Bram P. Raphael

Low Serum Citrulline Concentration Correlates With Catheter-Related Bloodstream Infections in Children With Intestinal Failure

BACKGROUND Serum citrulline concentration is used as a biomarker of enterocyte mass and enteral tolerance, and low serum concentrations are correlated with bacteremia in immunosuppressed adults undergoing hematopoietic stem cell transplant. The authors sought to determine if citrulline was associated with the development of catheter-related bloodstream infections (CRBSIs) in children with intestinal failure. METHODS Data were reviewed from 66 children treated in a multidisciplinary intestinal rehabilitation program, who had serum concentration citrulline measured between January 2007 and August 2009. All patients had a diagnosis of intestinal failure requiring parenteral nutrition (PN) support. Exclusion criteria included central venous catheter in situ <30 days, creatinine clearance <20 mL/minute, or a history of organ transplant/immunosuppression. RESULTS A total of 15 patients were excluded because of the above criteria. In this cohort of 51 patients, 26 (51%) developed CRBSIs. Both groups were similar in terms of gestational age, diagnosis, nutrition status, and biochemical liver function tests. The mean (± standard deviation [SD]) minimum serum citrulline concentration was significantly lower in patients who developed CRBSIs (6.7 ± 4.6 µmol/L) than in those who did not (11.3 ± 6.4 µmol/L, P = .004). Multivariate logistic regression analysis identified lower minimum serum citrulline concentration and longer central venous catheter duration as independently associated with CRBSI (P = .003 and P = .038, respectively). CONCLUSIONS Low serum citrulline concentration and longer central venous catheter time are independently associated with CRBSI in children with intestinal failure. Serum citrulline concentration may be a useful biomarker to identify patients with intestinal failure who are at high risk of developing a CRBSI.

Comparison of Body Composition Assessment Methods in Pediatric Intestinal Failure

Objectives: The aim of the study was to examine the agreement of multifrequency bioelectric impedance analysis (BIA) and anthropometry with reference methods for body composition assessment in children with intestinal failure (IF). Methods: We conducted a prospective pilot study in children 14 years or younger with IF resulting from either short bowel syndrome or motility disorders. Bland-Altman analysis was used to examine the agreement between BIA and deuterium dilution in measuring total body water (TBW) and lean body mass (LBM), and between BIA and dual-energy x-ray absorptiometry (DXA) techniques in measuring LBM and fat mass (FM). FM and percent body fat (%BF) measurements by BIA and anthropometry were also compared in relation to those measured by deuterium dilution. Results: Fifteen children with IF, median (interquartile range) age 7.2 (5.0, 10.0) years, and 10 (67%) boys, were studied. BIA and deuterium dilution were in good agreement with a mean bias (limits of agreement) of 0.9 (−3.2 to 5.0) for TBW (L) and 0.1 (−5.4 to 5.6) for LBM (kg) measurements. The mean bias (limits) for FM (kg) and %BF measurements were 0.4 (−3.8 to 4.6) kg and 1.7 (−16.9 to 20.3)%, respectively. The limits of agreement were within 1 standard deviation of the mean bias in 12 of 14 (86%) subjects for TBW and LBM, and in 11 of 14 (79%) for FM and %BF measurements. Mean bias (limits) for LBM (kg) and FM (kg) between BIA and DXA were 1.6 (−3.0 to 6.3) kg and −0.1 (−3.2 to 3.1) kg, respectively. Mean bias (limits) for FM (kg) and %BF between anthropometry and deuterium dilution were 0.2 (−4.2 to 4.6) and −0.2 (−19.5 to 19.1), respectively. The limits of agreement were within 1 standard deviation of the mean bias in 10 of 14 (71%) subjects. Conclusions: In children with IF, TBW and LBM measurements by multifrequency BIA method were in agreement with isotope dilution and DXA methods, with small mean bias and clinically acceptable limits of agreement. In comparison with deuterium dilution, BIA was comparable to anthropometry for FM and %BF assessments with small mean bias, but the limits of agreement were large. BIA is a reliable method for TBW and LBM assessments in population studies; however, its reliability in individual patients, especially for FM assessments, cannot be guaranteed.

Cisapride improves enteral tolerance in pediatric short-bowel syndrome with dysmotility.

