Choline pharmacokinetics during intermittent intravenous choline infusion in human subjects.

A study of choline pharmacokinetics was undertaken in four patients receiving long-term total parenteral nutrition. On consecutive days, 7, 14, 28, and 56 mmol choline chloride were intravenously infused over a 12-hour period in each subject. The choline concentration was determined in plasma at baseline, 1/4, 1, 3, 6, and 12 hours, and 3 and 12 hours after the infusion ended, and in daily 24-hour urine collections. Analysis of variance showed the data fit a two-compartment model in which elimination from the central compartment was saturable significantly better than a one-compartment model in all four subjects (p < 10(-8) in all cases), and significantly better than a nonsaturating model in three of the four subjects (p = 1.0 x 10(-9), 7.5 x 10(-6), 9.4 x 10(-11), respectively). The model allowed estimates of the rate constant for choline elimination at ambient levels, first-order rate constants for transfer between central and peripheral compartments, the dissociation constant for the saturable elimination process, the apparent volume of distribution in the central compartment, the steady-state volume of distribution, and the quantities of choline in the central compartment and in the readily exchangeable pool.

Growth retardation in children receiving long-term total parenteral nutrition: effects of ornithine alpha-ketoglutarate.

We evaluated the effect of ornithine ketoglutarate (OKG) in reversing abnormal growth in six prepubertal children receiving total parenteral nutrition (TPN) for 5-10 y. They were 1-4 SDs below their expected 50th percentile for height. The energy and nitrogen intakes were unchanged from 8 mo before the beginning of the study until its completion. Two consecutive periods of 5 mo each were studied. OKG (15 g) was added to the parenteral solution during the first period (OKG+) but not during the second period (OKG-). Height velocity (HV) increased (P < 0.05) from a median of 3.8 cm/y to 6.45 cm/y (range 1.8-6.7) during the OKG+ period, and decreased (P < 0.05) to a median of 3.65 cm/y in the OKG- period. Plasma concentrations of insulin-like growth factor 1 (IGF1), glutamine, and glutamate increased (P < 0.05) during the OKG+ period. Variations of IGF1 concentrations correlated with HV variations (r = 0.82, P < 0.005) during both periods. This study demonstrates that OKG is associated with statural growth acceleration and increased IGF1 concentrations.

Parenteral nutrition is associated with intestinal morphologic and functional changes in humans.

BACKGROUND: Numerous animal studies have demonstrated intestinal villus atrophy occurs when luminal nutrition is withheld and total parenteral nutrition (TPN) is provided. Intestinal morphologic and functional changes have not been well studied in humans during TPN. METHODS: Eight normal volunteers were hospitalized in the Clinical Research Center for 3 weeks. The subjects received TPN as an exclusive means of nutritional support for 14 days followed by 5 days of enteral refeeding with either a standard or a glutamine and arginine-supplemented formula. Endoscopic jejunal biopsies were taken before and after TPN and after enteral refeeding. Intestinal morphology was examined by light and transmission electron microscopy. Mucosa DNA, RNA, and protein concentrations were measured. Lactose breath hydrogen and intestinal permeability testing (urinary lactulose and mannitol excretion after an oral dose) were performed before and after TPN and after enteral refeeding. RESULTS: Total mucosal thickness decreased after TPN (645 +/- 19 to 512 +/_ 19 microns, p = .003) and increased significantly towards baseline after enteral refeeding (575 +/- 19 microns, p = .04). The change was related solely to villus height; crypt depth was unaffected. Villus cell count decreased from 179 +/- 15 to 163 +/- 12 after TPN (p = .03) and increased after enteral refeeding to 176 +/- 21 (p = .06). Crypt cell count was unaffected by TPN or refeeding. A nonsignificant decrease in the mitotic index after TPN was seen. Intracellular edema developed during TPN and resolved with enteral refeeding. The urinary lactulose-mannitol ratio increased with TPN [0.06 +/- 0.03 to 0.11 +/- 0.05 after TPN and 0.14 +/_ 0.09 after short-term enteral refeeding (p = .05)], indicating increased intestinal permeability. The urinary lactulose-mannitol ratio was significantly greater after refeeding with standard formula than the free amino acid peptide formula with glutamine and arginine (0.20 +/- 0.05, vs 0.08 +/- 0.01, p = .05). No significant differences were noted in mucosal RNA, DNA, protein, DNA-protein or RNA-DNA rations or breath hydrogen after lactose ingestion after either TPN or enteral refeeding. No significant difference in plasma glutamine was found during TPN (462.7 +/ 38.7 vs 491.8 +/- 46.1 mumol/L) or after enteral refeeding (457.3 +/- 51.4 mumol/L). CONCLUSIONS: Intestinal morphologic and functional changes occur in human for whom TPN is the sole nutritional source, although the findings in humans are substantially less significant than observed in animal models. The loss of mucosal structure may be sufficient to cause increased intestinal permeability, the clinical significance of which remains to be defined. Enteral nutrition is important in restoring and probably preventing morphologic intestinal changes associated with TPN, and a peptide and free amino acid-based formula supplemented with glutamine and arginine may have some added role. Our findings also suggest sepsis is associated with gut adaptation rather than degradation.

