Calciuretic effect of cyclic versus continuous total parenteral nutrition1 2

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1 Calciuretic effect of cyclic versus continuous total parenteral nutrition1 2 Richard J Wood, PhD, Jose M Bengoa, MD, Michael D Sitrin, MD, and Irwin H Rosenberg, MD Introduction ABSTRACT Metabolic bone has been reported in patientsreceiving long-term cyclic administration of totalparenteral nutrition (TPN). The exact etiology of this disturbance in mineral homeostasis has not been identified, however many of these patients are markedly hypercalciuric and in negative calcium balance. We have studied the effects of cyclical versus continuous infusion of nutrients on urinary calcium losses in a group of patients beginning a program of long-term home TPN. Cyclic TPN, when administered over either 18 or 12 hours, significantly increased dailyurinary calcium excretioncompared to continuous 24-h TPN infusion by 19 and 28%, respectively. During cyclic TPN, frank negative calcium balance was observed in 3 of 5 patients studied compared to 2 of 5 patients during continuous TPN. The pattern of urinary calcium loss during cyclic TPN was such that approximately 80% of the daily urinary calcium losses occurred during the 12 hours of TPN infusion. Cyclic administration of TPN increased the urinary calcium losses in all patients suggesting that an intermittent TPN infusion schedule, as typically utilized in home TPN programs, increases the risk of developing negative calcium balance, at least during the early phase of cyclic TPN administration. Am J C/in Nuir l985;4l: KEY WORDS Hypercalciuria, cyclic total parenteral nutrition, metabolic bone An increasing number of patients are receiving total parenteral nutrition (TPN) in a home program to permit maximal freedom for work and other activities. Home TPN programs are frequently structured as intermittent (12-hour-on; 12-hour-off) infusions. Moreover, some hospitalized patients receive TPN on a cyclical schedule and it has been recently suggested that this mode of TPN delivery should be preferred in hospitalized patients receiving TPN (1). However, a reduction in infusion time from 24 to 12 h per day necessitates a doubling of the rate of nutrient delivery and the effects of increased infusion rate on mineral homeostasis have not been well studied. Recently, metabolic bone has been reported in patients receiving long-term TPN (2-5). Although the exact etiology of the metabolic bone in these TPN patients has not been identified, many of these patients have been found to be markedly hypercal- ciuric and in negative calcium balance (2-5). The successful management of hypercalciuria and bone loss in long-term TPN patients is a challenging clinical problem that will gain in importance as increasing numbers of patients receive this treatment modality. Increasing the parenteral supply of calcium is possible, but in itself may not prevent negative calcium balance; furthermore, such an approach needs to be carefully evaluated within the context of increased risks of hypercalcemia and further increases in urinary calcium excretion (2). A number of factors in the TPN infusate, such as amino acids (6), calcium (7) or glucose (8), may contribute to increased uri- From the Department of Medicine, and Clinical Nutrition Research Center, The University of Chicago, Chicago, IL. 2Add reprint requests to: Irwin H Rosenberg, MD, Universityof Chicago, 5841 South Maryland, Box 400, Chicago, IL Received May 18, Accepted for publication September 18, The American Journal of Clinical Nutrition 41: MARCH 1985, pp Printed in USA 1985 American Society for Clinical Nutrition

2 CALCIURIA IN CYCLIC TPN 615 nary calcium excretion. For example, in a previous study of TPN patients we showed that increasing the amount of amino acids in the TPN infusate caused a marked increase in urinary calcium excretion (6). Others have shown that urinary calcium excretion in TPN patients is increased in relation to the amount of calcium infused (7). Oral ingestion of glucose can inhibit net renal tubular reabsorption of calcium in man (8). Since all nutritional factors are infused at increased rates during cyclic TPN the present study was designed to investigate whether the increased rate of nutrient infusion during cyclic TPN affected the urinary loss of calcium. The subjects in this study were patients who were beginning a program of long-term home TPN under the supervision of the Nutrition Support Service at the University of Chicago Hospitals and Clinics. Materials and methods Patient population The study group consisted of 5 female patients ranging in age from 19 to 72 years. The clinical summary of these patientsis presented in Table I. No patient had clinical or biochemical evidence of diabetes, liver