Parenteral nutrition and neonatal cholestasis

296

Brief clinical and laboratory observations

Table. Comparison of breast milk-fed and formula-fed infants with NEC Breast milk (N = 15)

Birth weight (gm) 1,315 _+ 340 Gestation (wk) 30.7 _+ 2 Sex ratio (M:F) 9:6 Permatal stress 9 (60%) Hyaline membrane disease 7 (47%) Respiratory distress-assisted 13 (87%) ventilation Umbilical catheters 13 (87%) Duration of umbilical catheter175 _-!-85.8 ization (hr) Diagnosis NEC suspected (days) 11.8 _+ 8.2 Surgery for NEC 4 (27%) NEC cause of death 3 (20%) Died (of all causes) 7 (47%)

Cow milk formula (N = 25)

2,187_+ 950 33.7 +_ 4 14:12 9 (36%) 5 (20%) 8 (32%)

The Journal of Pediatrics February 1979

milk compared with infants fed formula. Wells:' and Reisner and Garty ~ had described the occurrence of NEC in six infants fed exclusively with frozen human milk, but these infants were not compared with the other neonates who developed NEC. Frozen human milk does not protect the susceptible low-birth-weight infant from developing severe, possibly fatal, NEC although it may exert an effect on the incidence of this condition. REFERENCES

1. Baflow B, Santulli TV, Heird WC, Pitt J, Blanc WA, and SchuUinger JN: An experimental study of acute neonatal enterocolitis: The importance of breast milk, J Pediatr Surg 9:587, 1974. 2. BellMJ, Ternberg JL, Feigen RD, Keating JP, Marshall R, Barton L, and Brotherton T: Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging, Ann Surg 187:1, 1978. 3. Wells DH: Feeding techniques and neonatal necrotizing enterocolitis, Pediatr Res 12:1037, 1978 (abstr). 4. Reisner SH, and Garty B: Necrotizing enterocolitis despite breast feeding, Lancet 2:507, 1977.

14 (56%) 118 + 78.6 8.2 _+ 6.9 8 (32%) 3 (12%) 5 (20%)

catheterization (P < 0.05, Chi square with Yates correction). From this study, no comment can be made regarding the incidence of NEC in infants had exclusively human

Parenteral nutrition and neonatal cholestasis Frank P. Manginello* and Norman B. Javitt, New York, N. Y.

CHOLESTASIS has been reported to occur'. ~-during the course of parenteral nutrition given for the management of a variety of illnesses occurring in premature and newborn infants. The occurrence of cholestasis has not been related to a specific formulation, and instances have occurred independent of the use of fat emulsions. Detection of cholestasis has been dependent on the occurrence of hyperbilirubinemia during parenteral alimentation in association with elevations in serum alkaline phosphatase and/or 5'nucleotidase and transaminase values. It is now recognized~.4 that an elevation in the total serum bile acid concentration occurs prior to the appearFrom the Perinatal Center and the Department of Medicine, The New York Hospital-Cornell University Medical Center. Supported in part by the Dean Thiel Liver Foundation and Grant No. AM-16201 from the National Institutes of Health. *Reprint address: College of Medicine and Dentistry of New Jersey, Assistant Director of Newborn Nurseries, Director of Neonatal Research, St. Joseph's Hospital and Medical Center, Paterson, NJ 07503.

ance of jaundice during the development of cholestasis. Moreover, a change in serum bile acid concentration is more specific for the development of cholestasis, since hyperbilirubinemia may reflect hemolytic disease or isolated defects in bilirubin transport. For these reasons, the serum bile acid concentration was determined prospectively in a group of infants, some of whom required long-term parenteral nutrition. PATIENT POPULATION All infants admitted to the neonatal intensive care unit from January, 1976, to April, 1976, were entered into the study. Fourteen patients did not require parenteral nutrition and were fed orally as soon as such feedings were tolerated, using either fresh patient-specific breast milk or standard 20 calorie/ounce infant formula. Supplemental intravenous fluids containing glucose and electrolytes were given to maintain hydration. This group (Group 1) constituted the control population. The parenteral nutrition group of 24 infants represents those neonates in whom clinical considerations indicated 0022-3476/79/200296+03500.30/0 9 1979 The C. V. Mosby Co.

