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Intrahepatic Cholestasis Associated with Parenteral Nutrition in Premature Infants

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1,000-gm infant receiving PN, several articles28 have been published reporting the clinical experi ence and pathologic findings in this disease, and have suggested various theories on pathogenesis. However, there are few data defining the incidence and clinical course of this complication in prema ture infants. This retrospective analysis was con ducted in an attempt to answer these questions.

SUBJECTS AND METHODS

During 1976, 210 infants with birth weights less than 2,000 gm were admitted during the first week of life to our nursery intensive care unit. Of these infants, 73 (35%) received PN. Eleven patients with incomplete medical records, necrotizing enterocoli tis, and non-PN-related liver disease or bilirubin abnormalities were excluded from the study popu lation. The 62 remaining premature infants received PN for nutritional support during the acute stages of hyaline membrane disease, during the prolonged stages of chronic bronchopulmonary dysplasia, and during periods of severe apnea and bradycardia, until the infants were able to tolerate enteral feed ings.

These infants received either Amigen (Baxter Laboratories, Chicago, IL) or FreAmine II (McGaw Laboratories, Glendale, Ca) mixed with dextrose, electrolytes, and vitamins. Forty-one or 66% of the

infants also received Intralipid 10% (Vitrum Co,

Stockholm, Sweden). The composition of the stan dard PN solution used is shown in Table 1. These intravenous nutrients were administered either by peripheral intravenous infusions or by central jug ular vein catheters for lengths of time varying from one to 111 days. Trials of enteral feedings were common during the administration of PN. The vol umes and durations of enteral feedings were widely variable and dependent upon the individual infant's ability to tolerate the feedings. Average total caloric ABSTRACT. Sixty-two premature infantslessthan 2,000

gm birth weight received parenteral nutrition (PN) during periods of respiratory distress with feeding intolerance. Intrahepatic cholestasis (direct bilirubin 1.5 mg/dl) associated with PN developed in 14 or 239@ of these infants. The mean time on PN to onset of cholestasis was 42 days, and the cholestasis persisted as long as the infants continued to receive PN. All five infants who had serial follow-up laboratory studies showed an eventual return of direct bilirubin levels to normal. The direct l)ilirubin level appeared to be the best clinically available test to monitor for the onset and to follow the resolution of this complication. The very low birth weight infants < I .000 gm appeared to be at an increased risk of devel

()@)1ng cholestasis with an incidence of 509?. However,

there was no correlation between the length of time PN was administered to onset of cholestasis and the gesta tional age or birth weight of the infants. These tiny premature infants also received PN for significantly longer periods of time, and the longer the infusions were administered the greater was the risk of cholestasis de veloping. Pediatrics 64:342—347, 1979, parenteral nutri tion, prematurity, intrahepatic cholestasis.

Parenteral nutrition (PN) has been used rou tinely at the University of Florida Regional Nursery Intensive Care Center for several years in ill pre mature infants to minimize weight loss in the acute stages of their diseases and to provide adequate nutrition for growth and development when infants cannot tolerate enteral feedings during the chronic stages of their diseases. Of the many potential com plications from PN, the most worrisome in prema ture infants in our experience has been PN related intrahepatic cholestasis.

Since 1971 when Peden et al reported a single case of intrahepatic cholestasis and cirrhosis in a Received for publication July 7, 1978; accepted Feb 12, 1979. Reprint requests: to (E.F.B) Editorial office, Department of Pediatrics, University of Florida, College of Medicine, Box J-296, Gainesville, FL 32610.