or renal, or other clinical abnormalities known to specifically affect calcium homeostasis. Four subjects had Crohn s and 1 subject had radiation enteritis. Since the order of treatments could not be randomized in this group of patientstheurinary excretion of minerals were also compared to a previously studied group of 5 patients with Crohn s who received only continuous TPN for nine days (6). This group was used to assesswhether any changes occurred in mineral excretion in patientsreceiving TPN over an equivalent time period. All patients had received TPN for exactly the same length oftime.the clinical characteristicsof these patients hasbeen previously described (6).The studywas approved TABLE I Clinical summary of patients by the Clinical Investigation Committee of the University ofchicago, and informed consent was obtained from all subjects prior to the study. Study design All subjects received nothing by mouth during the 9-day study period. During the first 72 h of the study all subjects received a continuous 24-h infusion of TPN. During the next 72-h period the rate of infusion of the TPN solution was increased to deliver each day s TPN solution over an 18-h period. No changes in TPN composition or total volume delivered per 24 h were made during the 9-d study period. During the final 72 h of the study the infusion rate was adjusted to deliver the required daily TPN prescription over a 12-h period. During the 18-h and 12-h cyclic TPN phases of the study protocol the infusion catheter was heparinized and capped when the day s infusion was completed. The TPN formulae were prepared to deliver per day 1.5 g amino acid (Travasol, Travenol Laboratories, Inc., Deerfield, IL)/kg ideal body weight (IBW), 40 kcal/kg IBW with 30% of non-protein calories being supplied as lipid (Intralipid, Cutter Laboratories, Berkeley, CA), 10 to 14.9 meq calcium, 10 meq magnesium, 31 mmoles phosphorus, and additional electrolytes, vitamins and trace elements as previously described (6). Blood samples were obtained during the final 24 h of each of the 3 study phases at 8:00 PM, 12:00 PM and 7:00 AM. During cyclic TPN infusions began immediately following the 8:00 PM blood collection. Daily urine samples were collected separately for each of the 9 study days. During cyclic TPN urine samples were collected separately for periods on and off TPN. Creatinine clearance was determined by standard formula. Daily creatinine clearance during 12 h cyclic TPN treatment was taken as the average of clearance values determined during the 12-h period on TPN and during the 12-h off TPN period.urine creatinine was measured in separate 12-h pooled samples The value for serum creatinine used in the calculation for the period on TPN was the averageof the 12 PM (ie, 4 h after initiating TPN) and the 7 AM (ie,11 h after initiating TPN) serum creatinine values. The value of serum creatinine used in the clearancecalculationfor the 12-h off TPN period was the 8 PM fasting serum creatininelevel. Subject no Age Sex Initial weight Final weight Height Calcium infused TPN volume Diagnosis (kg) (kg) (cm) (nzg/d) (LId) 1 19 F Crohn s 2 20 F Crohn s 3 32 F Crohn s 4 57 F Crohn s 5 72 F Radiation ententis

3 616 WOOD ET AL >, (0 V ci E E 0 CO 0 C Group mean (mg/d) S.E.M. 4O-O----o Infusion Time, hours/day 215 ±40 256* 275* ±42 ±44 FIG 1. Urinary calcium excretion in TPN patients during continuous (24 h) or cyclic (18 h or 12 h) infusion schedules Urine calcium was significantly increased (paired t test, P <0.05) by 18- and 12-h infusion of TPN compared to continuous TPN. Darkened circles show patientsinwhich urine calcium exceeded infused calcium. Renal filtered calcium load was calculated by standard formula in a manner similar to our calculations for creatinine clearance. We did not measure the ultrafilterablefractionofserum calcium,but assumed itrepresented a constant fraction (60%) of total serum calcium. Laboratory determinations Blood measurements were made on untreated serum samples by routineclinical chemistry procedures, using a discrete sample analyzer (KDA, American Monitor, Indianapolis, IN). Serum 25-OH vitamin D was determined by the method of Haddad and Chyu (9). Urine samples were quantitatively collected into plastic jugs, acidified with concentrated HO (3% v/v), and stored frozen for subsequent analysis of creatinine (10), calcium (11), magnesium (11), and phosphorus (12). Statistical analysis Mean values between each of the study phases were compared by a two-tailed Student s paired t test (13). Urine valueswere averaged over the 3 d of each period. Results Since practical clinical considerations dictated the order of TPN treatments in sequential order in all patients in preparation for home TPN, we assessed the temporal change in urinary calcium