Volume 94 Number 2

its use, usually either severe respiratory distress or abdominal surgery. All solutions were prepared by a trained pharmacist under a laminar flow hood and were given by a Constant infusion technique. Dextrose concentrations were adjusted to prevent hyperglycemia or glucosuria and were increased progressively to a maximum of 20g/dl. Freamine 11 was used as a source of protein, with a maximum concentration of 2.5g/kg/24 hours. Intralipid, when used, was given in a 10% solution, initially at 1 grn/kg/24 hours, and was increased slowly to 4 gm/kg/24 hours or a maximum of 40% total calories. These solutions provided 90 to 120 calories/kg/24 hours and were given in combination with appropriate amounts of electrolytes and water. Generally, maximum glucose and protein concentrations were achieved by seven days of life, and maximum lntralipid concentrations by 15 to 20 days. All parenteral nutrition was given by the central route. PROCEDURES Patient care included routine laboratory studies; blood, urine, and cerebrospinal fluid cultures were drawn when sepsis was suspected. Appropriate antibiotics, most often ampicillin and gentamicin, were given whe n the diagnosis of sepsis was entertained, and changed when sensitivity testing was available. For monitoring liver function, serum bilirubin and SGPT were measured on entry into the unit and at weekly intervals. In addition, serum bile acid analyses (0.25 ml) were done by gas-liquid chromatography using modifications previously published in detail. ~ In the later phases of these studies, total serum bile acids were also estimated by a dual-beam spectrophotometric method' using 3asteroid dehydrogenase and requiring only 0.1 ml of serum. A correlation coefficient of greater than r = 0.9 was obtained for the two procedures. RESULTS There were no significant differences in the mean birth weight, estimated gestational ages, or time to first oral feeding, of the control and parenterally nourished groups (Table). Except in those infants with sepsis, Group liB, the serum bilirubin concentration was less than 1.5 mg/dl. The mean serum bile acid concentration was 13.1/~M in the control group and 13.7 btM in the parenteral nutrition Group IIA. Six neonates with either Escherichia coli or staphylococcol sepsis (Table) developed elevations in serum bile acid values. The mean value was 66 ~M with a range from 33 to 144/~M. As shown in the Figure, both serum bile acid and Conjugated bilirubin levels tended to rise together and fall to normal as sepsis was successfully treated. The total duration of parenteral nutrition, either with or without Intralipid, and the time to the first feeding in this group

Brief clinical and laboratory observations

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Cholestasis during sepsis and parenteral nutrition. During the course of parenteral nutrition the patient developed necrotizing enterocolitis (NEC) with E. coli sepsis. Elevated serum bilirubin and bile acid concentrations occurred which returned toward normal with antibiotic therapy.

Figure.

was not significantly different from the group in whom sepsis did not occur (Table). In three instances, total serum bilirubin concentration did not exceed 4.3 mg/dl, and jaundice was not detected clinically. DISCUSSION Parenteral nutrition has become an integral part of the management of a variety of problems occurring in neonates. Although this prospective study cannot exclude the possibility that this form of nutrition may have an adverse effect on liver function in some neonates, all of the instances of ch01estasis that occurred could be attributed to sepsis. This conclusion is further supported by the finding 'that cholestasis remitted while parenteral nutrition was continued, once the sepsis was treated successfully. Berstein and Brown 7 reported an association between neonatal sepsis and jaundice in 1962, prior to the use of protein and fat as part of parenteral nutrition. In their series, 13% of the patients with proven bacterial sepsis developed biochemical evidence of cholestatic jaundice that later was confirmed morphologically in those who died of the infection. In contrast, cholestasis disappeared with successful treatment of the infection. Rager and Finegold ~ believe that an association exists between the incidence of cholestasis diagnosed post mortem and the lack of early oral feeding. A suggested mechanism is a reduction in bile flow as a result of the lack of oral nutrients. No physiologic or biochemical data were provided to support the theory and the possibility of inapparent sepsis was not completely excluded. In the present study, there was no statistically significant difference in the number of days before oral feedings were begun and peak serum bile acid concentration. The mean serum bile acid concentration in the control population of premature infants was 13.1 ~M and

