Paul D. Mitchell

Challenges to Optimal Enteral Nutrition in a Multidisciplinary Pediatric Intensive Care Unit

OBJECTIVE To describe nutrient intake in critically ill children, identify risk factors associated with avoidable interruptions to enteral nutrition (EN), and highlight opportunities to improve enteral nutrient delivery in a busy tertiary pediatric intensive care unit (PICU). Design, Setting, and Measurements: Daily nutrient intake and factors responsible for avoidable interruptions to EN were recorded in patients admitted to a 29-bed medical and surgical PICU over 4 weeks. Clinical characteristics, time to reach caloric goal, and parenteral nutrition (PN) use were compared between patients with and without avoidable interruptions to EN. RESULTS Daily record of nutrient intake was obtained in 117 consecutive patients (median age, 7 years). Eighty (68%) patients received EN (20% postpyloric) for a total of 381 EN days (median, 2 days). Median time to EN initiation was less than 1 day. However, EN was subsequently interrupted in 24 (30%) patients at an average of 3.7 +/- 3.1 times per patient (range, 1-13), for a total of 88 episodes accounting for 1,483 hours of EN deprivation in this cohort. Of the 88 episodes of EN interruption, 51 (58%) were deemed as avoidable. Mechanically ventilated subjects were at the highest risk of EN interruptions. Avoidable EN interruption was associated with increased reliance on PN and impaired ability to reach caloric goal. CONCLUSIONS EN interruption is common and frequently avoidable in critically ill children. Knowledge of existing barriers to EN such as those identified in this study will allow appropriate interventions to optimize nutrition provision in the PICU.

Does Bacteremia Follow Colonoscopy

In order to determine the risk of bacteremia from colonoscopy, we cultured blood specimens from 40 patients the day before laxative and enema preparation; right after such preparation; and 15 min, 1 hr, and 4 hr after colonscopy. Bacteremia was not induced by either the vigorous preparation or the colonscopy which, in 27 patients, included polypectomy, biopsy, and/or fulgurations. On the basis of our data, we conclude that the risk of bacteremia following colonoscopy is small, and we doubt the need of antibiotic prophylaxis for those with susceptible hearts.

PerR Confers Phagocytic Killing Resistance and Allows Pharyngeal Colonization by Group A Streptococcus

The peroxide response transcriptional regulator, PerR, is thought to contribute to virulence of group A Streptococcus (GAS); however, the specific mechanism through which it enhances adaptation for survival in the human host remains unknown. Here, we identify a critical role of PerR-regulated gene expression in GAS phagocytosis resistance and in virulence during pharyngeal infection. Deletion of perR in M-type 3 strain 003Sm was associated with reduced resistance to phagocytic killing in human blood and by murine macrophages in vitro. The increased phagocytic killing of the perR mutant was abrogated in the presence of the general oxidative burst inhibitor diphenyleneiodonium chloride (DPI), a result that suggests PerR-dependent gene expression counteracts the phagocyte oxidative burst. Moreover, an isogenic perR mutant was severely attenuated in a baboon model of GAS pharyngitis. In competitive infection experiments, the perR mutant was cleared from two animals at 24 h and from four of five animals by day 14, in sharp contrast to wild-type bacteria that persisted in the same five animals for 28 to 42 d. GAS genomic microarrays were used to compare wild-type and perR mutant transcriptomes in order to characterize the PerR regulon of GAS. These studies identified 42 PerR-dependent loci, the majority of which had not been previously recognized. Surprisingly, a large proportion of these loci are involved in sugar utilization and transport, in addition to oxidative stress adaptive responses and virulence. This finding suggests a novel role for PerR in mediating sugar uptake and utilization that, together with phagocytic killing resistance, may contribute to GAS fitness in the infected host. We conclude that PerR controls expression of a diverse regulon that enhances GAS resistance to phagocytic killing and allows adaptation for survival in the pharynx.

Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid‐refractory colitis

Background: Children with severe corticosteroid‐resistant ulcerative colitis either need to undergo surgery or be treated with more intensive immunosuppression. Our aim was to characterize the short‐ and long‐term outcomes and adverse events associated with the use of tacrolimus in a steroid‐refractory pediatric population. Methods: We retrospectively reviewed the medical records of 46 children with steroid‐refractory colitis treated with tacrolimus at Childrens Hospital Boston between 1994 and 2008. Oral tacrolimus was initiated at a dose of 0.1 mg/kg twice a day and titrated to yield trough levels of 10–15 ng/mL for induction, and 5–10 ng/mL once in remission. The Pediatric Ulcerative Colitis Activity Index (PUCAI) and other measures of disease activity, adverse events, and long‐term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Ninety‐three percent of patients were discharged without undergoing surgery. The median length of stay after starting tacrolimus was 10 days (range 4–37 days). The mean PUCAI score was 68 ± 13 prior to initiating tacrolimus, and 27 ± 18 at the time of hospital discharge. The probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. The most common adverse events included hypertension (52%) and tremor (44%). There was one seizure and no deaths. Conclusions: Tacrolimus is useful as induction therapy in pediatric patients with corticosteroid‐refractory colitis and side effects are generally mild and reversible. Despite these findings, many patients develop exacerbations of colitis upon transition to maintenance therapies. The long‐term colectomy rate in this challenging population remains ≈60% over time. (Inflamm Bowel Dis 2011;)

Provision of a soy-based intravenous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates.