230 patient years of experience with home long-term parenteral nutrition in childhood: natural history and life of central venous catheters.

The records of 27 pediatric patients who required parenteral nutrition (PN) for 5 to 14.5 years (mean +/- SD, 8.5 +/- 3.8) were analyzed to determine the frequency of complications with their central venous catheters (CVC). This represents a 230 patient-year experience. Patients with short bowel syndrome and chronic intestinal pseudoobstruction syndrome (CIPS) accounted for all but two of the patients. Unsuccessful medical management of the exit site or CVC infection was responsible for removal of 62% of the 123 CVCs. Ninety-five episodes of line infection occurred in 24 patients. Fifty (52%) were successfully treated without catheter removal. The organisms responsible for catheter removal were fungal (14), mycobacterium species (5), gram-positive cocci (22), or gram-negative bacilli (19). The CVCs were infected an average of once every 884 days. The life of the second CVC (23.5 +/- 17.9 months) was significantly longer than that of the first (P < .05). Clotting of the CVC with unsuccessful lysis of the clot was responsible for removal of 24%, and breakage or unsuccessful repair was responsible for 14%. In no patient were all possible venous sites for CVC placement exhausted. Patients with CIPS had substantially fewer catheter complications (P < .05) than did those with short bowel syndrome. In conclusion, CVCs can "survive" without major complications for more than a decade. Numerous factors contribute to the increased rate of CVC survival over time, including improvement in PN self-care with greater experience, improvement in teaching, regular follow-up of patients, better management of infection, and better ability to treat CVC thrombosis or breakage.

Methodological factors affecting esophageal clearance.

To define some methodological factors that could affect the measurement of the esophageal clearance, we used three different protocols, on 41 healthy control subjects. In 20 subjects, we studied the influence of a naso-esophageal probe on the frequency of swallowing. We observed a significant (44 +/- 5%) decrease in the frequency of spontaneous swallows after 15 minutes, with stabilization after this 15 minute period of adaptation. In 11 subjects, we studied the influence of the pH of the esophageal content on esophageal clearance. We found an exponential relationship between the esophageal clearance (C) expressed in minutes and the initial pH of the lumen contents: C = 43.3 exp (-0.54 pH) In 10 other subjects, we studied the influence of the volume of the esophageal contents on esophageal clearance. We found no influence for volumes less than 30 ml and a significant increase of clearance for volumes greater than 30 ml. In summary, this study of the effects of methodological factors on esophageal clearance: Gives new information about the "accommodation phase" of the esophagus after distension by a naso-gastric probe; Allows us to propose a new quantitative method for evaluation of esophageal clearance Shows the small importance of the ingested volume.