298

Brief clinical and laboratory observations

The Journal of Pediatrics February 1979

Table. Serum bile acids in premature infants

Group

I IIA liB

Birth weight (gin)

1,963 (1,160-2,700) 1,444 (840-3,220) 1,442 (1,100-1,700)

N

14 18 6

Estimated gestational age (wk)

33.4 (28-30) 29.3 (24-36) 30 (28-32)

Parenteral nutrition (days)

28.3 (6-70) 29.5 (15-49)

Intralipid (days)

Deaths

-

0

23.6 (0-70) 13.7 (0-49)

6 4

Days to first oral feeding

Mean conjugated bilirubin (mg/dl)

Mean peak SBA * (~M)

3.5 (1-11) 4.6 (1-70) 3.2 (1-6)

1.5

13.1 (5.7-19.6) 13,7 (2.0-26.8) 66.1 (33-144.4)

1.5 5.6 (2.5-14)

SBA = Serum bile acids. *Highest SBA obtained at weeklyintervals during stay in Perinatal Center. N.B. = Raw data availableon request from authors. could represent some reduction in hepatic extraction efficiency. However, it is possible that shunting of blood via the ductus venosus occurs, and therefore bile acids returning from the intestine bypass the liver and enter the peripheral circulation. Postprandial elevations in serum bile acid values are known to occur following portacaval shunt in children with type II homozygous hypercholesterolemia who otherwise have normal liver function tests." In neonates, with frequent feeding schedules, it may be reasonable to assume that the bile undergoes a continual recirculation, and therefore random samples of serum may contain slightly elevated levels of bile acids. In three of six neonates with sepsis, conjugated hyperbilirubinemia was less than that causing visible jaundice. Total serum bile acid values in these instances were significantly elevated and indicated a disturbance in hepatic excretory function. Since only 0.1 ml of serum is necessary for enzymatic analysis of total serum bile acids, the determination may prove useful for monitoring neonates in regard to liver function. In this study, except in patients with sepsis, no relationship could be found between either the length of time or the components of parenteral nutrition neonates were given, and the incidence of cholestasis.

REFERENCES

1. Touloukian RJ, and Downing SE: Cholestasis associated with long-term parenteral hyperalimentation, Arch Surg 106:58, 1973. 2. Touloukian RJ, and Seashore JH: Hepatic secretory obstruction with total parenteral nutrition in the infant, J Pediatr Surg 10:353, 1975. 3. Javitt, NB: Cholestasis in infancy. Status report and conceptual approach, Gastroenterology 70:1172, 1976. 4. Deleze G, and Paumgartner G: Bile acids in serum and bile of infants with cholestatic syndromes, Helv Paediatr Acta 90:736, 1977. 5. Javitt NB, Keating JP, Grand RJ, and Harris RC: Serum bile acid patterns in neonatal hepatitis and extrahepatic biliary atresia, J PEDIATR90:736, 1977. 6. Siskos PA, Cahill PT, and Javitt NB: Serum bile acid analysis: a rapid, direct enzymatic method using dual beam spectrophotofluorimetry, J Lipid Res 18:666, 1977. 7. Bernstein J, and Brown AK: Sepsis and jaundice in early infancy, Pediatrics 29:873, 1962. 8. Rager R, and Finegold MJ: Cholestasis in immature infants: ls Parenteral Alimentation Responsible? J PEDIATR 86:264, 1975. 9. Bilheimer DW, Goldstein JI, Grundy SM, and Brown MS: Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia, J Clin Invest 56:1420, 1975.

Gonococcal vaginitis in a neonate Ann R. Stark, M.D.,* and Mary P. Glode, M.D.,** Boston, Mass.

From the Department of Pediatrics, Harvard Medical School, and Beth Israel Hospital *Reprint address: Joint Program in Neonatology, 221 Longwood A re., Boston, MA 02115. **Supported in part by National Institutes of Health fellowship No. 1 F32 A1 05729-01.

PASSAGE through an infected birth canal has been associated with neonatal gonococcal infection, including ophthalmia, scalp abscess, gum abscess, and arthritis. To our knowledge, this is the first report of symptomatic gonococcal vaginitis in a newborn infant. 0022-3476/79/200298 +02500.20/0 9 1979 The C. V. Mosby Co.