A great deal of controversy has arisen over the need for preoperative nutritional support. Although the vast majority of literature on this subject relates to adults, an extrapolation of many of these studies can help guide the pediatrician and pediatric surgeon in the care of their patients. Two well conducted studies have examined the use of preoperative enteral feedings. Patients in these studies were given between 10 and 21 days of an enteral diet ^{1, 2}. These studies showed a reduction in postoperative wound infections, anastomotic leakage, hepatic and renal failure and length of hospital stay. A meta-analysis of several previously performed studies has demonstrated only a marginal benefit to preoperative parenteral nutrition ³. The most definitive statement comes from the Veterans Administration Cooperative Studies Program which showed that peri-operative parenteral nutrition given 7 to 15 days preoperatively and 3 days post-operatively was of no benefit to mild or even moderately malnourished patients. In severely malnourished patients, however, a demonstrable benefit was noted in that there were fewer non-infectious complications ⁴. Infection rates, however, were overall higher in the TPN group and this association could not totally be explained by the use of central venous catheters, suggesting that use of TPN may actually predispose patients to increased infectious complications. Thus, unless there are clear indications of severe malnutrition, a delay in operative management in order to provide preoperative TPN is not indicated. An extrapolation of these findings to neonatal patients is difficult; however, because of similarities in the metabolic response to surgery, it seems reasonable to apply these same conclusions to the pediatric population.

Indications for Postoperative Nutrition

Use of aggressive postoperative nutritional support is an even more controversial area. For enteral feedings, some studies have noted a benefit in terms of a decreased level of septic morbidity and lower cost in the enterally fed group ^{5, 6}. However, it is important to note that others have shown that a number of patients are intolerant of very early enteral feedings after a major gastrointestinal operation ⁷, and others have noted deaths due to patients receiving enteral feedings ⁸. Although this data is confined to adult patients, it suggests that for indicated patients, postoperative nutrition should be started early and be delivered in a combined fashion, parenteral and enteral, until the gastrointestinal tract recovers.

The benefit of parenteral nutrition in the postoperative period is also unclear. Although some studies have shown the advantages of decreased healing time and shortened hospital stay ⁹, other studies have shown little or no benefit ^{10, 11}. A comparison of the use of parenteral versus enteral nutrition in the postoperative period shows higher infection rates in parenteral nutrition patients and little benefit in the enteral group due to feeding intolerance in some patients; a lack of improved outcome was noted in both groups ^{12, 13}. Similar studies on the effects of enteral versus parenteral feeding in the post-injury patient have been carried out. These studies have demonstrated findings similar to the previous study, namely more infectious episodes in the parenterally fed group and improved immunologic status in the enterally fed patients ^{14, 15}.

Because results in the area of postoperative nutritional support are not clear, we support aggressive postoperative feedings in only those patients who can receive enteral nutrition without complication. In those children who require parenteral nutrition, it should be restricted to those neonates who will not tolerate even a short period of starvation or to older children in whom it is anticipated that they will not start enteral nutrition for at least 5 to 7 days.

Biliary Atresia

The infant with biliary atresia, even after a clinically successful hepatic portoenterostomy, will generally have lower than normal amounts of bile flow into the intestine. This subsequently leads to a profound defect in fat digestion and absorption ¹⁶. Such a deficit may leave the infant with an essential fatty acid deficiency and inadequate absorption of fat soluble vitamins. As a consequence, this will lead to a lack of bone mineralization as well as failure to thrive. The essential goals for such an infant are to provide adequate calories using a formula which maximizes fat intake. Portagen (Mead Johnson & Company) has been used for a variety of causes of liver failure in infancy because of its high content of medium chain triglycerides. Medium chain triglycerides, which undergo intestinal luminal triglyceride hydrolysis, are less dependent on bile acids for absorption compared to long chain fatty acids. Portagen¨, however, contains a very limited amount of linoleic acid. A more ideal formula is Pregestimil¨ (Mead Johnson & Company). Although Pregestimil® contains less medium chain triglycerides than Portagen® (60% vs. 80%), this solution contains approximately 11% of its calories as linoleic acid. Thus, provision of essential fatty acid is better. When parenteral nutrition is needed, a standard crystaline amino acid solution appears to be ideal. Although there are claims that branch chain amino acid formulas (e.g. Hepatic-Aid¨, McGaw) are better, no proven benefit has been shown in pediatric patients. Breast feeding, although generally ideal in infancy, may actually be detrimental in patients with biliary atresia because breast milk has a much higher fat content than commercially available formulas. Vitamin supplementation is critical in patients with biliary atresia. Table 10 gives the current recommendations for fat soluble vitamin administration in patients with biliary atresia. Frequent monitoring of vitamin levels is essential to insure sufficient supplementation is being achieved. The addition of water soluble vitamins above those provided in standard infant formulas should be carried out by the administration of a multi-vitamin preparation. Iron, zinc, and calcium deficiencies should also be carefully screened for.

