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A contemporary analysis of parenteral nutrition–associated liver disease in surgical infants
Patrick J. Javid a,⁎, Frances R. Malone b , André A.S. Dick b , Evelyn Hsu c , Maria Sunseri a , Patrick Healey a,b , Simon P. Horslen b,c
Division of Pediatric General and Thoracic Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA b Division of Transplantation, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA c Division of Gastroenterology, Seattle Children's Hospital, University of Washington, Seattle, WA 98105, USA
Received 11 July 2010; revised 4 May 2011; accepted 1 June 2011
Parenteral nutrition; Cholestasis; Liver disease; Neonatal surgery; Abdominal surgery
Abstract Background/purpose: Despite advances in pediatric nutritional support and a renewed focus on management of intestinal failure, there are limited recent data regarding the risk of parenteral nutrition (PN)–associated liver disease in surgical infants. This study investigated the incidence of cholestasis from PN and risk factors for its development in this population. Methods: A retrospective review was performed of all neonates in our institution who underwent abdominal surgery and required postoperative PN from 2001 to 2006. Cholestasis was defined as 2 conjugated bilirubin levels greater than 2 mg/dL over 14 days. Nonparametric univariate analyses and multivariate logistic regression were used to model the likelihood of developing cholestasis. Median values with range are presented. Results: One hundred seventy-six infants met inclusion criteria, and patients received PN for 28 days (range, 2-256 days). The incidence of cholestasis was 24%. Cholestatic infants were born at an earlier gestational age (34 vs 36 weeks; P b .01), required a 3-fold longer PN duration (76 vs 21 days; P b .001), had longer inpatient stays (86 vs 29 days; P b .001), and were more likely to be discharged on PN. The median time to cholestasis was 23 days. Cholestasis was an early development; 77% of cholestatic infants developed cholestasis by 5 weeks of PN exposure. On multivariate regression, only prematurity was significantly associated with development of cholestasis (P b .05). Conclusion: In this analysis, the development of PN-associated liver disease occurred early in the course of exposure to PN. These data help to define the time course and prognosis for PN-associated cholestasis in surgical infants. © 2011 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Tel.: +1 206 987 6129; fax: +1 206 987 3925. E-mail address: email@example.com (P.J. Javid). 0022-3468/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.06.002
Liver disease associated with the administration of parenteral nutrition (PN) remains a challenge in the care of pediatric surgical patients. Among infants who receive prolonged courses of PN, the incidence of liver injury ranges
elevation in serum conjugated bilirubin is observed at an early stage. Cary. prematurity (defined as b36 weeks gestation). We chose to study all neonates who underwent abdominal surgery at our institution over a multiyear period to better understand the occurrence of PNassociated cholestasis as well as the time course and risk factors for its development in a broad surgical population. Lipid modification. new elemental formulas for children with feeding intolerance. Javid et al. Variables collected included gestational age. 1). and 77% of infants who developed cholestasis did so within 5 weeks of PN exposure.1914 from 18% to 67% and is characterized histologically by bile duct proliferation. SAS 9. The overall mortality rate was 5%. 2 illustrates the time to development of cholestasis as well as the prevalence of cholestasis at each week of PN exposure. P.1. and recent data have focused primarily on specific subgroups of neonates [12-14]. given the recent renewed clinical emphasis on nutritional support and enteral nutrition in these infants. Initiation and advancement of enteral nutrition were encouraged. surgical diagnosis. and PN duration before onset of cholestasis with the risk of developing cholestasis. 2-256 days. 2-sample Wilcoxon's test for continuous variables and Fisher's Exact test for categorical variables) were used to compare the characteristics of patients who developed cholestasis with that of those who did not develop cholestasis. Fig. In general. but the ultimate enteral nutrition regimen was provider dependent. The overall incidence of cholestasis was 24%. length of stay. Patient data and outcomes were measured to the date of initial discharge from the hospital. Patients who died at less than 14 days of age were excluded from this analysis. infants on PN underwent serum sampling for liver function on a weekly basis. Clinically. Per institutional protocol. and Table 1 lists the surgical diagnoses in this cohort. Although all cholestatic infants met criteria for cholestatic liver disease by 9 weeks of PN exposure. and serum bilirubin values. P b . for these subjects. Results One hundred seventy-six infants met study criteria. new data on PNassociated cholestasis are lacking. Parenteral nutrition was ordered by the pediatric surgical team for all patients except for extremely low-birth-weight neonates who 2. Our institutional protocol for PN used estimated energy requirements of 90 to 120 and 85 to 105 kcal/kg per day for preterm and term infants. A KruskalWallis test was used to test differences in the distribution of continuous measures by diagnosis. NC) was used for all analyses.5 to 3 g/kg per day. duration of PN. Several promising advances in the nutritional support of surgical infants have evolved over the past decade. protein allotment of 2 to 4 g/kg per day. and ultimately cirrhosis [1-5]. respectively. was not used during this study period. Methods After receiving approval from the Seattle Children's Hospital Institutional Review Board. revised guidelines for caloric allotment in the critically ill infant. Multivariate exact logistic regression was used to evaluate the association between diagnosis. and the administration of ursodiol for hyperbilirubinemia [6-11]. All patients less than 10 days of age who met the definition for cholestasis were reviewed to rule out indirect hyperbilirubinemia as the primary etiology. including lower lipid allotment and ω-3 fatty acid supplementation. 40% of infants on PN at this time never developed cholestasis. In this study. bridging fibrosis. of subjects 48 43 27 25 15 5 6 7 % 27 24 15 14 9 3 3 4 Surgical diagnosis Necrotizing enterocolitis Gastroschisis Jejunoileal atresia Duodenal atresia Omphalocele Volvulus Meconium disease Other . Fig. and the development of cholestasis was an early phenomenon.J. Table 1 Surgical diagnoses in the study population No. The median time to cholestasis was 23 days. We hypothesized that the rate of PN-associated cholestasis in surgical infants would be lower than prior estimates. Despite this progress in pediatric nutrition. subjects were deemed to have cholestasis only when the unconjugated bilirubin had normalized. mortality. Cholestasis was defined as 2 consecutive conjugated bilirubin levels greater than 2 mg/dL over a minimum of 14 days. and lipid provision of 2.3 (SAS. we conducted a retrospective review of all infants who underwent abdominal surgery at less than 30 days of age and received postoperative PN at our institution from January 2001 through June 2006. Median values with range are presented. we sought to measure the contemporary incidence of PN-associated cholestasis in a population of surgical infants. ursodiol (30 mg/kg per day divided in 3 doses) was administered to patients who met the definition for cholestasis. Macronutrient goals for full PN support included a dextrose infusion rate of 10 to 14 mg/kg per minute. the composition of PN was managed by the neonatal intensive care service with input from the attending pediatric surgeon. portal inflammation. Nonparametric univariate analyses (eg. primarily resided on the neonatal intensive care service.05 was considered to be statistically significant. 1. Basic descriptive statistics were calculated for the population. These include an early emphasis on enteral nutrition. Infants were exposed to PN for a median duration of 28 days (range.
associated liver disease in surgical infants 100 90 80 1915 % Subjects on PN 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Weeks Fig. Finally. when all cholestatic subjects had developed liver injury. P b . various advances in the nutritional support of surgical neonates have been reported. M ec on iu m . 95% confidence interval. Using a multivariate regression model adjusted for diagnosis and duration of PN before the onset of cholestasis. The median duration of PN exposure was 28 days. Discussion Cholestatic liver disease remains a frequent complication of PN administration. Conversely. P = . and revised caloric allotments have been suggested .17].001). Recently.34. 0. There has been a renewed focus on the provision of adequate protein to optimize wound healing.05). As listed in Table 2. P b . Techniques for continuous and postpyloric feedings as well as elemental and hypoallergenic formulas have helped to promote the use of enteral nutrition [9.001).15]. alternative lipid solutions rich in ω-3 fatty acids have shown promise in reversing the biochemical changes associated with PN-associated liver disease [16. 3). In the past decade. full-term infants were associated with one-third the risk of developing cholestasis as compared with premature infants (odds ratio. and 77% of cholestatic subjects met the definition for liver injury by 5 weeks of PN exposure. ursodiol has been studied for its effects on reducing hyperbilirubinemia associated with PN. P b . the prevalence of cholestasis was lower than expected at all time-points. Although multiple theories have been proposed to explain its pathogenesis. 40% of subjects remained free of cholestasis. the precise mechanism remains unknown and is thought to be multifactorial [5. 100 90 Percentage of Subjects 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 Duration of PN (Weeks) Time to development of cholestasis Prevalence of cholestasis 3.PN . although z % of patients with Cholestasis 40 35 30 25 20 15 10 5 0 e EC si el si si us ul Vo lv se At re tre oc ea N hi tro sc ph al la di s O th er a a s Fig. and were more likely to be discharged on PN (17% vs 6%. On univariate analysis. and improve overall developmental outcome [18-20]. Differences in the incidence of cholestasis by surgical diagnosis were not statistically significant (Fig.01). Inpatient mortality was significant higher in infants with cholestasis (17% vs 2%. de na as m G O uo D Fig. it has been demonstrated that critically ill and postoperative infants do not increase their energy expenditure. Even at 9 weeks of PN exposure. minimize whole-body protein breakdown. The median time to cholestasis was 23 days. 2 The development of cholestasis in this series was an early phenomenon. 3 There were no differences in the incidence of cholestasis when compared by diagnostic cohort. For example. required a 3-fold longer duration of PN (76 vs 21 days.05). 1 The duration of PN administration is illustrated. only prematurity was significantly associated with the development of cholestasis.05).12-0.18]. 0. infants who developed cholestasis were born at an earlier gestational age (34 vs 36 weeks. had longer inpatient lengths of stay (86 vs 29 days. P b . P b .87.
77 (0. NEC. However. Clearly.24-2. These data regarding the early time course for PN-associated liver disease are References  Moss RL. and it is possible that a prolonged duration of high levels of PN support would be associated with cholestasis. Overall. This study has helped to define the prognosis for the development of PN-associated cholestasis in young surgical infants. we found that the development of cholestasis from PN was an early phenomenon. there are deficiencies in this study that must be addressed.34 (0.9139 1 1 1 . the incidence of cholestasis remained lower than other published data when stratified by specific surgical diagnosis (Fig. it is possible that an injurious element in PN may act as a source for PN-associated cholestasis. 3). the incidence of PN-associated liver injury was lower than expected. or duration of PN [12-14]. corroborated by a recent analysis of cholestasis in the neonatal population at a separate institution . Hence. NEC) Atresia 0. Postoperative infants who are dependent on PN but do not develop cholestasis within the first 2 months of PN exposure may have a reasonable chance of avoiding further liver injury.01) cholestasis) Gestational age (≥36 0. From these data. Finally. The data were collected before the implementation of new parenteral lipid minimization regimens and the use of ω-3 fatty acid supplementation to determine our baseline incidence of cholestasis. every subject in this long-term PN subgroup had developed cholestasis by 7 weeks of PN exposure. all infants still dependent on PN had developed cholestasis. This is explained in part by the fact that the study population included subgroups of children not expected to have high rates of PN-associated cholestasis. since the accrual of these data. surgical diagnosis. Another possibility is a more recent hypothesis that standard parenteral lipid solutions may create a proinflammatory state. Regardless of the mechanism. We felt that these data would be helpful in counseling families of postsurgical newborns as to the risks of developing PN-associated liver disease. the early development of cholestasis suggests that early initiation of enteral nutrition may be beneficial when possible. Raffensperger JG.01-9. The absence of the latter data is important because increasing amounts of enteral nutrition have been shown to ameliorate the progression of cholestasis in PN-dependent children . Nonetheless. birth weight.82) Omphalocele 0. the typical surgical neonate still receives similar PN support today.59 (0.75) Time on PN (before 0.8994 . predisposed the surgical neonate to the development of cholestasis.11-14. rather than a chronic deficiency of trophic factors in enteral nutrition.39) Duodenal atresia 0. For example. infants with gastroschisis had an incidence of cholestasis of only 21% despite consistent and prolonged exposure to PN. Taken together. The data collection was retrospective in nature and encompassed several years. or administration of hepatotoxic medications.J. P. data on intestinal length and specific allotments of enteral nutrition were not consistently available. Hence. It is also plausible that an early external variable.85 (0.1916 Table 2 Multivariate regression analysis Exact odds ratio for developing P cholestasis (95% CI) Diagnosis (reference. our study population was broad and included specific surgical diagnoses that are not classically associated with prolonged PN administration. More importantly.66) Meconium disease 1. By 5 months of PN exposure. Javid et al. necrotizing enterocolitis.21]. the percent caloric allotment) was not factored into the multivariate analysis.96-1.3457 . The median time to cholestasis was just over 3 weeks. such as infants with omphalocele or duodenal atresia. Total parenteral nutrition– associated cholestasis: clinical and histopathologic classification. The collection of these variables was beyond the scope of this retrospective study. This study sought to review a single institution's contemporary experience with PN-associated cholestasis over a multiyear period in all infants who underwent an abdominal operation within the first 30 days of life. Unlike other recently published data. Das JB.96) Other 0.87) vs b36 weeks) CI indicates confidence interval. and most infants with cholestasis had developed biochemical liver disease by 5 weeks of PN exposure. .55 (0. the degree of PN support (ie.12-0. hemodynamic instability.19-2. these data suggest that factors in addition to prolonged PN exposure may play a role in the development of cholestatic liver disease. In fact. thereby increasing the potential for error. For example. all of these infants on long-term PN had already developed cholestasis at a much earlier time-point. The data presented here have direct relevance to the current care of surgical infants. These data may be used to compare rates of cholestasis with more recent and innovative nutritional therapies designed to prevent PN-associated liver disease. To better define the risk factors associated with PN-associated cholestasis. such as ω-3 fatty acid supplementation and lipid minimization strategies.34 (0-2.99 (0. which directly results in liver injury .28:1270-4. it is likely that the development of cholestatic liver injury occurs early in the postoperative course of surgical infants.78) Volvulus 0. such as sepsis.12-2. In addition. there are now a number of innovative nutritional modalities to treat cholestasis in highrisk groups.11-4.0222 recent prospective data question its efficacy in preventing hyperbilirubinemia [10. . however.2002 .6172 .71 (0. J Pediatr Surg 1993.87) Gastroschisis 0. Nonetheless. large prospective multicenter analyses will be required.81 (0. this study did not exclude subjects based on gestational age.
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