Complications of parenteral nutrition

Complications of parenteral nutrition

1408 CORRESPONDENCE The study by Tobi et al. 6 in which omeprazole inhibited tumor cell growth also bears little similarity to our study. Although t...

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The study by Tobi et al. 6 in which omeprazole inhibited tumor cell growth also bears little similarity to our study. Although this in vitro study claims to show a "direct negative effect o f . . . a pharmacological concentration o f . . . omeprazole on tumor cells of colonic origin," this statement is quite misleading. Cells were incubated for at least 4 days in "1.7 gM/ml" (sic) omeprazole, presumably equivalent to 1.7 mmol/L. Even our highest dose of omeprazole (40 mg/kg intragastric) results in a peak plasma drug level of 7.25 ].tmol/ L, which quickly decreases to zero by 3 hours after dosing] Thus, the concentration of omeprazole bathing the cells, considered "pharmacological" by Tobi et al., 6 is several orders higher than our peak plasma level and surely above the zero concentration that circulated for 21 of 24 hours each day. The only surprise is that their high, probably toxic, concentration inhibited growth in only one of the three cell lines they studied, i.e., NCI-H716, a line with "carcinoid tumor features" unlike most colon tumors, including those resulting from MAM. Furthermore, how could these investigators postulate that omeprazole suppressed gastrin-stimulated cell growth when "counts were unaffected by gastrin alone in all three cell lines"? The study by Nielsen et al., * while fascinating, bears little direct relevance to our findings. They suggest that ranitidine (300 mg twice daily) improves survival of patients with metastatic colon cancer, perhaps by inhibiting a histamine-mediated immune response. This would not explain why we found that hypergastrinemia induced by omeprazole (not ranitidine) had no trophic effects on colon cancer. It should also be noted that McGregor et al. 9 were unable to show a statistically significant enhancement of size or number of colon tumors by surgically induced hypergastrinemia. We therefore agree with Rehfeld 1° that there is no evidence that hypergastrinemia induced by acid-suppressing surgery or drugs stimulates growth of colon tL1Enors.


Division of Clinical Pharmacology Department of Medicine BRUCE F. KIMLER, PH.D.

Department of Radiation Oncology DAVID M. PINSON, D.V.M., PH.D.

Department of Pathology and Laboratory Medicine University of Kansas Medical Center Kansas City, Kansas 66160-7320 1. Pinson DM, Havu N, Sztern MI, Mattsson H, Looney GA, Kimler BF, Hurwitz A. Drug-induced hypergastrinemia" absence of trophic effects on colonic carcinoma. Gastroenterology 1995; 108:1068-1074. 2. Penman ID, El-Omar E, McGregor JR, Hillan KJ, O'Dwyer PJ, McColl KEL. Omeprazole inhibits colorectal carcinogenesis induced by azoxymethane in rats. Gut 1 9 9 3 ; 3 4 : 1 5 5 9 - 1 5 6 5 . 3. Andersson T. Omeprazole drug interaction studies. Clin Pharmacokinet 1991; 2 1 : 1 9 5 - 2 1 2 . 4. Fiala ES, Casweil N, Sohn OS, Felder MR, McCoy GD, Weisburger JH. Non-alcohol dehydrogenase-mediated metabolism of methylazoxymethanol in the Deer mouse, Peromyscus maniculatus. Cancer Res 1 9 8 4 ; 4 4 : 2 8 8 5 - 2 9 2 1 . 5. Fiala ES, Sohn OS, Hamilton SR. Effects of chronic dietary ethanol on in vivo and in vitro metabolism of methylazoxymethanol and on methylazoxymethanol-induced DNA methylation in rat colon and liver. Cancer Res 1 9 8 7 ; 4 7 : 5 9 3 9 - 5 9 4 3 . 6. Tobi M, Goo R, Maliakkal B, Reddy J, Mehta M, Lindqvist M, Oberg B, Luk GD. The in vitro effects of gastrin and omeprazole on tumor cells of colonic origin (abstr). Gastroenterology 1990;98:A315.