Short Bowel Syndrome (SBS)

The nutritional support of a child with the short bowel syndrome is complex and requires a multidisciplinary approach with the pediatric surgeon, pediatric gastroenterologist, pharmacist and dietitian working together. The care of such an infant can be divided into three stages 17. The first stage of care begins after resuscitation of the patient in the post-operative period or at the time the diagnosis of short bowel syndrome has been made. The syndrome is associated with increased gastric output, due to a loss of intrinsic intestinal negative feedback, and increased stool output, which often leads to fluid and electrolyte shifts and losses of nutrients and trace elements. During this time a permanent silastic central venous catheter (e.g. BROVIAC® catheter) needs to be inserted. Since the child will need long-term venous access, each access site must be carefully cared for and protected. The child's main or sole caloric source will be via the parenteral route for a considerable period of time. Nevertheless, enteral feedings should be initiated within 1 to 2 weeks after the onset of the short bowel syndrome. Enteral feedings will both stimulate small bowel adaptation and prevent the development of parenteral nutrition associated cholestasis. The ideal enteral solution should be isotonic, or nearly isotonic as this will be better tolerated by the gastrointestinal tract. The protein source should be predominately di- and tripeptides, since this source of protein is most easily and efficiently absorbed ¹⁸. The solution should have a fair amount of medium chain triglycerides, as this source of fat is well absorbed through the baso-lateral wall of the intestinal enterocytes. However, medium chain triglyceride contain no essential fatty acids, thus these fats cannot be the sole source of lipids in these patients. Table 5 gives recommended formulas for different age children. In infants, we prefer to initiate feedings with Pregestamil (Mead Johnson¨), and in children over one year of age we generally utilize Petamen Junior (Clintec¨, can be given to children up to 10 years of age). High stool output is associated with excessive losses of zinc; thus, zinc supplementation, above that normally required, should be provided in the parenteral nutrition solution. Finally, the loss of sodium and bicarbonate in such patients can be dramatic and a total body sodium depletion has been shown to be associated with failure to thrive, despite the administration of adequate amounts of calories ^{19, 20}. A simple way to detect such a deficit is to measure a spot urine sodium. A urine sodium of less than 10 meq/L may well indicate total body sodium depletion and supplementation via the oral route should be given on a daily basis.

During the second phase of support, a more stabilized state has been reached, at which point careful monitoring of the patient's nutritional status is very important. Electrolytes, liver function tests and assessment of protein status (total protein albumin and total iron binding capacity) should be done initially and on a weekly basis. Fat soluble vitamin levels should be assessed approximately every six months to assure that adequate amounts are being absorbed. Serum levels of vitamins A, D, and E can be assayed. A prothrombin time will be indicative of vitamin K levels. Patients with a significant loss of the terminal ileum should have a vitamin B12 level assessed on a yearly basis. Supplementation of fat soluble vitamins, if depleted, should follow the recommendation outlined in the previous section on biliary atresia. The child's stool should intermittently be assessed for pH, reducing substances and qualitative fecal fats. A stool pH less than or equal to 5.5 or a reducing substance level greater than one-half percent will indicate malabsorption of carbohydrates. Elevation in fecal fats will suggest fat malabsorption, which may require modification of the child's enteral diet (i.e. increase the percent of medium chain triglycerides). Formulas with sucrose as the carbohydrate will not yield a positive reducing substance test despite carbohydrate malabsorption.

The final phase of nutritional support consists of weaning the patient off of parenteral nutrition. During this stage, which may last from months to years, a variety of factors must also be monitored. These include an assurance that the child will develop normal suck and swallow reflexes and not develop an aversive to oral feedings. Also, the child should be monitored for normal length and weight gain. Finally, patients with an intact colon should be evaluated for the development of renal oxalate stones, and, thus, should avoid a high oxalate diet.

Recently, an interest in 'rehabilitating' the intestinal remnant in these in patients has surfaced. Use of enteral glutamine, high fiber diet and systemic growth hormone has been tried in patients on long-term TPN. A three week course of this therapy apparently resulted in improved caloric absorption from the intestine and decreased stool output ²¹. Experience in children, however, is lacking and further work in this age group will be needed to confirm these findings. More recent work in this area has actually demonstrated no improvements in small bowel morphology, stool losses, or macronutrient absorption ²². Predictions of survival appear to directly correlate to the development of sepsis and cholestatic liver disease.

Failure to Thrive

Malnutrition in childhood is associated with poor growth and development. The diagnosis of failure to thrive is based on a weight more than 2 1/2 standard deviations below the mean weight percentile of both parents. Failure to thrive is either symmetric, whereby height, length, and development of other body organs are all below the fifth percentile, or asymmetric, in which case, weight is lower than the fifth percentile, but length and head circumference are within normal limits. In general, those patients with symmetrical failure to thrive have more profound malnutrition and suffer from greater neurologic maldevelopment than those with asymmetric failure to thrive, who have reasonably normal cognitive development. More recent investigations have shown that abnormal cognitive development in patients with failure to thrive may well be due to a poor social environment and is often reversible ^{23, 24}.

The approach to feeding a patient with failure to thrive should include a multidisciplinary assessment of medical, social and psychologic factors. A systematic evaluation to rule out neurologic pathology, swallowing disorders, feeding aversion, malabsorption and metabolic disorders should be carried out. A trial of feeding the child in a hospital setting can often identify a problem with the child's home and social environment. Nutritional support for an infant should begin at approximately 50 Kcals/kg/day and advance by 20 to 25 Kcal/kg/day, as long as there is adequate gastrointestinal tolerance to the feedings. Stool weight should be less than 150 grams per day in young infants. Feedings may increase up to 150 to 240 Kcal/kg/day to achieve adequate catch-up growth ²⁵. Additional potassium up to 5 mEq/kg/d may also be required during the first week of nutritional rehabilitation. Levels of potassium, magnesium and phosphate need to be closely monitored as they will often drop rapidly during the initiation of feedings. A commonly utilized formula for estimating catch-up growth is ²⁶:

                          Calories required for Ideal weight
                          weight/age(kcal/kg/day) X for age (kg)
    Catch-up            __________________________________________
growth (kcal/kg/day) =
                                   Actual weight(kg)

Estimated protein requirements can similarly be estimated using a similar formula by substituting protein required (g/kg) for calories required. Not infrequently, this formula overestimates nutritional needs. Another simple formula is that for each gram of tissue weight gain per day one desires, one should provide 5 additional calories.

The Handicapped Child

Between 10 and 20% of children in the United States have special health care needs because of chronic illness and developmental disorders ²⁷. Among these disorders are several in which pediatric surgeons take an active part in the nutritional care, including neurologic impairment, developmental delay, cerebral palsy and a variety of genetic syndromes such as Trisomies 13, 18, and 21, Cornelia de Lange and Rett syndromes. Very often the pediatric surgeon is responsible for providing nutritional access in many of these patients as well as for maintaining nutritional care both before and after surgery. Potential factors which may contribute to poor nutrition in these patients include feeding disorders, uncoordinated tongue movements, poorly coordinated swallowing reflexes, gastroesophageal reflux with associated nutrient loss, and increased energy expenditure due to muscle spasticity or athetosis. Because measuring energy expenditure in these children may be impractical, estimates of energy needs can be based on previous studies of resting energy expenditure. Children with spastic type (hypertonia) cerebral palsy may have lower energy needs than normal, approximately 1200 to 1300 kcal per day in total energy needs for an adolescent ^{28, 29}. Children with athetosis (mixed pattern of too much and too little muscle tone) may require a higher than normal calorie intake, sometimes more than double the recommended daily allowance (RDA). Children with myelomeningocele are quite inactive compared to their peers and for that reason may need only 50 to 60% of estimated energy needs of normal children (Table 11).

Often the child's body habitus is markedly abnormal; in this case a more appropriate estimate of energy needs should be based on surface area rather than weight. Repeated assessments of the child's growth during nutritional supplementation is essential since the development of obesity in these impaired children is common, which can cause a considerable burden on the family and care givers because of the increased difficulty in moving an overweight child.