excretion in 5 additional patients participating in another study (6) who received only continuous TPN. Calcium, phosphorus, magnesium and creatinine cxcretion was measured on day 3 and day 9 during their first 9 d of continuous TPN treatment. Urinary calcium, phosphorus, magnesium and creatinine excretion in those subjects were not significantly different at these two time points. Results of studies of calcium excretion in 5 patients receiving continuous and cyclic TPN have shown that daily urinary calcium excretion was significantly increased by cyclic TPN over the level of calcium excretion observed during continuous 24-h TPN infusion (Fig 1). This effect was seen whether cyclic TPN was administered over either an 18- or 12-h period. Increasing the rate of nutrient infusion by 50% and 100% over continuous TPN infusion rates, during 18- and 12-h cyclic TPN respectively, increased 24-h urinary calcium excretion by 19% and 28% over levels observed during continuous TPN. Cyclic TPN increased urinary calcium excretion in all subjects. Frank negative calcium balance was observed in 2 of the 5 patients while on continuous TPN and in 3 of 5 of the patients while on cyclic TPN. As shown in Table 2, 12-h cyclic TPN treatment had no effect on the renal filtered calcium load or fractional calcium excretion when these parameters were calculated over TABLE 2 Serum calcium, estimated renal filtered calcium load, urinary calcium, percent fractional calcium excretion, urinary phosphorus, creatinine clearance, and urine volume in TPN patients during continuous TPN infusion compared to 12-h cyclic TPN infusion. Mean ± SEM Continuous TPN Cyclic TPN Serum calcium mg/dl 9.20 ± t ± 0.23 Filtered calcium load mg/mm 3.36 ± ± 0.63 Urinary calcium mg/mm ± ± Fractional Ca excretion % 5.26 ± ± 1.06 Urinary phosphorus mg/mm ± ± 0.09 Creatinine Urine clearance mi/mm 60.6 ± ± 11.3 volume mi/mm 0.74 ± ±.06 * P <0.05; Student s paired I test. t Average of 8 PM, 12 PM and 7 AM samples.

4 CALCIURIA IN CYCLIC TPN 617 a total 24-h period. Moreover, cyclic TPN treatment had no effect on the rate of creatmine clearance when considered over a 24-h time period. The individual response of daily creatinine clearance to cyclic TPN was vanable; some patients had increased creatinine clearance, while others had decreased creatinine clearance or showed no change when switched from continuous to cyclic TPN. The effects of cyclic TPN on various blood parameters are shown in Table 3. When serum values were compared between treatments the mean of the 12 PM and 7 AM values was used for comparative purposes. No significant changes were observed for serum calcium, phosphorus, magnesium, creatinine, protein, albumin or 25(OH) vitamm D as a result of cyclic TPN. Moreover, hypercalcemia was never observed in any of the patients studied. However, significant increases were noted during cyclic TPN for serum glucose, insulin, and blood urea nitrogen. Moreover, no significant effects of cyclic TPN were observed on daily urinary phosphorus or serum electrolytes and bicarbonate. It was possible to investigate the pattern of calcium excretion during cyclic infusion, since urine samples were collected during TABLE 3 Serum value* during continuous and cyclic TPN, Mean ± SEM 24-h infusion l8.h infusion 12-h infusion Calcium mg/dl 9.2 ± ± ±.2 Phosphorus mg/dl 3.8 ± ± ±.2 Magnesium mg/dl l.7±.l l.8±.l l.8±.l Creatinine mg/dl 0.64 ± ± ±.07 Glucose mg/dl 104±9 lll±l2t 140±26 Insulin U/ml 60 ± ± 25t 147 ± 24t BUN mgjdl 13±3 16±4 18±3t Protein g/dl 6.3 ± ± ±.3 Albumin g/dl 3.3 ± ± ±.2 25 (OH)D ng/ml 26.8 ± ± ± 2.3 * Average of 12 PM and 7 AM blood samples. t P <0.05, by paired t test compared to continuous 24-h infusion. TABLE 4 Serum calcium, estimated renal filtered calcium load, urinary calcium, percent fractional calcium excretion, urinary phosphorus, creatinine clearance, and urine volume in TPN patients during 12 h or TPN infusion compared to 12 h without TPN infusion. Mean ± SEM Serum calcium I2hoffTPN I2honTPN mg/dl 9.l21 ± ± 0.20 Filtered calcium load mg/mm 2.68 ± ± 0.99 Urinary calcmum mg/mmn ± ± 0.046t Fractional Ca excretmon % 3.38 ± ± l.l6t Urinary phosphorus mg/mmn ± ± 0. I 3 Creatinine clearance mi/mm 51.2 ± ± 18.2 Urine volume mi/mm 0.47 ± ±.15 * P < 0.05; tp < 0.01; P < 0.001; Student s paned i test. Pre-mnfusion 8 PM sample., Average of 12 PM and 7 AM samples. cyclic TPN periods both on and off infusion. As shown in Table 4, approximately 80% of the daily calcium excretion was excreted during the 12-h period of nutrient infusion during cyclic TPN. Striking differences were found in many parameters, which could affect renal calcium handling, during the 12-h period of nutrient infusion (Table 4), when, in fact, the majority ofurinary calcium was excreted. For example, during