7. Watanabe K, Furuno K, Eto K, Oishi R, Gomita Y. First-pass metabolism of omeprazole in rats. J Pharm Sci 1 9 9 4 ; 8 3 : 1 1 3 1 1134. 8. Nielsen HJ, Hammer JM, Larsen T, Nielsen H, Moesgaard G, Kehlet H. Ranitidine improves overall immune function and survival in patients with hepatic metastasis from coloreetal cancer (abstr). Gastroenterology 1994;106:A421. 9. McGregor DB, Jones RD, Karlin DA, Romsdahl MM. Trophic effects of gastrin on colorectal neoplasms in the rat. Ann Surg 1982; 1 9 5 : 2 1 9 - 2 2 3 . 10. Rehfeld JF. Gastrin and colorectal cancer: a never-ending dispute. Gastroenterology 1995; 1 0 8 : 1 3 0 7 - 1 3 1 0 . Reply. Tobi et al. deserve much credit for pointing out that suggestions about inhibition of colorectal cancer growth by omeprazole and ranitidine no longer are heretical but are now supported experimentally from different laboratories. Accordingly, they correctly conclude that interpretation of studies on colorectal cancers and hypergastrinemia induced by omeprazole or ranitidine require extra caution. Their comment emphasizes that the possible cancer protection of omeprazole and ranitidine now deserves intensive research. As to the original question about the effect of gastrin on colon cancer, the models for future studies depends on the specific hypothesis to be examined. In this context, the multi-genetic model of Fearon and Vogelstein for sporadic colorectal tumorigenesis 1 appears particularly attractive: Normal epithelium "~ ~ 5q: mutation or loss of FAP gene Hyperprotiferative epithelium *- Gastrin (?) Early adenoma +- 12q: mutation of K-ras gene Intermediate adenoma 1" *-- 18q: loss of DCC gene (?) Late adenoma "~ +- 17p: loss of p53 gene Carcinoma

{ Metastasis We suggest that the tumorigenic role of gastrin perhaps should be sought at the level of hyperproliferation of colorectal epithelium. Models for evaluation of this hypothesis are now under consideration. JENS F. REHFELD0 M.D. FINN CILIUS NIELSEN, M.D.

Department of Clinical Biochemistry Rigshospitalet Copenhagen, Denmark 1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 6 1 : 7 5 9 - 7 6 7 .

Complications of Parenteral Nutrition Dear Sir: The report by Messing et a l ) has enhanced our knowledge about long-term home parenteral nutrition. It has great merit in being a binational cohort study and in the completeness of the followup. Although it was mentioned that 8 deaths (11%) were related


October 1995

to home parenteral nutrition, the authors did not take the opportunity to describe complications related to this form of nutrition. Besides the complications related to the time and technique of insertion, venous thrombosis and sepsis are common and major longterm problems. Incidence of overt venous thrombosis is thought to be up to 5% with a further 4% as subclinical thrombosis.2 Fortunately, pulmonary embolism is surprisingly rare. Catheters made of silicone elastomer or polyurethane are thought to reduce the risk. Addition of heparin ( 1 - 3 U/mL) to the infusion may also help in prevention. Significant thrombosis is best treated by removal of catheter and 6 12 weeks of anticoagulation, although some use thrombolytic therapy as an alternative. Line-related sepsis (no anatomic septic focus identified and resolution on removal of hyperalimentation catheter) is secondary to ingrowth of skin organisms along outside of the catheter or breaks in a closed system, permitting organisms to gain access to inside catheter. The summarised incidence from large institutional series is 4 . 5 % - 1 1 % . 2 As Messing et al. have alluded to, the risk is diminished by using specialized teams and standardized protocols. In situ treatment of catheter-related sepsis, both gram positive and gram negative, with improved salvage rates with systemic antibiotics and local thrombolytic agents has been reported. 3'4 Catheter removal re-

mains the treatment of choice for any unstable patient or temporary access.21 invite the authors of the report on home parenteral nutrition to share their experience with us. .&JAY KUMAR, M.D.

Division of Gastroenterology University of Tennessee Memphis, Tennessee38163 1. Messing B, k~mann M, kandais P, Gouttebel M-C, G6rard-Boncompain M, Saudin F, Vangossum A, Beau P, Gu6don C, Barnoud D, Beliah M, Joyeux H, Bouletreau P, Robert D, Matuchansky C, Leverve X, Lerebours E, Carpentier Y, Rambaud J-C. Prognosis of patients with nonmalignant chronic intestinal failure receiving longterm home parenteral nutrition. Gastroenterology 1995;108: 1005-1010. 2. Flowers JF, Ryan Jr JA, Gough JA. Catheter related complications of total parenteral nutrition. In: Fischer JE, ed. Total parenteral nutrition. 2nd ed. Boston: Little Brown and Company, 1991:2547. 3. Glynn MFX, Langer B, Jeejeebhoy KN. Therapy for thrombotic occlusion of long term alimentation catheters. J Parenter Enteral Nutr 1980; 4:387-390. 4. Schuman ES, Winter V, Gross GF, Hayes JF. Management of hickman catheter sepsis. Am J Surg 1985;149:627-628.