small patient population, lack of standardized prokinetic therapy and follow-up, and a T1/2 calculation based upon extrapolated emptying time curves from only 60 min of imaging time. Although an empirical trial of prokinetic therapy is likely to remain more valuable and less costly, a prospective study involving a larger patient population may be helpful to further clarify the role of this test in the management of this difficult problem. William D. Lyday II, M.D. John K. DiBaise, M.D. Division of Gastroenterology and Hepatology University of Nebraska Medical Center Omaha, Nebraska

REFERENCES 1. Verne GN, Eaker EY, Hardy E, Sninsky CA. Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction. Dig Dis Sci 1995;40: 1892–901. 2. Camilleri M, Balm RK, Zinsmeister AR. Determinants of response to a prokinetic agent in neuropathic chronic intestinal motility disorder. Gastroenterology 1994;106:916 –23. 3. Hyman PE, Di Lorenzo C, McAdams L, et al. Predicting the clinical response to cisapride in children with chronic intestinal pseudo-obstruction. Am J Gastroenterol 1993;88:832– 6. 4. Yap L, Wycherley AG, Morphett AD, Toouli J. Acalculous biliary pain: Cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101: 786 –93. 5. Domstad PA, Kim EE, Coupal JJ, et al. Biologic gastric emptying time in diabetic patients, using Tc-99m-labeled res-

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Figure 1. Symptom response at 1 and 12 months among responders and nonresponders to i.v. metoclopramide based on scintigraphy and controls. No significant difference was seen among the three groups, although the control group did appear to have a worse response to prokinetic therapy. GSS ⫽ global symptom scale.

6. 7. 8. 9.

10.

in-oatmeal with and without metoclopramide. J Nucl Med 1980;21:1098 –100. Prakash C, Lustman PJ, Freedland KE, Clouse RE. Tricyclic antidepressants for functional nausea and vomiting— clinical outcome in 37 patients. Dig Dis Sci 1998;43:1951– 6. Ricci DA, Saltzman MB, Meyer C, et al. Effect of metoclopramide in diabetic gastroparesis. J Clin Gastroenterol 1985; 7:25–32. Talley NJ, Verlinden M, Jones M. Can symptoms discriminate among those with delayed or normal gastric emptying in dysmotility-like dyspepsia? Am J Gastroenterol 2001;96:1422– 8. Jian R, Ducrot F, Ruskone A, et al. Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspepsia. A double-blind, placebo-controlled evaluation of cisapride. Dig Dis Sci 1989;34:657– 64. Kellow JE, Cowan H, Shuter B, et al. Efficacy of cisapride therapy in functional dyspepsia. Aliment Pharmacol Ther 1995;9:153– 60.

Reprint requests and correspondence: John K. DiBaise, M.D., Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, 982000 Nebraska Medical Center, Omaha, NE 68198-2000. Received Mar. 13, 2002; accepted Mar. 25, 2002.

Orthotopic Liver Transplantation After Subacute Liver Failure Induced by Therapeutic Doses of Ibuprofen TO THE EDITOR: The nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used medications worldwide for the treatment of a variety of common chronic

and acute inflammatory conditions. Despite the overall low incidence of NSAIDs-induced hepatotoxicity, their enormous consumption has caused them to become an important class of drugs responsible for liver injury (1). Among them, acetylsalicylic acid and paracetamol are intrinsically toxic by high production of reactive metabolites in the liver, whereas most other NSAIDs induce injury to the liver by an idiosyncratic reaction (2). Since its introduction in the United States in 1974, ibuprofen has been shown to be safe and effective for the treatment of pain, dysmenorrhea, inflammation, and fever (3). Nevertheless, several few cases of ibuprofen-related acute hepatotoxicity by overdose have been reported (4, 5). We report here the first case of subacute liver failure requiring orthotopic liver transplantation in patients without previous hepatic disorders after therapeutic doses of ibuprofen. A 59-yr-old woman had been treated with dobesilate (Doxium) during several years for moderate insufficient peripheral venous blood flow. Her past medical history was unremarkable without alcohol and herbal product intake. The patient was prescribed ibuprofen (600 mg/8 h) for moderate pain at the left hip, but 5 days later she presented choluria, jaundice, and fatigue without fever or allergic reaction. Ten days after ibuprofen treatment, the symptoms progressed, and she was admitted in a secondary care center interrupting drug intake. The laboratory data obtained showed normal hemogram, AST 1550 U/L (normal ⬍35), ALT 2089 U/L (normal ⬍45), ALP 737 U/L (normal ⬍280), ␥-glutamyl transferase 348 U/L (normal ⬍50), total bilirubin 20 mg/dL (normal ⬍1), direct bilirubin 15 mg/dL