the 12-h time period during cyclic TPN treatment in which nutrients were being infused (8 PM to 8 AM), urinary calcium excretion was increased threefold, from to mg per mm, compared to the 12-h fasting levels (8 AM to 8 PM). Fractional calcium excretion during the 12-h infusion period on TPN was significantly increased to 6.9% compared to 3.4% during the 12-h off period. Serum calcium was significantly lower during the 12 h oftpn infusion, while creatinine clearance and the estimated renal filtered load of calcium tended to be greater, but these differences were not statistically significant when compared to fasting period values. Discussion Our results demonstrate that cyclic TPN significantly increased the urinary loss of

5 618 WOOD ET AL calcium over the level observed during continuous 24-h TPN infusion. Moreover, since cyclic TPN increased the renal loss of calcium in all patients, it can be concluded that the administration of TPN on an intermittent schedule, as typically utilized in home TPN programs, increases the risk of negative calcium balance, at least during the early phase of cyclic TPN administration. The natural course of hypercalciuria in patients receiving long-term TPN, however, has not been well studied. For example, in the reports of TPNinduced hypercalciuria and metabolic bone by Shike et al (2) and Klein et al (3) patients had been receiving home TPN for 2 to 89 months before clinical recognition of metabolic bone. It cannot be discerned from those reports whether, in patients with hypercalciuria and metabolic bone, the hypercalciuria was apparent from the initiation of home TPN, or developed subsequent to long-term TPN treatment. Our results suggest that a significant proportion of home TPN patients may develop hypercalciuria and negative calcium balance early in the course of a home TPN program. Additional studies will be necessary, however, to ascertain whether urinary calcium excretion adapts during the course of long-term cyclic TPN. It is noteworthy that, even on continuous TPN infusion, 2 of 5 of our subjects were in frank negative calcium balance, since urine calcium excretion alone exceeded the amount of calcium infused. This finding is consistent with that found in our study of amino acidinduced hypercalciuria in TPN patients receiving 1 g amino acids/kg and 240 mg of calcium per day during continuous TPN (6). Moreover, since endogenous fecal losses of calcium were not measured in the present study, it is likely that some patients may have been in a greater negative calcium balance than reflected by the urinary calcium losses alone. For example, Rudman et al (14) have reported daily stool calcium losses of 1.6 mg/kg during calcium balance studies in adult TPN patients receiving no oral intake. These findings would suggest that our subjects may have been losing as much as an additional 80 to 120 mg calcium per day via endogenous fecal losses. In future studies measurement of indices of bone turnover, such as urinary hydroxyproline or serum osteocalcin, and in longer term studies measurements of bone mineral losses, would be helpful in the interpretation of the data. The mechanism of increased urinary calcium loss in patients receiving cyclic TPN is uncertain. Since we found no change in urinary calcium excretion in 5 subjects receiving continuous TPN for 9 d it suggests that the significant increase in urinary calcium during cyclic TPN is most likely not attributed to some cumulative effect of TPN over time. This position is strengthened by Jacobson et al who have recently reported that urinary calcium excretion rate is stable for up to 56 d of continuous TPN administration in Crohn s patients (15). The most likely explanation for increased urinary calcium losses during cyclic TPN is that the augmented filtered calcium load occurring during the 12-h TPN infusion period was largely responsible since a majority of the calcium excreted in the urine during the cyclic TPN regimen occurred during the actual time of TPN infusion. Since we did not measure the ultralilterable fraction ofserum calcium directly (see Methcxls), we can only estimate the filtered calcium load. It is conceivable that the ratio of ultrafilterable to total serum calcium may have been altered during cyclic TPN administration which in turn could affect urinary calcium excretion. This possibility deserves further investigation. Additional factors may be operative during cyclic TPN infusion which may also affect renal calcium handling. For example, the significantly increased level of blood urea nitrogen found during cyclic TPN reflects the increased metabolic load of amino acids metabolized during this time period. We have shown previously in TPN patients that doubling the quantity of amino acids delivered during continuous TPN markedly increases urinary calcium losses and increases fractional calcium excretion (6). The increase BUN during cyclic TPN probably contributed to greater solute excretion during the 12-h period of TPN infusion, which may be a factor leading to increased calciuria. In addition, we noted significantly increased blood levels of insulin during cyclic TPN. DeFronzo et al (16) have shown that increased serum insulin levels can increase urinary calcium excretion in man under conditions of either