Background and Objectives:Gastrointestinal dysmotility is common in pediatric short-bowel syndrome, leading to prolonged parenteral nutrition dependence. There is limited literature regarding the safety and efficacy of cisapride for this indication. The aim of the study was to describe the safety and efficacy of cisapride for enteral intolerance in pediatric short-bowel syndrome. Methods:Open-labeled pilot study in a limited access program for cisapride. Indications were short-bowel syndrome with underlying dysmotility and difficulty advancing enteral feeds despite standard therapies and without evidence of anatomic obstruction. Patients received cisapride 0.1 to 0.2 mg/kg per dose for 3 to 4 doses per day. We collected electrocardiogram, nutrition, and anthropometric data prospectively at study visits. Results:Ten patients with mean (SD) age of 30.3 (30.5) months were enrolled in our multidisciplinary pediatric intestinal rehabilitation program. Median (interquartile range [IQR]) duration of follow-up was 8.7 (3.1–14.3) months. Median (IQR) residual bowel length was 102 (85–130) cm. Median (IQR) citrulline level was 14.5 (10.5–31.3) μmol/L. Diagnoses included isolated gastroschisis (n = 3), gastroschisis with intestinal atresia (n = 4), necrotizing enterocolitis (n = 2), and long-segment Hirschsprung disease (n = 1). Six subjects had at least 1 prior bowel-lengthening procedure. Median (IQR) change in percentage enteral energy intake was 19.9% (15.4%–29.8%) during follow-up (P = 0.01). Seven patients improved in enteral tolerance during treatment and 2 were weaned completely from parenteral nutrition. Complications during therapy were prolonged corrected QT interval (n = 2), gastrointestinal bleeding (n = 2), D-lactic acidosis (n = 1), and death due to presumed sepsis (n = 1). Longitudinal analysis (general estimating equation model) showed a strong positive association between cisapride duration and improved enteral tolerance. Mean percentage of enteral intake increased by 2.9% for every month of cisapride treatment (P < 0.0001). Conclusions:Cisapride is a potentially useful therapy in patients with pediatric short-bowel syndrome with gastrointestinal dysmotility. We observed modest improvement in feeding tolerance where prior treatments failed; however, patients treated with cisapride require careful cardiac monitoring because corrected QT prolongation occurred in 20% of our cohort.

Necrotizing enterocolitis is associated with earlier achievement of enteral autonomy in children with short bowel syndrome.

PURPOSE Necrotizing enterocolitis (NEC) remains one of the most common underlying diagnoses of short bowel syndrome (SBS) in children. The relationship between the etiology of SBS and ultimate enteral autonomy has not been well studied. This investigation sought to evaluate the rate of achievement of enteral autonomy in SBS patients with and without NEC. METHODS Following IRB approval, 109 patients (2002-2014) at a multidisciplinary intestinal rehabilitation program were reviewed. The primary outcome evaluated was achievement of enteral autonomy (i.e. fully weaning from parenteral nutrition). Patient demographics, primary diagnosis, residual small bowel length, percent expected small bowel length, median serum citrulline level, number of abdominal operations, status of the ileocecal valve (ICV), presence of ileostomy, liver function tests, and treatment for bacterial overgrowth were recorded for each patient. RESULTS Median age at PN onset was 0 weeks [IQR 0-0]. Median residual small bowel length was 33.5 cm [IQR 20-70]. NEC was present in 37 of 109 (33.9%) of patients. 45 patients (41%) achieved enteral autonomy after a median PN duration of 15.3 [IQR 7.2-38.4]months. Overall, 64.9% of patients with NEC achieved enteral autonomy compared to 29.2% of patients with a different primary diagnosis (p=0.001, Fig. 1). Patients with NEC remained more likely than those without NEC to achieve enteral autonomy after two (45.5% vs. 12.0%) and four (35.7% vs. 6.3%) years on PN (Fig. 1). Logistic regression analysis demonstrated the following parameters as independent predictors of enteral autonomy: diagnosis of NEC (p<0.002), median serum citrulline level (p<0.02), absence of a jejunostomy or ileostomy (p=0.013), and percent expected small bowel length (p=0.005). CONCLUSIONS Children with SBS because of NEC have a significantly higher likelihood of fully weaning from parenteral nutrition compared to children with other causes of SBS. Additionally, patients with NEC may attain enteral autonomy even after long durations of parenteral support.

Preservation of Biochemical Liver Function With Low-Dose Soy-Based Lipids in Children with Intestinal Failure Associated Liver Disease

Objectives: Intestinal failure–associated liver disease (IFALD) contributes to significant morbidity in pediatric patients with intestinal failure (IF); however, the use of parenteral nutrition (PN) with a fish oil–based intravenous (IV) emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: because it can be administered only under Food and Drug Administration compassionate use protocols requiring special monitoring, it is not available as a 3-in-1 solution and is more expensive than comparable soy-based IV lipid emulsion (SO). Because of these pragmatic constraints, a series of patient families were switched to low-dose (1 g kg−1 day−1) SO following biochemical resolution of cholestasis. The present study examines whether reversal of cholestasis and somatic growth are maintained following this transition. Methods: The present study is a chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons were performed using the Wilcoxon signed-rank test. Results: Seven patients ages 25.9 (16.2–43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow-up of 13.9 (4.3–50.1) months, there were no significant differences between pretransition and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z scores. Because of recurrence of cholestasis, 1 patient was restarted on FO after 4 months on SO. Conclusions: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6 of 7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select patients with home PN.

Prevention and Treatment of Intestinal Failure–Associated Liver Disease in Children

Intestinal failure-associated liver disease (IFALD), a serious complication occurring in infants, children, and adults exposed to long-term parenteral nutrition (PN), causes a wide-spectrum of disease, ranging from cholestasis and steatosis to fibrosis and eventually cirrhosis. Known host risk factors for IFALD include low birth weight, prematurity, short bowel syndrome, and recurrent sepsis. The literature suggests that components of PN may also play a part of the multifactorial pathophysiology. Because some intravenous lipid emulsions (ILEs) may contribute to inflammation and interfere with bile excretion, treatment with ILE minimization and/or ILEs composed primarily of omega-3 fatty acids can be helpful, but requires careful monitoring for growth failure and essential fatty acid deficiency (EFAD). Data from randomized controlled trials are awaited to support widespread use of these approaches. Other IFALD treatments include cycling PN, ursodeoxycholic acid, sepsis prevention, photoprotection, and polyvinylchloride-free tubing. Management and prevention of IFALD remains a clinical challenge.

Necrotizing Enterocolitis and Central Line Associated Blood Stream Infection Are Predictors of Growth Outcomes in Infants with Short Bowel Syndrome

OBJECTIVES To describe the natural history of growth patterns and nutritional support in a cohort of infants with short bowel syndrome (SBS), and to characterize risk factors for suboptimal growth. STUDY DESIGN A retrospective chart review of 51 infants with SBS followed by our intestinal rehabilitation program. Weight and length data were converted to age, sex, and gestational age-standardized weight-for-age z-scores (WAZ) and length-for-age z-scores (LAZ). RESULTS Median (IQR) age at enrollment was 8.3 (0.9-14.6) weeks, and follow-up duration was 10 (8-13) months, including both inpatient and outpatient visits. Both WAZ and LAZ followed a U-shaped curve, with median for newborns (WAZ = -0.28; LAZ = -0.41), a nadir at age 6 months (-2.38 and -2.18), and near recovery by age 1 year (-0.72 and -0.76). Using multivariable regression analysis, diagnosis of necrotizing enterocolitis was independently associated with significant decrements of WAZ (-0.76 ± 0.32; P = .02) and LAZ (-1.24 ± 0.32; P = .0001). ≥ 2 central line-associated bloodstream infections was also independently associated with decreases in WAZ (-0.95 ± 0.33; P = .004) and LAZ (-0.86 ± 0.32; P = .007). CONCLUSION In a cohort of infants with SBS, we observed a unique pattern of somatic growth, with concomitant deceleration of both WAZ and LAZ and near recovery by 1 year. Inflammatory conditions (necrotizing enterocolitis and central line-associated bloodstream infections) represent potentially modifiable risk factors for suboptimal somatic growth.

Intestinal Rehabilitation Programs in the Management of Pediatric Intestinal Failure and Short Bowel Syndrome

Intestinal failure is a rare, debilitating condition that presents both acute and chronic medical management challenges. The condition is incompatible with life in the absence of the safe application of specialized and individualized medical therapy that includes surgery, medical equipment, nutritional products, and standard nursing care. Intestinal rehabilitation programs are best suited to provide such complex care with the goal of achieving enteral autonomy and oral feeding with or without intestinal transplantation. These programs almost all include pediatric surgeons, pediatric gastroenterologists, specialized nurses, and dietitians; many also include a variety of other medical and allied medical specialists. Intestinal rehabilitation programs provide integrated interdisciplinary care, more discussion of patient management by involved specialists, continuity of care through various treatment interventions, close follow-up of outpatients, improved patient and family education, earlier treatment of complications, and learning from the accumulated patient databases. Quality assurance and research collaboration among centers are also goals of many of these programs. The combined and coordinated talents and skills of multiple types of health care practitioners have the potential to ameliorate the impact of intestinal failure and improve health outcomes and quality of life.

Central Line–Associated Bloodstream Infections in Neonates with Gastrointestinal Conditions: Developing a Candidate Definition for Mucosal Barrier Injury Bloodstream Infections

OBJECTIVE To develop a candidate definition for central line-associated bloodstream infection (CLABSI) in neonates with presumed mucosal barrier injury due to gastrointestinal (MBI-GI) conditions and to evaluate epidemiology and microbiology of MBI-GI CLABSI in infants. DESIGN Multicenter retrospective cohort study. SETTING Neonatal intensive care units from 14 US childrens hospitals and pediatric facilities. METHODS A multidisciplinary focus group developed a candidate MBI-GI CLABSI definition based on presence of an MBI-GI condition, parenteral nutrition (PN) exposure, and an eligible enteric organism. CLABSI surveillance data from participating hospitals were supplemented by chart review to identify MBI-GI conditions and PN exposure. RESULTS During 2009-2012, 410 CLABSIs occurred in 376 infants. MBI-GI conditions and PN exposure occurred in 149 (40%) and 324 (86%) of these 376 neonates, respectively. The distribution of pathogens was similar among neonates with versus without MBI-GI conditions and PN exposure. Fifty-nine (16%) of the 376 initial CLABSI episodes met the candidate MBI-GI CLABSI definition. Subsequent versus initial CLABSIs were more likely to be caused by an enteric organism (22 of 34 [65%] vs 151 of 376 [40%]; P = .009) and to meet the candidate MBI-GI CLABSI definition (19 of 34 [56%] vs 59 of 376 [16%]; P < .01). CONCLUSIONS While MBI-GI conditions and PN exposure were common, only 16% of initial CLABSIs met the candidate definition of MBI-GI CLABSI. The high proportion of MBI-GI CLABSIs among subsequent infections suggests that infants with MBI-GI CLABSI should be a population targeted for further surveillance and interventional research.

Discrepancies Between Prescribed and Actual Pediatric Home Parenteral Nutrition Solutions.

BACKGROUND Home parenteral nutrition (HPN) is increasingly prescribed for pediatric patients with complex medical conditions. Commercial vendors are widely available to compound HPN. The aim of this study was to determine the frequency of discrepancies between written HPN prescriptions and commercially compounded solutions, as well as to record the associated severity of harm from discrepancies. METHODS From January to April 2013, 2 clinical pharmacists independently and prospectively reconciled HPN compounding records with electronic prescriptions (gold standard) during all routine ambulatory encounters to a multidisciplinary HPN program. Types, severity, and causes of discrepancies were recorded. RESULTS Sixty-one unique patients were identified for inclusion during 117 visits. HPN solutions were compounded at 13 unique vendors across 14 states. Of all 100 compounding records, 46 (46%) contained at least 1 discrepancy, with a total of 60 discrepancies identified, affecting 34 of 61 (56%) patients. There was at least 1 discrepancy in solutions originating from 10 of 13 (77%) home infusion companies. Discrepancies were classified as Medication Error Reporting and Prevention levels C (n = 37) and D (n = 23; ie, all reaching patient but not causing harm). CONCLUSIONS We found an alarmingly high rate of preparation discrepancies in a cohort of pediatric patients receiving HPN. Routine reconciliation of HPN compounds with intended prescriptions may be critical for ambulatory patients receiving this high-risk therapy. While home infusion commercial vendors provide an indispensable function, discrepancies and errors with potential for harm may be more common than previously appreciated.