Intrahepatic Cholestasis Associated with

Parenteral Nutrition in Premature Infants

E. F. Beale, MD, R. M. Nelson, MD, R. L. Bucciarelli, MD,

w. H. Donnelly,MD, and D. V. Eitzman,MD

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TABLE 1. Standard Compositionof Parenteral Nutrition Solution

Protein 2—3gm/kg

Dextrose 100—200gm/liter

NaC1 30 mEq/liter

K2HPO4 20 mEq/liter

Ca2@(gluconate) 10% 10 mEq/liter

MgSO4 5 mEq/liter

M.V.L* 1 amp/liter

Vitamin B,2 6.6 pg/liter

Folic acid 0.5 mg/liter

Aqua mephyton 0.2 mg/liter

Intralipid 10% 1-4 gm/kg

* Multi-Vitamin Infusion, USV Laboratories, Division USV Pharmaceutical Corp, Tuckahoe, NY.

intake ranged from 100 to 150 kcal/kg/day, and all infants established acceptable weight gain. Liver function tests and total and direct bilirubins were obtained at approximately weekly intervals to mon itor for PN complications. A serum direct bilirubin of 1.5 mg/dl or greater was considered abnormal and evidence for an hepatic secretory defect.9

None of the 62 study patients had clinical or laboratory evidence of other forms of hepatic, bili ary tract, or hemolytic diseases. Therefore, the pres ence of a rising direct biirubin more than 1.5 mg/dl was considered presumptive evidence for PN-re lated intrahepatic cholestasis.

Percutaneous liver biopsies were performed on three infants suspected of having an hepatic secre tory defect. Eight infants in the study group died, and postmortem examinations were performed. Histopathologic diagnoses made from the liver specimens obtained from these procedures were reviewed by one of the authors (W.D.).

RESULTS

Of the 62 study patients, 14 (23%) developed elevated levels of direct bilirubin of 1.5 mg/dl or more during the course of their PN. Clinical data on these 14 infants are shown in Table 2.

The number of days of PN administered until the onset of cholestasis ranged from 5 to 83 days with a mean of 42 days. Two infants, who had their PN stopped as soon as their direct bilirubins exceeded 1.5 mg/dl, showed a rapid fall in the direct biirubin levels to normal over several days to two weeks. The remaining 12 infants continued to receive PN

after cholestasis was detected because of unsuc cessful attempts to feed them enterally. The direct

biirubin continued to rise in all 12 of these patients while on PN. After the first week of life, the indirect fraction was generally less than 3 mg/dl and re mained fairly constant. The bilirubin levels began to fall in nine of 12 of these infants as soon as the PN was stopped. The three remaining infants con tinued to show a rise in their direct bilirubin for two

to three weeks after the PN had been discontinued. Five of these 12 infants continued to have serial bilirubin determinations performed and all five eventually returned to normal.

Eight of the 14 infants who developed direct hyperbilirubinemia also developed elevated SGPT values suggesting hepatocellular damage. The ab normal SGPT values occurred 12 to 50 days after the rise in the direct bilirubins had exceeded 1.5 mg/dl. All eight of these infants were among the 12 infants described above who were continued on PN despite clinical evidence for hepatobiliary dysfunc tion. The two infants whose PN was stopped at the

first indication of cholestasis did not develop ele vated SGPT values.

The overall incidence of PN-related cholestasis was 23%. Studying the infants' data in three birth weight groups (Table 3), it appeared that the tiny premature infants less than 1,000 gm at birth were at an increased risk of developing this complication with an incidence of 50%. The infants with birth weights between 1,000 and 1,499 gm and 1,500 to 2,000 gm had incidence rates of 18% and 7%, re spectively. The higher incidence in the less than 1,000 gm infants was statistically significant as corn pared to the other two groups.

A comparison of the patients with and without direct hyperbiirubinemia is shown in Table 4. Those infants who developed evidence of cholesta sis were significantly smaller at birth, received PN solutions and Intralipid 10% for significantly longer periods of time, and received a greater total intake and greater average daily intake of protein per kilogram.

When the infants in each birth weight group are considered as a whole, the 14 infants less than 1,000 gm received PN for a mean of 37 days as compared to those infants in the 1,000 to 1,499 gm and 1,500 to 2,000 gm groups who were intravenously ali mented for means of 17 and 14 days, respectively.

To assess further the relationship of prematurity and PN-related cholestasis, the time to onset of direct hyperbilirubinemia was plotted against birth weight and gestational age. There was no correla tion between the duration of PN until cholestasis and these parameters of prematurity.