6 CALCIURIA IN CYCLIC TPN 619 hyper- or euglycemia. Moreover in the rat, changes in insulin are largely responsible for the calciuretic effect of infused glucose or amino acids (17). Abnormalities in parathyroid hormone and vitamin D metabolism, have been reported in patients receiving cyclic TPN (5) and could have additional effects on renal calcium handling. Unfortunately, they were not measured in this study. It is possible that some degree of volume expansion during the shorter infusion times during cyclic TPN may contribute to natriuresis and calciuresis. Sodium and calcium excretion have been shown to be correlated in some studies (18, 19), but can be dissociated (19, 20). In this study we did not measure urinary sodium excretion. In 4 of 5 patients, where we measured serum sodium and filtered sodium load, we found no correlation between these variables and urinary calcium excretion. In conclusion, the results of this study indicate that a significant proportion of patients receiving continuous TPN infusion can be in negative calcium balance. Moreover, this condition can be accentuated by the increased urinary calcium excretion caused by the increased rate of nutrient delivery occurring during cyclic TPN. This increased loss of urinary calcium in patients receiving cyclic TPN, if persistent, could become a significant factor in the maintenance of negative calcium balance and the development of osteopenia in some patients receiving longterm home TPN. References 1. Matuchansky C, Morichau-Beauchant M, Druort F, Tapin J. Cyclic(nocturnal)totalparenteral nutrition in hospitalized adult patients with severe digestive s.report of a prospective study. Gastroenterology 1982;8 1: Slake M, Harrison JE, Sturtridge WC, et al. Metabolic bone in patients receiving long-term parenteral nutrition.ann Intern Med 1980;92: Klein GL, Targoff CM, Ament ME, et al. Bone associated with total parenteral nutrition. Lancet l980;2:lo4l Shike M, Sturtridge WC, Tam CS, et al. A possible role of vitamin D in the genesis of parenteral nutrition-induced metabolic bone. Ann Intern Med 1981;95: Klein GL, Horst RL, Norman AW, Ament ME, Slatopolsky E, Coburn JW. Reduced serum levels of la,25-dihydroxyvitamin D during long-term total parenteral nutrition. Ann Intern Med 198 l;94: Bengoa JM, Sitrin MD, Wood Ri, Rosenberg IH. Amino acid-induced hypercalciuria in patients on total parenteral nutrition. Am J Clin Nutr l983;38: Sloan GM, White DE, Brennan MF. Calcium and phosphorus metabolism during total parenteral nutrition. Ann Surg l983;197:l Lemann J, Lennon EJ, Piering WR, Prier EL Ricanati ES. Evidence that glucose ingestion inhibits net renal tubular reabsorption of calcium and magnesium in man. J Lab Gin Med l970;75: Ha&Iad JO, Chyu KJ. Competitive protein-binding assay for 25-hydroxycholecalciferol. J Clin Endocrinol 197 1;33: Heinegard D, Tiderstrom G. Determination of serum creatinine by a direct colorimetric method. Clin Chim Acta l973;43:305-l Willis JB. Determination ofcalcium and magnesium in urine by atomic absorption spectroscopy. Anal Chem l96l;33: Chen PS, Toribara TY, Warner H. Microdetermination of phosphorus. Anal Chem l956;28: I 3. Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames, Iowa: Iowa State University Press, Rudman D, Millikan Wi, Richardson Ti, BixlerTi, Stackhouse Wi, McGarrity WC. Elemental boiances during intravenous hyperalimentation of underweight adult subjects. J Clin Invest l975;55: Jacobson 5, Plantin L-O, Carlmark B. Urinary excretion and blood concentration of trace elements and electrolytes during total parenteral nutrition in Crohn s. Dig Dis Sci l984,29:606-l DeFronzo PA, Cooke CR, Andes P.,Faloona GR, Davis Pi. The effectof insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest l975;55: Wood Ri, Allen LH. Evidence for insulininvolvement in albinine- and glucose-induced hypercalciuria in the rat. i Nutr l983;l13: McCarron DA, Rankin LI, Bennett WM, Krutzik 5, McClung MR. Luft FC. Urinary calcium excretion at extremes of sodium intake in normal man. Am i Nephrol 1981;1: Modlin M. The interrelation of urinary calcium and sodium in normal adults. Invest Urol l966;4: Lindeman RD. Adler 5, Yiengst Mi, Beard ES. Influence of various nutrients on urinary divalent cation excretion. i Lab Gin Med 1967;70: