Total Parenteral Nutrition in the Pediatric Patient

Total Parenteral Nutrition in the Pediatric Patient

Current Strategies in Surgical Nutrition 0039-6109/91 $0.00 + .20 Total Parenteral Nutrition in the Pediatric Patient Lesli Taylor, MD,* andJamesA...

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Current Strategies in Surgical Nutrition

0039-6109/91 $0.00

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Total Parenteral Nutrition in the Pediatric Patient Lesli Taylor, MD,* andJamesA. O'Neill,Jr., MDt Many of the things we need can wait. The child cannot. Right now is the time his bones are being formed. His blood is being made and his senses developed. To him we cannot answer tomorrow-'His name is today. GABRIEL MISTRAL

HISTORICAL OVERVIEW The urgency of growth for children has made the advances in hyperalimentation dramatic and important in the fields of pediatrics and pediatric surgery. 56 In an ill, low-birthweight infant requiring surgery, dependable nutritional support can truly be considered an emergency. Not only must baseline organic functions be maintained, but the extra anabolic needs of growth and the stress of illness must be addressed. The limitations of physiologic immaturity must be recognized. In 1944, Helfrick and Abelson first reported the possibility of complete intravenous nutrition in an infant with Hirschsprung's disease. 41 However, it was not until the late 1960s that Dudrick and Wilmore were able to report growth and development in an infant receiving only parenteral nutrition. 26, 86 With the introduction of a silicone catheter with a cuff for chronic parenteral nutrition by Broviac and associates in 1973,11 delivery of intravenous nutrition became safer and more dependable. Gradual refinement of amino acid solutions, lipid emulsions, and vitamin and trace mineral supplements improved compatibility and effectiveness. Today, several aspects of pediatric parenteral nutrition are under close scrutiny, and thousands of children who must live without enteral intake benefit from continued research. *Pediatric Surgery Fellow, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Assistant Professor of Pediatric Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina tc.E. Koop Professor of Pediatric Surgery, University of Pennsylvania School of Medicine; and Surgeon-in-Chief, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Surgical Clinics of North America-Vol. 71, No.3, June 1991

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CONSEQUENCES OF NUTRITIONAL DEFICIENCY The consequences of nutritional deficiency can be devastating and are well documented. 67 Impaired immunity leading to an increased risk of sepsis is a serious problem, and poor wound healing in surgical patients can have disastrous consequences. Critically ill children may be unable to be weaned from ventilatory support without adequate nutrition. Performance of some surgical procedures such as replacement of the esophagus was previously limited by malnutrition. Growth failure is of concern in children and manifests not only as poor weight gain or failure to achieve normal height but also as delay of development of secondary sexual characteristics. 33 The most important aspect of growth failure is the possibility of mental retardation and subnormal development in the infant under 1 year of age who receives suboptimal nutrition. 53 In children with abnormalities of the gastrointestinal tract that prevent enteral intake, malnutrition can exacerbate an already lifethreatening situation. 65 Nutritional deficiencies can cause loss of insulating fat, mucosal atrophy, thinning of the muscular wall of the bowel, flattening of the microvilli with decreased absorptive area, and reduced secretion of gastric and intestinal enzymes and hormones, leading to further impairment of nutrition. This decreased absorptive capacity causes diarrhea, pseudodysentery, flatulence, colic, and increased small-bowel transit time.