Gastric physiology and function: effects of fruit juices.

The stomach stores food and starts digesting protein and fat. Lipids, sugars, certain amino acids, and nutrients of high osmolality trigger sensory mechanisms from the intestine which inhibit gastric emptying. Food rich in carbohydrates leaves the stomach slower than protein-rich food, and emptying is slowest after a meal containing lipid. For carbohydrate beverages, the gastric emptying rate is primarily determined by the volume, caloric content, and osmolality of fluid ingested. Gastric emptying rates vary among isocaloric beverages of different type (e.g., sucrose, fructose, galactose) or forms (e.g., maltodextrins, starches) of carbohydrate. For instance, gastric emptying is faster for a fructose solution compared with isocaloric glucose and galactose solutions. A maltodextrin or a sucrose solution empties faster than a glucose solution. This is possibly due to the greater inhibitory feedback associated with the introduction of glucose in the duodenum. In addition, fruit juices contain soluble fibers which further modulate the gastric emptying. Noninvasive methods to study gastric emptying have recently been developed. The pattern of the myoelectric activity of the gastric contraction and the effect of meals on this pattern can now be recorded by cutaneous electrodes. In healthy children ingesting different juices, the myoelectric pattern of the stomach (indicator of the gastric emptying) correlates with the carbohydrate absorption (measured by breath hydrogen excretion). Fast gastric emptying was associated with greater production of breath hydrogen. The malabsorption of juice carbohydrates may in part be related to their effect on gastric motility.

Effect of gastric myoelectric activity on carbohydrate absorption of fruit juice in children.

Juices have a different rate of gastric emptying than other foods. This may alter the rate of delivery of carbohydrates to the small bowel for absorption. The aim of the study is to demonstrate that faster gastric emptying is associated with greater production of hydrogen through a randomized, crossover study of 39 healthy children. The electrogastrography (indicator of the gastric myoelectric activities) and breath hydrogen tests (indicator of carbohydrate malabsorption) were performed at baseline and after ingestion of 240 to 330 mL of grape or pear juice given in a random order. The cutaneous electrogastrogram was analyzed by running spectral analysis to compute pre- and postprandial period dominant power (PDP) and running spectrum total power (RSTP). Postprandial PDP and RSTP were higher (p < 0.02) in the pear juice group than in the grape juice group, suggesting higher antral myoelectric activities. Twenty three percent of the subjects had significant movement artifacts that suggested discomfort after drinking pear juice compared to 5% after grape juice (p < 0.03). Breath hydrogen test was more frequently positive (increase >20 part per million [ppm] above baseline) after pear juice (52.2%; mean, 36 +/- 33 ppm) than after grape juice (4.3%, 6 +/- 6 ppm). In a multiple regression analysis, the most predictive independent variable of hydrogen concentration was found to be either postprandial PDP (r2 = 0.24; p < 0.002), or RSTP (r2 = 0.37; p < 0.001). Juices affect gastric myoelectric activity. Grape juice induces lower antral myoelectric activities and is better absorbed. The malabsorption of carbohydrates of juices is in part related to their effect on the gastric physiology.

Excessive urinary oxalate excretion occurs in long-term TPN patients both with and without ileostomies.

OBJECTIVE: To determine if excessive oxalate and deficient citrate excretion were associated with TPN-associated nephropathy. DESIGN: Crossectional cohort. SETTING: Outpatient clinic. SUBJECTS: Twenty-five patients (15 males, 10 females) aged 51 +/- 17 (mean +/- SD) years who had received home total parenteral nutrition (TPN) for 10 +/- 4 years. Fifteen subjects had ileostomies (Group A) and 10 had functional colons (Group B). OUTCOME MEASURES: Glomerular filtration rate (GFR), tubular reabsorption of phosphate (TRP), urinary oxalate and citrate excretion. RESULTS: The mean GFR was 68.1 +/- 34.5 ml/minute/1.73 m2 and did not differ between Groups A and B. The mean TRP was 65.0 +/- 32.2% for Group A and 80.5 +/- 16.0% for Group B. The difference was not statistically significant. Urinary oxalate and citrate excretion were 40.2 +/- 30.2 and 324.4 +/- 239.0 mg/day respectively for Group A, and 63.2 +/- 34.2 and 474.8 +/- 936.3 respectively for Group B. The differences were not statistically significant. Thirty-eight percent (38%) of patients with ileostomies and 78% of patients without ileostomies had excessive urinary oxalate excretion (> 40 mg/day). Fifteen percent (15%) of patients with ileostomies and 50% of patients without ileostomies had decreased urinary citrate excretion (< 140 mg/day). CONCLUSIONS: Increased endogenous oxalate production may occur in patients receiving long-term TPN.

Carnitine status of children receiving long-term total parenteral nutrition: a longitudinal prospective study.

Nine children receiving carnitine-free total parenteral nutrition for 7.2 +/- 2.6 years since birth were prospectively studied for 3 years. Plasma values of total and free carnitine were 50% lower than those of age-matched healthy control subjects (p less than 0.02) but did not decrease further during the 3-year period. No significant abnormalities in free fatty acids, triglycerides, or cholesterol were found. The mean levels of alanine and aspartate aminotransferases and of alkaline phosphatase were slightly increased (p less than 0.02) at the initiation of the study but remained in the same range 3 years later. The low plasma carnitine values appeared to be without clinical consequence after 10 years of carnitine-free total parenteral nutrition.

Renal function of children receiving long-term parenteral nutrition.

Renal function was assessed in 13 children at a mean (+/- SD) age of 9 +/- 4.9 years who had been receiving total parenteral nutrition for 7.9 +/- 4.1 years. All children had normal blood pressure, urinary sediment, and serum creatinine concentrations (58.3 +/- 1.0 mumol/L). Glomerular filtration rate was measured by plasma clearance of diethylenetriaminepentaacetic acid labeled with indium 111. All 13 children had decreased glomerular filtration rate (65.5 +/- 11.9 ml/min per 1.73 m2; range 49.5 to 83.7). Creatinine clearance was 69.1 +/- 10.9 ml/min per 1.73 m2. No tubular damage, as assessed by beta 2-microglobulinuria, was detectable. Renal ultrasonography showed normal architecture with no evidence of nephrocalcinosis in all subjects. The kidney size was normal in seven children; six had reduced (less than -1 SD) size. No relationship was seen between the true glomerular filtration rate and diagnosis, number of episodes of infections, or antibiotics used. The duration of total parenteral nutrition was inversely correlated with the true glomerular filtration rate (r = -0.66, p less than 0.01). The decrease in glomerular filtration rate was not related to the underlying disease or to the nephrotoxic drugs used; the mechanism was not identified. We conclude that long-term total parenteral nutrition is associated with a decrease in glomerular filtration rate.

Immunoproliferative small intestinal disease in a 16-year-old boy presenting as severe malabsorption with excellent response to tetracycline treatment.

Immunoproliferative small intestinal disease (IPSID) is a rare lympho-proliferative disorder of the upper small intestine. It is considered a special form of MALT lymphoma with propensity to malignant transformation. This disorder is rare in pediatric literature. We report a case of IPSID in a 16-year-old boy with low-grade malignant transformation, presenting as severe malnutrition and a possible association with Helicobacter pylori. The patient responded well to an extended treatment with tetracycline and eradication of H. pylori.

Excessive chromium intake in children receiving total parenteral nutrition.