Because the infants who developed cholestasis received PN for significantly longer periods of time, prevalence data were calculated at ten-day intervals (Figure). The data show a progressive increase in the prevalence of cholestasis with increasing dura tion of PN.

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PatientBirthGestationalAgeI)aysWeightAgeStartOnset atAge atNo. ofAverageType PNNo. ofDays

ofProteinSolution*(gm)(wk)of

PNCholestasisPN

toIntakeIntralipid(days)(days)CholestasisUntiltoCholestasisCholestasis(gm/kg/day)K.K.1,09028974592.0A0AG.84026491832.3A36E.V.96026664562.0F53FT.79026631251.8F24B.B.1,10029655492.2A37A.J.72034319151.6F14TD.700261756392.1F33TB.1,240302972.3F7V.N.89028254522.6F45T.G.90027264522.6F46AD.1,25028387791.9F54J.S.1,32030738282.1F12DM.1,80032437332.4F25JS.1,030283853.4F5

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(gm)______________________________<1,00014501,000-1,49934181,500—2,000147Total6223 TABLE 2. Clinical Data on Infants with Cholestasis

* Abbreviations used are: A, Amigen 5%; F, FreAmine II 8.5%.

solution. There was essentially no difference in the occurrence of direct hyperbilirubinemia on the two formulations. Of the infants on Amigen 18% devel oped direct hyperbilirubinemia vs 24% of infants on FreAmine II.

Forty-one infants received Intralipid 10% with their PN solutions. Thirteen infants (32%) devel oped cholestasis. Of the 21 infants who did not receive Intralipid 10%, one (5%) developed cholesta sis. Conversely, Intralipid 10% was administered to 13 (93%) of the 14 infants who developed cholestasis vs 28 (58%) of the 48 who did not.

Of the 14 infants five (36%) did not receive any enteral feedings before the onset of cholestasis. The remaining nine infants received intermittent feed ings in varying amounts which never supplied more than one third of the daily caloric intake. The ratio of the number of days of enteral feedings to the number of days of PN for these nine patients was 1:4.

Because sepsis is a common complication during PN, blood cultures were obtained promptly on any infant with symptoms consistent with sepsis before beginning antibiotic coverage. Of the 14 infants who developed cholestasis, one infant had a positive blood culture during PN before the onset of chole stasis. Three of the 48 infants who did not develop clinical cholestasis had positive blood cultures dur ing the course of their PN.

The three patients, on whom percutaneous liver biopsies had been performed to evaluate their din ical cholestasis, had moderate canalicular cholesta sis, trace to mild cellular bile retention, and mod erate to severe diffuse ballooning degeneration of hepatocytes.

Six of the 14 infants who developed direct hyper biirubinemia during PN died from chronic pulmo

TABLE 3. Incidenceof Direct Hyperbilirubinemia During Parenteral Nutrition by Birth Weight

Birth Weight No.

nary insufficiency, and five were autopsied. Four of these infants had mild to severe canalicular bile stasis, mild cellular cholestasis, and mild to severe fatty metamorphosis. One infant (A.D.) had only trace histologic evidence of canalicular or cellular cholestasis and mild fatty metamorphosis. He was autopsied 2½months after the development of din ical cholestasis and the discontinuance of the PN. This infant's direct bilirubin had been within nor ma! limits for three weeks before his death. Three infants who did not develop clinical cho!estasis dur ing PN were autopsied, and none had histologic evidence of cho!estasis.

DISCUSSION

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1)irectNo. ofBirthDaysTotalAveragel)ays onBilirubinInfantsWeighton

PN*ProteinProteinIntralipid@(nig/di)(gm)IntakeIntake--@-@1.5141,045t

±293(gm/kg)@(gm/kg/day)*42t±2490.6t ±53.42.2@ ±0.428t ±20<1.5481,340

±31814 ±1731.4 ±41.71.9 ±0.58 ±13

TABLE 4. Total Population Receiving Parenteral Nutrition (mean ±1 SD)

tP< .005.

t P< .05.

* Data on number of days of PN and Intralipid, and total and average protein intakes in the group with direct bilirubin 1.5 mg/dl calculated to the onset of cholestasis.

nous infusions improve the survival of low birth weight infants.' :@.

@ 4

Both total PN and parenteral supplementation have been found to be associated with numerous metabolic, infectious, and catheter-related compli cations.'@2' By routinely monitoring for such corn plications, we have found a high incidence of he patobiliary dysfunction with a clinical, laboratory, and histopathologic picture of intrahepatic chole stasis.

The 14 infants with cholestasis in this review all had either significant pulmonary disease secondary to hyaline membrane disease and subsequent bron chopulmonary dysplasia or severe apnea and brady cardia. None could tolerate total enteral nutrition, and most required prolonged periods of total PN during periods of ventilatory support with mechan ical ventilation or continuous distending airway pressure with nasal prongs. The presence of a pat ent ductus arteriosus or chronic lung disease with cor pulmonale often necessitated fluid restriction. The high calorie to fluid ratios provided by PN made intravenous feedings a useful option under these circumstances.

However, the high frequency of this complication is disturbing, particularly when one considers the numbers of premature infants who receive PN and how little we know about the etiology, pathogenesis, or acute and chronic effects on hepatobiliary func tion.

The onset of intrahepatic cholestasis during PN in our population was quite variable. Although the average length of time on PN until the onset of cholestasis was 42 days, the range was very wide. Some infants developed cholestasis during the first week of PN whereas others were fed intravenously for almost three months before showing a rise in the direct bilirubin. This wide variability points to the need for periodic routine monitoring. Total and direct direct bilirubin concentrations and liver func tion studies should be checked at weekly intervals. The clinical course of this complication during the resolution phase suggests that PN is in some way responsible for the cholestasis. Discontinuance

Cl) C,)

(I) Lu

0 U-0 Lu

0

z

Lu -J

Lu

DURATION OF PN TO CHOLESTASIS(days)

Figure. Risingprevalenceof cholestasiswith increasing duration of parenteral nutrition in the 62 study patients.

of PN in 11 infants was followed by a definite fall in the direct bilirubin levels within 14 days. Although direct bilirubin levels remained elevated or even continued to rise in the other three infants after stopping the infusate, they too eventually demon strated a gradual fall in bilirubin levels toward normal. This temporal association suggests a cause and effect relationship.

The five infants in our series from whom follow up laboratory data were obtained all demonstrated an eventual return of the bilirubin levels to normal. This observation has also been reported by other authors.4

@ Clinically, it appears that the cholesta

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the hepatocytes by certain amino acids. However, cholestasis with long-term PN may be due to a deficiency of certain amino acids. Touloukian and co-workers2'4 have suggested that such deficiencies could interfere with normal bile salt formation re suiting in cholestasis.

Intralipid 10% was administered to 58% of the infants without cholestasis and 93% of the infants with cholestasis. Infants who developed cholestasis received Intralipid 10% for significantly longer pe riods of time. Several reports have described the deposition of a lipid-like pigment in the reticuloen dothelial system and hepatic cells of patients re ceiving Intralipid 10%.2425 However, there is no evidence that these deposits cause any hepatocel lular probiem.s,24 and cholestasis has not been re ported as a complication of Intralipid 10% alone. In addition, we had seen PN-related cholestasis for several years before the introduction of Intralipid 10% into our PN protocol.

The association of cholestasis with longer courses of PN might also be explained by the fact that these infants were receiving little or no nutrition enter ally. In 1975, Rager and Finegold3 reviewed the neonatal courses of 15 extreme low birth weight infants who died after 5 days of age and had re ceived PN. Nine infants developed cholestasis by histopathology, and the other six had no evidence of cholestasis. The clinical courses of these infants were similar except that those infants who devel oped cholestasis had failed to tolerate enteral feed ings. The authors suggest that fasting and the lack of the stimulatory effect of food in the upper gas trointestinal tract on bile metabolism and bile flow could produce cholestasis in these infants. Perhaps if infants who cannot tolerate adequate enteral feedings are given minimal enteral feedings along with PN, bile flow can be stimulated to the point of preventing cholestasis. Additional studies are needed to answer this question.

Sepsis is a common complication of PN and has been mentioned as a possible risk factor in the etiology of PN-related cholestasis.3 Of our infants with cholestasis 7% had positive blood cultures, whereas positive cultures were obtained in 6% of infants without cholestasis. Although sepsis should not be totally disregarded, it can hardly be consid ered a major cause of this complication in our population.

Other conditions such as hypersensitivity reac tions, hyperosmolar states, hyperosmolar dehydra tion, bowel obstruction, hyperammonemia, essen tial fatty acid deficiencies, trace element deficien cies, chronic hypoxia, pulmonary oxygen toxicity, and the chronic use of central venous catheters have been mentioned as possible etiologic factors. @-8 Although these conditions may be important in Of the commonly ordered liver function studies,

the direct bilirubin was by far the most predictive index of the development of this complication. The clinical course of our infants, especially patient A.D. discussed above, would suggest that the direct bii rubin is also a good parameter for monitoring the resolution phase of the disease.

No abnormal SGPT values were noted in the two infants whose PN was discontinued as soon as direct hyperbilirubinemia occurred. The eight infants who developed abnormal SGPT values continued to re ceive PN after the development of direct hyperbi lirubinemia. In all eight infants, the direct biirubin became elevated weeks before the SGPT values. These facts suggest that hepatocellular damage oc curs after cholestasis and is due either to a more prolonged insult to the liver or occurs secondary to the cholestasis. These points also suggest that hep atocellular damage might be avoided if the PN is stopped at the first signs of cholestasis.

Our incidence data by birth weight suggest that the very low birth weight infant less than 1,000 gm is at a significantly greater risk of developing cho lestasis than the larger premature infant. However, if the tiny premature infant is truly at an increased risk of developing cholestasis because of extreme prematurity and immature hepatic function as has been suggested in the literature,4'6 one might expect that these infants would develop cholestasis at an earlier point in the course of PN. This was not the case in our population where there was no correla tion between birth weight or gestational age and the length of time PN was administered before cholestasis occurred. The data also show, as ex pected, that the premature infant less than 1,000 gm is more likely to receive PN for a significantly longer period of time, and that the longer PN is administered, the greater the chance of developing cholestasis. From this retrospective analysis, we cannot separate degree of prematurity from length of PN administration as to their relative importance as etiologic factors.

We are unable to say specifically why long-term PN appears to be injurious to the liver. Our infants with cholestasis received PN for longer periods of time and therefore received greater amounts of protein. The hepatobiliary dysfunction may be due

to the prolonged intravenous administration of pro

(6)

isolated cases, or in combination with other factors such as prematurity and length of protein infusion, there is no evidence to point to them as primary causes of PN-related cholestasis.

In summary, we have found an alarmingly high incidence of intrahepatic cholestasis in premature infants receiving PN. Serial direct bilirubin levels appear to be the best clinically available test to monitor for the development and resolution of the disease. Once cholestasis is present in premature infants, it will persist as long as PN is administered, and resolve slowly after PN is stopped. Research is needed to answer questions on etiology, pathogen esis, and acute and chronic effects on hepatobiiary structure and function. Until such answers are available the decision to risk the continued use of PN in the presence of cholestasis must be weighed against the risk of malnutrition in the premature infant.

ACKNOWLEDGMENTS

This investigation was supported in part by National Institutes of Health Growth and Development Training grant 5T01 HD 00054-16.

This investigation is also funded in part under an agree ment with the Department of Health and Rehabilitative Services, State of Florida.

REFERENCES

1. Peden V, Witzleben C, Skelton M: Total parenteral nutrition. J Pediatr 78:180, 1971

2. Touloukian R, Downing S: Cholestasis associated with long-term parenteral hyperalimentation. Arch Surg 106:58,1973

3. Rager R, Finegold M: Cholestasis in immature new bor infants: Is parenteral alimentation responsible? J Pediatr 86:264, 1975

4. Touloukian R, Seashore J: Hepatic secretory obstruc tion with total parenteral nutrition in the infant. J Pediatr Surg 10:353, 1975

5. Zarif M, Pildes R, Szanto P, et al: Cholestasis ciated with administration of L-amino acids and dex trose solutions. Biol Neonate 29:66, 1976

6. Rodgers B, Hollenbeck J, Donnelly W, et al: Intra hepatic cholestasis with parenteral alimentation. Am JSurg 131:149, 1976

7. Bernstein J, Chang C, Brough A, et al: Conjugated

hyperbiirubinemia in infancy associated with par enteral alimentation. J Pediatr 90:361, 1977 8. Wirtschafter D, Ermocilla R, Harris H, et al: Neonatal

intrahepatic cholestasis. Pediatr Res 9:310, 1975 9. Odell G: Neonatal jaundice. Prog Liver Dis 5:457,

1976

10. Discoll J, Heird W, Schullinger J, et al: Total intra venous alimentation in low-birth-weight infants: A preliminary report. J Pediatr 81:145, 1972

11. Peden V, Karpel J: Total parenteral nutrition in premature infants. J Pediatr 81:137, 1972

12. Benda G, Babson S: Peripheral intravenous alimen tation of the small premature infant. J Pediatr 79: 494,1971

13. Bryan M, Wei P, Hamilton J, et al: Supplemental intravenous alimentation in low-birth-weight infants.

J Pediatr 82:940, 1973

14. Pildes R, Ramamurthy R, Cordero G, et al: Intrave nous supplementation of L-amino acids and dextrose in low-birth-weight infants. J Pediatr 82:945, 1973 15. Cashore W, Sedaghatian M, Usher R: Nutritional supplements with intravenously administered lipid, protein hydrolysate, and glucose in small premature infants. Pediatrics 56:8, 1975

16. Heird W, Winters R: Total parenteral nutrition. J Pediatr 86:2, 1975

17. Shaw J: Parenteral nutrition in the management of sick low-birth-weight infants. Pediatr Clin North Am 20:333, 1973

18. Ghadimi H, Abaci F, Kumar S, et al: Biochemical aspects of intravenous alimentations. Pediatrics 48: 955,1971

19. Johnson J, Albritton W, Sunshine P: Hyperammo nemia accompanying parenteral nutrition in newborn infants. J Pediatr 81:154, 1972

20. Heird W, Dell R, Driscoll J, et al: Metabolic acidosis resulting from intravenous alimentation mixtures containing synthetic amino acids. N Engl J Med 287: 943, 1972

21. Brans Y: Parenteral nutrition of the very low-birth weight neonate: A critical view. Clin Perinatol 4:367,

1977

22. Cohen M, Litt I, Schonberg S, et a!: Hepatic dysfunc tion associated with parenteral alimentation: Clinical and experimental studies. Pediatr Res 7:334, 1973 23. Cohen M: Changes in hepatic function, in Winters R,

Hassilmeyer E, (eds): Intravenous Nutrition in the

High Risk Infant. New York, John Wiley and Sons,

mc, 1975, p 243

24. Koga Y, Swanson V, Hays D: Hepatic “¿intravenous fat pigment―in infants and children receiving lipid emulsion. J Pediatr Surg 10:641, 1975

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1979;64;342

Pediatrics

E. F. Beale, R. M. Nelson, R. L. Bucciarelli, W. H. Donnelly and D. V. Eitzman

Intrahepatic Cholestasis Associated with Parenteral Nutrition in Premature Infants

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1979;64;342

Pediatrics

E. F. Beale, R. M. Nelson, R. L. Bucciarelli, W. H. Donnelly and D. V. Eitzman

Intrahepatic Cholestasis Associated with Parenteral Nutrition in Premature Infants

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Figure

TABLE 1.Standard Compositionof ParenteralNutritionSolution
TABLE 3.Incidenceof Direct HyperbilirubinemiaDuringParenteralNutritionby BirthWeight
TABLE 4.Total Population ReceivingParenteral Nutrition (mean ±1 SD)

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