NUTRITIONAL ASSESSMENT Children are different from adults in many respects, most of which bear significantly on their nutritional needs. They have a higher ratio of surface area to body weight, causing increased evaporative loss. Their basal metabolic rate is higher. Their immature kidneys have decreased water clearance. Assessment of nutritional adequacy in children should begin with an evaluation for protein-calorie malnutrition. Standard growth curves should be used for comparison and are important in differentiating acute from chronic malnutrition. 17 For example, weight loss usually indicates an acute nutritional insult, whereas lack of growth in height is a gauge of past nutritional inadequacy. Calculation of the ratio of weight for height indicates wasting, and calculation of the ratio of height for age indicates stunting of growth. In infants and young children, head circumference can be affected by malnutrition until 3 years of age; this measure correlates with brain development. As in adults, anthropometric measurements such as subscapular skinfold thickness, triceps skinfold thickness, and midarm muscle circumference can be used to assess baseline nutritional status and improvement during nutritional rehabilitation. These are gauges of somatic protein and fat stores. Four visceral proteins can also be surveyed for nutritional assessment. Serum albumin levels between 2.8 and 3.5 g/dl indicate moderate malnutrition, and levels below 2.8 g/dl indicate severe malnutrition. Although

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serum albumin has a half-life of 20 days and therefore cannot precisely reHect the present nutritional status, it is the easiest protein to measure and has become a simple standard of nutritional adequacy. Other helpful visceral proteins are serum transferrin, prealbumin, and retinol-binding protein. Transferrin has a half-life of 8 days, and levels less than 150 mg/dl indicate malnutrition. Prealbumin and retinol-binding protein have halflives of 2 days and 10 hours, respectively, and therefore can give more current information about nutritional adequacy, but the means for measuring these proteins are not generally available. It must be remembered, however, that visceral protein is a relatively small component of the total protein pool. As in the adult, nitrogen balance based on a 24-hour urine collection is a well-accepted index of pediatric nutritional status. It is less useful in pediatric patients, however, because of the difficulty of obtaining accurate urine collections without catheterization. For older children, the urine creatinine-height index is a useful nutritional assessment tool. In neonates, the ratio of urinary 3-methylhistidine to creatinine has been reported to be of value. 68 Tests of immune responsiveness such as total lymphocyte count and intradermal skin tests for antigen sensitivity are not as easy to interpret in young children because of the immaturity of the immune system. Accordingly, they are not generally used in this group. Specific clinical syndromes of vitamin or trace mineral deficiency are as recognizable in children as in adults and may alert one to the child's nutritional status.

INDICATIONS FOR PARENTERAL NUTRITION Surgical Conditions An important indication for parenteral nutrition in the pediatric population is the short-bowel syndrome. 14, 46 The causes of extensive intestinal loss include necrotizing enterocolitis of prematurity, malrotation with midgut volvulus, intestinal atresias, and complicated meconium ileus. Abnormalities of the abdominal wall in newborns, including gastroschisis, omphalocele, and cloacal exstrophy, can also lead to extensive loss of bowel length. 73 In the case of gastroschisis and ruptured omphalocele, exposure of the bowel to amniotic Huid can cause prolonged ileus and impaired function despite normal length. Progress in parenteral nutrition has dramatically changed the prognosis for survival and the quality of life for these children. 13 Children with tracheoesophageal fistula and esophageal stricture from other causes may require a period of parenteral nutrition before enteral feeding can be accomplished. Infants with diaphragmatic hernia requiring extracorporeal membrane oxygenation support also require an initial period of parenteral nutrition. Severe inHammatory bowel disease necessitates parenteral support for maintenance of nutritional adequacy as well as preoperative rehabilitation. The role of hyperalimentation has been studied extensively in both Crohn's disease and ulcerative colitis. 47, 49, 61, 69 Other surgical conditions that may

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require parenteral support include enterocutaneous fistulas, enterostomy complications, and total colonic aganglionosis. 7 , 31, 42 Trauma is a major cause of pediatric disability, and parenteral nutrition can contribute to rehabilitation. Although most head trauma victims can eventually be fed enterally, many children experience an initial ileus. Maintenance of nutrition is extremely important for optimal recovery. 88 Abdominal trauma can lead to duodenal hematoma, which usually is treated nonoperatively, and most children with this condition require parenteral nutrition for 7 to 10 days during the resolution of the hematoma. 87 The less common traumatic pancreatitis and chylous ascites usually require parenteral nutritional support.24 Enteral nutrition may not be possible in the acute phase of major burn injury, and parenteral nutrition can be lifesaving. This is particularly true for infants. 23, 55 With the recent expansion of liver transplantation in pediatric patients, parenteral nutrition has become invaluable in supporting the recipients through the postoperative periodY Unusual surgical indications for parenteral nutrition include postoperative chylothorax and chylous ascites of all causes 18 ,30 (Table 1). Medical Conditions Numerous medical conditions are indications for parenteral nutrition in children, Oncology is a major area in which parenteral nutrition is vital to clinical success. Sequelae of chemotherapy including nausea, vomiting, diarrhea, mucositis, anorexia, and impaired taste all contribute to malnutrition in the pediatriC cancer patient. Chemotherapeutic agents inhibit intestinal proliferation and can cause malabsorption on that basis. A particularly noxious effect of cancer treatment is radiation enteritis, which can lead to progressive, long-term, debilitating gastrOintestinal symptoms and even bowel obstruction. 33 Inanition caused by energy expenditure related Table 1. Some Indications for Total Parenteral Nutrition in Pediatric Patients Short-bowel syndrome Intestinal atresias Necrotizing enterocolitis Midgut volvulus Complicated meconium ileus Abdominal wall defects Gastroschisis Omphalocele Cloacal exstrophy Other Esophageal stricture Tracheoesophageal fistula Diaphragmatic hernia on extracorporeal membrane oxygenation Intestinal fistula Inflammatory bowel disease Malignancy Severe colitis, chronic diarrhea Trauma, burns Hepatic or renal disease Postoperative infections

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to tumor growth can be counteracted by parenteral nutrition. 64 Parenteral nutrition is essential in the management of bone-marrow transplant patients. Gastrointestinal tract disorders such as chronic diarrhea and pseudomembranous colitis and enteropathies such as intestinal pseudo-obstruction may require long-term parenteral nutrition for survival and growth. 82, 83, 89 Children with conditions as diverse as acute renal failure, cardiac cachexia, sepsis, AIDS, cystic fibrosis, spontaneous chylothorax, anorexia nervosa, and various inborn errors of metabolism have benefited from total parenteral nutrition. 20, 22, 43, 79 Newborns of all gestational ages have special nutritional requirements, They have a high metabolic rate: the ratio of their metabolic rate to their body weight is three times that of adults, yet they have limited energy sources and a greater potential morbidity from malnutrition, including mental retardation. Recent work in neonates has demonstrated deficiencies of enzymes essential for the synthesis of some amino acids such as cystine, taurine, tyrosine, and histidine; therefore, these must be considered essential amino acids in this age group, Newborns have a relatively large requirement for calcium and phosphorus to support normal bone growth and development, Because of these special needs, the duration of starvation that can be tolerated by a neonate ranges from 1 to 5 days, compared with 7 to 10 days in an older child or adult. Significant advances in neonatology have expanded our ability to save babies with extreme prematurity; most require parenteral nutrition for some part of their postnatal course. 40, 51 Fat stores are minimal, approximating 5% of total body weight compared with 15% in the full-term infant, Liver glycogen stores can be exhausted in a matter of hours after birth, Vitamin accumulation does not occur in utero until the third trimester; therefore, most premature infants need special vitamin supplementation, Premature newborns may require parenteral nutrition for ileus of prematurity or for bowel rest in necrotizing enterocolitis that does not require surgery, Most premature infants suffering perinatal asphyxia require a period of parenteral nutrition, CONTRAINDICATIONS TO PARENTERAL NUTRITION The indications for parenteral nutrition have been discussed above from the point of view of both nutritional assessment and specific clinical conditions, A major contraindication to the use of parenteral nutrition is the presence of an adequately functioning gastrointestinal tract. Babies who are unable to suckle can be fed enterally with a nasoduodenal, transgastric jejunal, or gastrostomy tube, Although total parenteral nutrition is lifesaving for those with enteral disability, it is not risk free and should not be used if some form of adequate enteral nutrition is possible, A more specific contraindication to the use of lipids is in the neonate with hyperbilirubinemia, Because bilirubin and fatty acids competitively bind to albumin, bilirubin is displaced in the presence of lipids, increasing the risk of kernicterus, A controversial area of parenteral nutrition is its use in patients with

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pulmonary compromise. The metabolism of glucose substrates increases carbon dioxide production, which may increase respiratory work and precipitate respiratory failure. 2 Weaning patients from respiratory support may be more difficult. This effect may be partially ameliorated by using lipids rather than glucose as the main calorie source.

NUTRITIONAL REQUIREMENTS Water is the most basic "nutrient" (Table 2). Calculation of fluid requirements should take into account the child's hydration status and body weight or surface area; environmental conditions, such as radiant warmers, phototherapy, or mist tents; and disease state, such as fever or the presence of abnormal losses from vomiting, fistulous output, or water-loss stools. Premature infants have high insensible water losses because of the poorly developed stratum corneum. Also, the transition from intrauterine to extrauterine life includes several changes that require special consideration when calculating fluid needs in the newborn: contraction of the extracellular fluid space, obligatory sodium diuresis, an increase in glomerular filtration rate, and a decrease in trans epidermal water 10ss.60 Underhydration can lead to dehydration, hypernatremia, and hyperosmolarity. The child receiving parenteral nutrition is dependent on the surgeon to fulfil fluid needs and must be monitored carefully to ensure adequate hydration. Similarly, overhydration can have serious consequences such as peripheral edema, pulmonary edema, congestive heart failure, and exacerbation of cardiac or renal conditions or of brain injury. The premature neonate is particularly vulnerable to fluctuations in the status of hydration, which, if excessive, may lead to bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, or persistence of a patent ductus arteriosus. Electrolyte balance must also be carefully maintained. Especially important are modulation of potassium, calcium, and phosphorus. Abnormal losses of electrolytes in succus entericus through a fistula or ostomy or by rapid-transit stools should be assessed and replaced on a daily basis by adjusting the electrolyte content of the parenteral solution. Caloric components are a major consideration. Current recommendaTable 2. Basal Nutritional Requirements AGE OR WEIGHT

Water

Calories

Lipid Protein

0-10 kg 11-20 kg >20 kg Infants Children Adolescents Infants Children

AMOUNT/24 HOURS

100 mllkg 1000 1500

+ 50/kg over 10 kg + 20/kg over 20 kg 120-150 kcallkg 80-100 kcallkg 30-75 kcallkg 2-3 g/kg 2.5-3.0 g/kg 1.5-2.0 g/kg

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tions are that carbohydrates make up 50% of the total calories, with protein constituting 15% and fat 35%.21 The daily requirements of a premature infant range from 85 to 130 kcallkg, depending on stress factors such as surgery or intercurrent illness. Children from 1 to 7 years of age require 75 to 90 kcalJkg per day, while those from 7 to 18 years need 60 to 75 kcalJ kg per day. After age 18, caloric requirements approximate those of adults at 30 to 60 kcalJkg per day. The need for additional calories because of stress (fever, surgery, sepsis) must be calculated on a regular, even daily, basis. 77 Lipids are essential components of pediatric parenteral nutrition, particularly in premature infants, who are born with mild essential fatty acid deficiency.72, 84 Most current formulations use long-chain triglycerides derived from soybean oil or sunflower oil. These solutions provide linoleic and linolenic acids, which are essential fatty acids. Lipids also serve as the vehicle for fat-soluble vitamins. Current recommendations are to start with 0.5 g/kg per day and increase gradually to 2 to 3 g/kg per day. Recently, the efficacy and safety of intravenous medium-chain triglycerides in children have been studied. There appears to be increased clearance and oxidation of fat when the fat emulsion is presented as a mixture of 50% mediumchain and 50% long-chain triglycerides. 8, 52 Glucose is the most common source of carbohydrate used in total parenteral nutrition solutions. Peripheral parenteral nutrition uses 10% to 12,5% glucose, whereas in central parenteral nutrition, up to 25% glucose can be used because of the high rate of blood flow in the central veins, Hyperglycemia must be avoided in premature infants, who are particularly susceptible to hyperosmolar coma and intraventricular hemorrhage. Children taking corticosteroids may require insulin when given solutions with a high glucose content, but other children usually do not. As mentioned, hyperglycemia may increase carbon dioxide production and be deleterious to children with respiratory disorders. All essential amino acids must be present simultaneously for efficient utilization. Furthermore, carbohydrate must be infused simultaneously with nitrogen to maximize amino acid utilization and to prevent prerenal azotemia. In children, a positive nitrogen balance usually requires 200 kcalJ g of nitrogen. This ratio may vary depending on the degree of catabolism. A current area of research is the possibility of using lipid for protein sparing to avoid the problems of high glucose infusion. 16, 59 The current recommendation for parenteral protein supplementation in infants is 2.5 to 3 g/kg per day, while for older children, it is 1.5 to 2 g/kg per day. Vitamins are essential micronutrients. 29 Minimum daily requirements and intravenous formulations of vitamins for children have been published. 38 Essential trace minerals need not be supplied for patients receiving total parenteral nutrition for less than 2 weeks. These minerals are copper, zinc, chromium, manganese, selenium, iodine, and iron, 71, 80 Heparin is frequently added to nutrient solutions at 0.5 Vlml to decrease venous thrombosis. Other compatible additives include insulin, cimetidine, and some antibiotics. 36 Several avenues exist for the provision of adequate nutrition. As mentioned, the gastrointestinal tract should be used exclusively if at all

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possible. If intravenous supplementation is needed, a peripheral formula consisting of 2.5% protein and 12.5% glucose may be given. This provides 0.53 kcallml. Lipids, which can be given peripherally or centrally, are then required as a major calorie source. Central nutrition can maximize nutrient intake to 3.5% protein and 25% glucose providing 1 kcal/ml. Patients able to take even small amounts of enteral feedings should receive them, either by mouth or by bolus or continuous infusion, as there is clear evidence that enteric stimulation is crucial to the maintenance of the integrity of the gastrointestinal tract. 85 Children weighing more than 30 kg can tolerate an adult formulation of total parenteral nutrition. Recent experience with "total nutrient admixtures" (amino acids, glucose, and lipids as a single solution) shows that they can be safe and cost-effective. 28, 54 Special intravenous formulations for use in the presence of renal and hepatic failure are available for children.

TECHNIQUES OF CENTRAL CATHETER PLACEMENT IN CHILDREN Currently, silicone rubber catheters are placed routinely in children in the external or internal jugular, the anterior facial, the cephalic, the subclavian, or the femoral vein via the saphenous vein. A cutdown technique is usually employed in infants, although a 5-F peel-away percutaneous kit for subclavian puncture is available. Children who have exhausted these access sites during long-term use or who have superior vena cava or distal inferior vena cava thrombosis may have a catheter placed in the vena cava through a transhepatic or translumbar approach using ultrasonic or fluoroscopic guidance. 62 In neonates, the umbilical vein and artery have been used as catheter sites in the past, but because of a high rate of serious complications such as vasospasm, portal venous thrombosis, embolism, hypertension, hemorrhage, vascular damage, and necrotizing enterocolitis, these vessels are no longer recommended if other sites are available. Catheters with implanted chambers such as the Infusaport or Port-a-Cath are not useful for total parenteral nutrition in children because they require a needle to be seated in the chamber through the skin for infusion. As nutrient solutions usually are infused over 12 to 24 hours on a daily basis, this technique is impractical for most children.

MANAGEMENT AND MONITORING During initiation of total parenteral nutrition in hospitalized children, careful monitoring is essential. This includes daily weighing, strict measurement of all fluid intake and output, and daily electrolytes until stabilization is achieved. Electrolytes may be checked twice weekly thereafter. Surveillance for hyperglycemia and hypoglycemia includes serum glucose measurements every 8 to 12 hours initially and urine glucose measurement for glucosuria. Neonates have a lower renal threshold for glucose and may

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be euglycemic although showing glucosuria. Serum triglycerides and free fatty acids should be measured weekly. Liver function tests should be determined on a biweekly basis. As growth is of major concern in pediatric patients, documentation of growth by measurement of weight, height or length, and head circumference, as well as by anthropometric measurements should be made routinely. A weight gain of 10 to 20 g/kg per day is expected; fluid retention should be suspected if weight gain is greater. Because many children require long-term, even lifelong support, home total parenteral nutrition was developed in the mid 1970s. Parents can learn catheter care and infusion techniques. Nutrient infusion can be cycled so that the child receives the infusion during sleep and is free to participate in normal activities during the day. To accomplish this in a patient on 24hour parenteral nutrition, the time of infusion is decreased by 2 hours each day with a concomitant increase in the infusion rate. Thus, the feeding regimen can be gradually reduced to a 10- to 12-hour night-time infusion. 65 Home parenteral nutrition is one third to one half the cost of hospital use and has the added psychosocial benefit of letting the child be at home. Patients have used total parenteral nutrition at home for more than 7 years. 6 , 81 Cycling does not adversely affect growth and development. 76 For children whose condition permits cessation of total parenteral nutrition, administration should be tapered gradually as enteral nutrition is introduced. Both continuous and intermittent feeding schedules for reintroduction of enteral nutrition are feasible. A commonly used protocol for infants progressing to formula is as follows. The nutrient infusion is decreased to half rate when 50% of the desired volume of enteral feeding at half strength is tolerated. It is then decreased to quarter rate when 75% of the desired volume of half-strength enteral feeding is tolerated. The strength of enteral formula is advanced to three fourths for 24 hours and then to full strength if tolerated, and the infusion is stopped. Careful monitoring is required so that calories are not deficient during the transition period. If bolus feedings are not tolerated, continuous drip feedings can be used with a similar advancement schedule. 1O

COMPLICATIONS: PREVENTION AND MANAGEMENT Complications of total parenteral nutrition fall into two main categories: metabolic and catheter related (Table 3). Metabolic and nutritional complications may present either acutely or, more commonly, after long-term use. Acute metabolic complications include hypoglycemia and hyperglycemia, which careful monitoring will easily detect. Hypoglycemia can be avoided if the infusion is tapered rather than abruptly stopped. Sepsis should always be suspected in the presence of unexpected hyperglycemia. Fatty acid deficiency can develop over a period of a few weeks or less, depending on the patient's age and previous nutritional status. 57 Linoleic acid deficiency is indicated by a triene-tetraene ratio exceeding 0.4 on analysis of total plasma lipids. Premature infants are particularly vulnerable and may develop fatty acid deficiency in a matter of 1 or 2 days. Signs

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Table 3. Complications of Parenteral Nutrition Metabolic Hyperglycemia Hypoglycemia Metabolic acidosis Fatty acid deficiency Vitamin deficiency Trace element deficiency Cholestatic jaundice Osteopenia

Catheter related Pneumothorax Hemothorax Cardiac tamponade Air embolism Line sepsis Tract abscess Catheter thrombosis

include dry skin and hair, thrombocytopenia, impaired wound healing, and growth retardation. To prevent essential fatty acid deficiency, 2% to 4% of the total daily calories must be supplied as a fat emulsion. Continuous infusion of fat emulsions over the entire 24 hours promotes clearance from the blood and minimizes hypertriglyceridemia. Metabolic acidosis was a more common complication in the past with protein hydrolysate formulations and with the early amino acid mixtures. Current crystalline amino acid formulations have solved this problem. 75 A high protein load can also cause metabolic acidosis, and recommended maximum dosages should not be exceeded. Metabolic acidosis may also be caused by excess chloride infusion in low birth-weight neonates receiving chloride in the infusion solution and normal saline flushes through other catheters. A total chloride infusion of 3 to 6 mEqlkg per day is recommended. To prevent excessive chloride administration, acetate is usually substituted for chloride in parenteral nutrient solutions. 39 Hepatobiliary abnormalities are a serious complication of long-term pediatric total parenteral nutrition. 5, 32 Cholestatic jaundice in children receiving parenteral nutrition was first reported by Peden and associates in 1971. 58 The spectrum of this disorder ranges from asymptomatic elevation of liver function indices, fatty liver, biliary sludge, and gallstones to severe cholestasis and jaundice occasionally leading to cirrhosis and liver failure. 4 Cholestasis induced by total parenteral nutrition is most predictable in premature infants.70 For example, 50% of infants under lOOO g exhibit this complication compared with only 7% of those weighing 1500 to 2000 g. The onset of cholestatic jaundice may overlap with the period of physiologic unconjugated hyperbilirubinemia, and detection may be delayed. The incidence is low in children receiving total parenteral solution for less than 2 weeks, but in those children requiring long-term parenteral nutrition, it is a major limiting factor. Touloukian and Seashore found that in infants who require long-term parenteral nutrition without any enteral supplementation, cholestatic jaundice was a leading cause of death, more common than sepsis and malnutrition. 78 Although immaturity of hepatic excretory function is a primary factor in the pathogenesis of this cholestasis, contributing factors include hypoxic insults, sepsis, and gastrointestinal tract surgery. Direct hyperbilirubinemia (bilirubin >2 g/dl) is the most sensitive indicator. A recent study by Drongowski and Coran found that the number of days of intravenous antibiotics and the number of surgical procedures as well as the duration

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of time without enteral intake were significantly greater in neonates who developed cholestatic jaundice while receiving total parenteral nutrition. Those authors hypothesized that the correlation with the number of surgical procedures was related to surgical stress or anesthetic exposure. 25 Cholestatic jaundice is usually reversible unless there is progression to cirrhosis. Recent investigation shows that the jaundice may predispose infants to gram-negative sepsis. 9 Intravenous fat does not seem to contribute to cholestatic jaundice. Hepatic synthetic function remains normal, e. g., albumin and coagulation factors are not affected. Ultrasound and liver biopsy may be necessary to rule out other treatable causes of jaundice. The differential diagnosis includes hepatitis, congenital hypothyroidism, cystic fibrosis, alpha-I-antitrypsin deficiency, drug reaction, ABO and Rh incompatibility, and extrahepatic biliary obstruction. Management includes diminishing protein intake, cycling of total parenteral nutrition, and addition of enteral feeding, even if minimal. 19 Calories should be adequate but not excessive. Oral gentamicin may have' a prophylactic effect.74 Gallbladder distention as an isolated finding has also been described recently in infants receiving total parenteral nutrition. Management is nonoperative. 1 Trace mineral deficiency may occur in children receiving long-term parenteral nutrition. 35 Zinc deficiency is characterized by anorexia, growth retardation, lymphopenia, impaired wound healing, skin rash, and abnormalities of keratinization. Copper deficiency is heralded by anemia, growth retardation, kinky hair, and fractures and bone changes similar to those seen in scurvy and rickets. Magnesium deficiency produces ileus and hyperreflexia. Selenium deficiency was recently described in a child who exhibited loss of motor milestones and tender myopathy of skeletal muscles. 45 Vitamin D deficiency is especially likely after ileal resection or during cholestyramine therapy. Premature infants are particularly susceptible to osteopenia and even pathologic fractures from bone demineralization. 48 Inadequate infusion of calcium, phosphorus, or vitamin D during long-term total parenteral nutrition is the probable cause. Recently, Freeman et al pointed out an association with staphylococcal septicemia in infants receiving intravenous lipids, a finding that must be confirmed by further experience. 34 Catheter complications are an important cause of morbidity in children receiving total parenteral nutrition. Complications of insertion include pneumothorax, hemothorax, air embolism, and cardiac perforation. 50 Line sepsis is the most common complication in both short-term and long-term use. Current incidence rates range from 6% to 20%. Fever, leukocytosis, and glucosuria are the usual early signs. As access sites are so precious in infants and children on long-term parenteral nutrition, bacterial infections should be treated with antibiotics through the line rather than by line removal. Even as many as three or four episodes of bacterial line sepsis can be tolerated. Fungal infections require removal of the catheter and several weeks of intravenous antifungal therapy. Infections of the subcutaneous tract should be treated by catheter removal and incision and drainage of any abscess. All catheters are susceptible to thrombosis. 13. 63 Thrombosis can be

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documented by radiocontrast study or echocardiography and treated with urokinase, which has been demonstrated to be safe for use in children. 44 Catheters may also become occluded by precipitation of crystalline components of the nutrient solution. Hydrochloric acid has recently been shown to be efficacious in clearing such occlusions. 27 With careful maintenance and vigilant antisepsis, a single catheter can be used for several years. Catheter migration and dislodgment have occurred, and intrathoracic infusion can be a serious consequence. Mural thrombi and pericardial tamponade have recently been described as potentially lethal complications. 3.50 Echocardiography is a useful modality for establishing a diagnosis. 15

SUMMARY Over the past 50 years, tremendous advances have been made in the management of children who cannot receive enteral nutrition. Challenges for the future include devising techniques to decrease catheter sepsis, particularly in children with a short bowel, who have a disproportionate number of septic episodes, possibly related to bacterial translocation. The delineation of risk factors for cholestasis associated with total parenteral nutrition and refinement of administration of such nutrition in premature neonates to decrease the incidence of this complication, as well as the morbidity of osteopenia, will extend our ability to help these children.

REFERENCES 1. Arad I, Peleg 0, Udassin R, et al: Gallbladder distention in premature neonates receiving parenteral nutrition. J Perinat Med 17:337, 1989 2. Askanazi J, Nordenstrom J, Rosenbaum S, et al: Nutrition for the patient with respiratory failure. Anesthesiology 54:373, 1981 3. Bagwell C, Marchildon M: Mural thrombi in children: Potentially lethal complication of central venous hyperalimentation. Crit Care Med 17:295, 1989 4. Bailey P, Connors R, Tracy T, et al: Changing spectrum of cholelithiasis and cholecystitis in infants and children. Am J Surg 158:585, 1989 5. Balistreri W, Novak D, Farrell M: Bile acid metabolism, total parenteral nutrition and cholestasis. In Lebenthal E (ed): Total Parenteral Nutrition: Indications, Utilization, Complications and Pathophysiological Considerations. New York, Raven Press, 1986, p 319 6. Bendorf K, Meehan J: Home parenteral nutrition for the child with cancer. Issues Contemp Pediatr Nurs 12:171, 1989 7. Bergmeijer J, Tibboel D, Molenaar J: Total colectomy and ileorectal anastomosis in the treatment of total colonic aganglionosis: A long term follow-up study of six patients. J Pediatr Surg 24:282, 1989 8. Bientz J, Frey A, Schirardin H, et al: Medium-chain triglycerides in parenteral nutrition in the newborn: A short term clinical trial. Infusionstherapie 15:96, 1988 9. Bos A, Tibboel D, Hazebroeck F, et al: Total parenteral nutrition associated cholestasis: A predisposing factor for sepsis in surgical neonates? Eur J Pediatr 149:351, 1990 lO. Braunschweig C, Wesley J, Clark S, et al: Rationale and guidelines for parenteral and enteral transition feeding of the 3- to 30-kg child. J Am Diet Assoc 88:479, 1988 11. Broviac J, Cole J, Scribner B: A silicone rubber atrial catheter for prolonged parenteral hyperalimentation. Surg Gynecol Obstet 136:602, 1973 12. Bruce J: Thrombus associated with central venous catheters in infants and children. J Pediatr Surg 24:253, 1989

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