Metabolic Bone Disease in the Premature Infant

With improved medical and surgical care pediatric surgeons are caring for a larger number of preterm infants. The incidence of metabolic bone disease in these infants is as high as 30% in infants less than 1500 grams and 70% in infants less than 800 grams at birth ³⁰. The factors which tend to exacerbate the development of rickets in pre-term infants include prolonged use of parenteral nutrition as well as the use of thiazide diuretics. The detection of this disorder is essential and requires the use of both biochemical tests and radiologic assessment. Biochemical tests include measurements of calcium phosphate, vitamin D and serum alkaline phosphatase levels. Calcium levels are often normal in patients with rickets; however, phosphate levels will characteristically be low in these patients. Alkaline phosphatase levels will be elevated in a large number of infants with rickets ³¹. Because elevated levels of alkaline phosphates may also be due to parenteral nutrition- associated cholestasis, interpretation may be somewhat difficult. Characteristically alkaline phosphatase levels will be five times higher than normal adult levels . Fractionation of the alkaline phosphates may help determine the etiology of its elevation (bone vs. liver). Unfortunately, standard chest and extremity x-rays will only detect advanced cases of rickets, well after the full clinical development of the process. A more precise assessment of rickets can be done using X-ray or photon absorptiometry ³².

Treatment of neonatal rickets ideally begins with prevention. Neonates receiving long-term parenteral nutrition should receive maximal amounts of calcium and phosphate, at a calcium: phosphate ratio of 1.3:1 to 1.7:1 which provides good retention rates with little or no disturbance to mineral homeostasis ³⁰. Further increases in calcium concentration run the risk of the development of precipitation of calcium phosphate salt and occlusion of the intravenous catheter or ectopic calcium deposition ³³. The administration of cysteine HCl has been used to improve calcium and phosphate solubility by decreasing the pH of the parenteral nutrition solution. The risks of adding such a solution include the development of a metabolic acidosis as well as a potential leaching of calcium salts from bone. Probably no higher than 4 mg/dL of cysteine should be added to the parenteral nutrition formula. For neonates receiving enteral feedings, use of either liquid or powdered human milk fortifiers or a pre-term infant formula (see Table 5) should be instituted. If commercial fortifiers are not available, calcium di-sodium phosphate should be added to either breast milk or standard formula. Both the level and activity of vitamin D are quite adequate in most preterm infants. Thus, no additional vitamin D is needed Supplementation should continue until the infant obtains a weight of 3 to 3.5 kilograms (term weight).

Parenteral Nutrition-Associated Cholestasis

The initial association between cholestasis and parenteral nutrition was made four years after parenteral nutrition was first used in neonates ³⁴. Histologically the liver shows bile duct proliferation in the portal triad region, with the subsequent formation of large tracts of fibrosis between normal appearing hepatocytes.

Several factors have been found to be associated with parenteral nutrition-associated cholestasis (PNAC). The most prominent risk factors are low birth weight and prematurity ^35-37. The duration of TPN administration has also been shown to increase the risk of cholestasis. PNAC leads to cirrhosis, sepsis and increased mortality rates. Although reversible in its early stage, eventually irreversible cirrhosis will develop. Clearly, liver failure is the ultimate complication. The group at greatest risk of PNAC are those infants on long-term TPN for the short bowel syndrome. In one series, the incidence of sepsis was 56% in PNAC babies, compared to 13% in those babies on TPN with normal bilirubin levels ³⁸. The higher infection rates in these patients is most likely explained by a number of immunologic deficiencies which develop as shown in animal models of bile duct ligation, and which include decreased T-lymphocyte function and lymphocytic proliferation 39, 40. Infants with PNAC have a 31% mortality compared to a 3% mortality for those on TPN without cholestasis 38. In our group of patients with the short bowel syndrome, the majority of those who died developed a significant rise in direct bilirubin level within 4 months of their development of SBS. Those patients with a sustained direct bilirubin of greater that 4 mg/dl for more than 6 months had an 80% mortality. The etiology of cholestasis is unknown. Several potential causes have been considered and are discussed below (see Figure 1).

TPN Solution
The parenteral nutrition solution may either have a toxic-like substance in it or it may be missing one or more critical nutritional factors which are needed to prevent liver injury. Virtually every possible factor included in the TPN formula has been implicated as the causative agent at one time or another. Among the more likely factors is a lack of taurine. A lack of taurine prevents the conjugation of bile salts, which are needed for their excretion. Taurine supplemented TPN has been compared to standard parenteral nutrition in a limited number of studies. Although some of these studies have suggested a decreased incidence of cholestatsis in those neonates receiving taurine, no adequate study has been performed ⁴¹. More recently, phytosterols, found in intravenous lipid compounds and derived from plant products, have been suspected to have a role in the development of PNAC. Patients with PNAC have been shown to have elevated plasma levels of phytosterols ⁴², and these levels may accumulate in other types of patients with cholestasis ⁴³. More recently, phytosterols have been implicated in the pathogenesis of PNAC, itself, using a rabbit model ⁴⁴. Recently, use of methionine, although needed in premature infants, has been suggested as a cause of PNAC ⁴⁵.
Overfeeding
One clear cause of liver injury is overfeeding, most commonly with an excessive administration of carbohydrates. The liver pathology in this condition, however, is different in that the only finding is hepatic steatosis, without bile duct proliferation. Clearly, by limiting the amount and type of delivered calories, this problem can be avoided.
Bacterial Translocation
A more recently proposed etiology is that of bacterial translocation. The incidence of bacterial translocation is higher in a fasting animal. During the process of bacterial translocation, a release of endotoxins can lead to the secretion of various cytokines including TNF and interferon-g, by either peritoneal or hepatic macrophages. These cytokines could then potentially cause liver injury. The administration of antimicrobial agents such as metronidazole has been hypothesized to reduce the incidence of cholestasis by reducing the colonization of the GI tract and subsequently the incidence of bacterial translocation. In one study on rats receiving TPN, the degree of hepatic steatosis was reduced with oral antibiotic treatment, however, bilirubin levels remained unchanged, suggesting that the etiology of hepatic steatosis is most likely different than that of cholestasis ⁴⁶.
Lack of Enteral Stimulation
The last area which has been considered in the etiology of PNAC is the lack of enteral stimulation. During prolonged periods of fasting, the GI tract lacks sufficient enteral stimulation for the release of a variety of hormones which promote bile flow. Such hormones may be critical in preventing biliary stasis. Use of cholecystokinin to relieve this problem have been attempted in both experimental animals as well as in clinical trials with moderate success ^{47, 48}. Cholecystokinin given near the beginning of the TPN administration appeared to have an even greater benefit in preventing the development and severity of PNAC ⁴⁹.

An associated problem related to prolonged use of TPN is the development of cholelithiasis. Approximately 10% of patients with the short bowel syndrome, develop gallstones ⁵⁰. Because many of these infants were not specifically studied for the presence of gallstones, the incidence of cholelithiasis may in fact be much higher. In general, many of these stones regress over time. The majority are asymptomatic and thus, do not require cholecystectomy.

Figure 1. Potential etiologies of parenteral nutrition associated cholestasis. A. Direct toxic effect of the parenteral nutrition solution itself. B. An essential factor may be missing from the parenteral nutrition solution. In this case taurine which is needed to solubilize bile salts may be necessary for adequate excretion of bile. C. A lack of enteral stimulation may lead to a lack of normal hormonal stimulation of the hepatobiliary tree. Cholecystokinin, as an example, is needed for both intrahepatic bile flow as well as gallbladder contraction. D. A lack of enteral feedings may lead to mucosal barrier breakdown causing bacterial translocation. This may lead to an increase in endotoxins, tumor necrosis factor (TNF) or interferon gamma (INF- g) in the portal blood stream, all of which may cause hepatic injury.

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Suggested readings authored by the University of Michigan, Section of Pediatric Surgery

Coran, AG, Spivak, D, Teitelbaum, DH: An analysis of the morbidity and mortality of short-bowel syndrome in the pediatric age group. Eur J Pediatr Surg 9:28-230, 1999.
Teitelbaum DH: Parenteral Nutrition-Associated Cholestasis. Current Opinion in Pediatrics 9:270-275, 1997.
Jones, KR, Kovacevich, DS, Teitelbaum, DH: Establishing a comprehensive database for home parenteral nutrition: Six years of data. Nutrition in Clinical Practice 15(6): 279-286, 2000.
Teitelbaum, DH, Coran, AG: Perioperative Nutrition Support of Pediatrics. Nutrition Support and Pediatric Surgery. Nutrition, 14(1): 130-142, 1998.

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