Various expert bodies have recommended that the daily parental intake of chromium in children receiving total parenteral nutrition (TPN) should be 0.20 micrograms/kg. To test whether this recommendation is appropriate, we assessed chromium intake, serum chromium concentrations, and renal function in 15 children receiving TPN. The median duration of TPN use was 9.5 (range 1.3-14) years. The children's glomerular filtration rate (GFR), measured by plasma clearance of indium-111-DTPA was lower than that of non-TPN controls (70 [SD 17] vs 110 [10] ml/min per 1.73 m2). The daily chromium intake averaged 0.15 (0.09) micrograms/kg daily but the serum chromium concentration was 20 (4 to 42) times higher than that of the controls (2.1 [1.2] vs 0.10 [0.03] micrograms/l; p less than 0.0001). GFR was significantly inversely correlated with serum chromium concentration (r = -0.60, p less than 0.02), daily chromium intake (r = -0.69, p less than 0.01), cumulative parenteral chromium intake (r = -0.72, p less than 0.01), and TPN duration (r = -0.52, p less than 0.05). We discontinued chromium supplementation of TPN solutions and reassessed the children a year later. Contaminating chromium concentrations were 1.0-1.8 micrograms/l in TPN solutions and 0.9 micrograms/l in fat emulsions. Drinking water contained 4.3-5.7 micrograms/l. Thus, the chromium intake without supplementation was only 0.05 (0.01) micrograms/kg daily. The mean serum chromium concentration fell to 0.50 (0.30) micrograms/l but was still significantly higher than that in the controls (p less than 0.01). The GFR did not change significantly (65 [14] ml/min per 1.73 m2). No patient has shown signs of chromium deficiency. Although our patients were receiving less than the recommended chromium intake during supplementation, their high serum concentrations suggested excessive intake. The recommended parenteral chromium intake for children should be lowered.

Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation.

Patients receiving long-term total parenteral nutrition (TPN) develop hepatic steatosis as a complication. Our previous studies have shown this to be caused, at least in part, by choline deficiency. We studied four patients (1 man, 3 women) aged 50 +/- 13 years who had low plasma-free choline concentrations 4.8 +/- 1.7 (normal, 11.4 +/- 3.7 nmol/mL). The patients had received TPN for 9.7 +/- 4.7 years. They received parenteral nutrition solutions containing choline chloride (1 to 4 g/d) for 6 weeks. Abdominal computed tomography (CT) was performed at baseline, biweekly during the choline supplementation, and 4 weeks after discontinuation of choline. During choline administration, the plasma-free choline concentration increased into the normal range within 1 week in all four patients and remained at or above the normal range for all 6 weeks, but decreased back to baseline when choline supplementation was discontinued. Hepatic steatosis resolved completely, as estimated by CT. Liver density increased from -14.2 +/- 22.3 Hounsfield units (HU) to 8.4 +/- 10.3 HU at week 2 (P = .002); 9.6 +/- 10.7 HU at week 4 and 13.1 +/- 7.3 HU at week 6, as determined by the liver-spleen CT number difference obtained by the subtraction of the average spleen CT number (in HU) from the average liver CT number. This improvement continued up to 4 weeks after choline supplementation (13.8 +/- 2.8 HU). Hepatic steatosis was shown to have recurred in one patient after 10 weeks of return to choline-free parenteral nutrition. The hepatic steatosis associated with parenteral nutrition can be ameliorated, and possibly prevented, with choline supplementation. Therefore, choline may be an essential nutrient for patients who require long-term parenteral nutrition.

Iodine supplementation in children receiving long-term parenteral nutrition.

In 18 children receiving long-term total parenteral nutrition (TPN) without iodide supplements, thyroid function test results were normal but serum iodide levels were greater than in control subjects (p less than 0.01). Iodine contamination of TPN solutions and fat emulsions accounted for only half of the recommended parenteral intake. Skin absorption of topical iodinated disinfectant may explain the adequate, if not excessive, iodine intake. We conclude that iodine is an unnecessary supplement in TPN solutions.