BACKGROUND One of the most common and severe complications of long-term parenteral nutrition (PN) is PN-associated cholestasis. The soybean oil-based lipid emulsion administered with PN has been associated with cholestasis, leading to an interest in lipid reduction strategies. The purpose of this study was to determine whether the provision of a soybean oil-based lipid emulsion at 1 g/kg/d compared with 2-3 g/kg/d is associated with a reduced incidence of cholestasis. METHODS Retrospective review of neonates admitted between 2007 and 2011 with a gastrointestinal condition necessitating ≥ 21 days of PN support. Neonates were divided into 2 groups based on the intravenous lipid emulsion dose: 1-g group (1 g/kg/d) and 2- to 3-g group (2-3 g/kg/d). The primary outcome measure was the incidence of cholestasis. RESULTS Sixty-one patients met inclusion criteria (n = 29, 1-g group; n = 32, 2- to 3-g group). The 2 groups did not differ in any baseline characteristics other than associated comorbidities that were more common in the 2- to 3-g group. The duration of PN, the number of operative procedures and bloodstream infections, and enteral nutrition (EN) were similar between groups. The incidence of cholestasis was not different between groups (51.7%, 1-g group; 43.8%, 2- to 3-g group; P = .61), and there was no difference between groups in the time to cholestasis (32.6 ± 24.1 days, 1-g group; 27.7 ± 10.6 days, 2- to 3-g group; P = .48). Overall, 44.8% of patients with cholestasis were transitioned to full EN, and 55.2% were transitioned to a fish oil-based lipid emulsion after which the direct bilirubin normalized in all patients. CONCLUSION Lipid reduction to 1 g/kg/d does not prevent or delay the onset of cholestasis in neonates.

Treatment of Vitamin D Insufficiency in Children and Adolescents with Inflammatory Bowel Disease: A Randomized Clinical Trial Comparing Three Regimens

CONTEXT Vitamin D insufficiency [serum 25-hydroxyvitamin D (25OHD) concentration less than 20 ng/ml] is prevalent among children with inflammatory bowel disease (IBD), and its treatment has not been studied. OBJECTIVE The aim of this study was to compare the efficacy and safety of three vitamin D repletion regimens. DESIGN AND SETTING We conducted a randomized, controlled clinical trial from November 2007 to June 2010 at the Clinical and Translational Study Unit of Childrens Hospital Boston. The study was not blinded to participants and investigators. PATIENTS Eligibility criteria included diagnosis of IBD, age 5-21, and serum 25OHD concentration below 20 ng/ml. Seventy-one patients enrolled, 61 completed the trial, and two withdrew due to adverse events. INTERVENTION Patients received orally for 6 wk: vitamin D(2), 2,000 IU daily (arm A, control); vitamin D(3), 2,000 IU daily (arm B); vitamin D(2), 50,000 IU weekly (arm C); and an age-appropriate calcium supplement. MAIN OUTCOME MEASURE We measured the change in serum 25OHD concentration (Δ25OHD) (ng/ml). Secondary outcomes included change in serum intact PTH concentration (ΔPTH) (pg/ml) and the adverse event occurrence rate. RESULTS After 6 wk, Δ25OHD ± se was: 9.3 ± 1.8 (arm A); 16.4 ± 2.0 (arm B); 25.4 ± 2.5 (arm C); P (A vs. C) = 0.0004; P (A vs. B) = 0.03. ΔPTH ± SE was -5.6 ± 5.5 (arm A); -0.1 ± 4.2 (arm B); -4.4 ± 3.9 (arm C); P = 0.57. No participant experienced hypercalcemia or hyperphosphatemia, and the prevalence of hypercalciuria did not differ among arms at follow-up. CONCLUSIONS Oral doses of 2,000 IU vitamin D(3) daily and 50,000 IU vitamin D(2) weekly for 6 wk are superior to 2,000 IU vitamin D(2) daily for 6 wk in raising serum 25OHD concentration and are well-tolerated among children and adolescents with IBD. The change in serum PTH concentration did not differ among arms.

Neonates With Short Bowel Syndrome: An Optimistic Future for Parenteral Nutrition Independence

IMPORTANCE The introduction of hepatoprotective strategies and multidisciplinary management has significantly improved the outcome of neonates with short bowel syndrome (SBS) who require parenteral nutrition (PN). OBJECTIVE To determine the probability of weaning from PN based on intestinal length in neonates with SBS amidst the new era of hepatoprotective strategies and multidisciplinary management. DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review at a single-center academic institution. Neonates with no more than 100 cm of small intestine at a corrected gestational age of no more than 30 days who were diagnosed with a surgical gastrointestinal disease and PN dependent for at least 2 weeks were included. Data were collected from January 1, 2004, through June 1, 2012. EXPOSURE Neonates with SBS requiring PN. MAIN OUTCOMES AND MEASURES The probability of wean from PN without reinitiation for at least 1 year, as determined by logistic regression. Predictors of wean were evaluated using exact conditional logistic regression. Predictors of time to wean were determined by Cox proportional hazards regression. RESULTS Sixty-three patients with a median (25th percentile, 75th percentile [interquartile range (IQR)]) gestational age of 31 (27, 35) weeks, birth weight of 1423 (895, 2445) g, small intestinal length of 41.0 (24.0, 65.0) cm, and predicted length of 29.0% (17.1%, 45.5%) underwent analysis. Fifty-one patients (81%) received a fish oil-based lipid emulsion (1 g/kg/d), 40 (63%) were weaned, 11 (17%) remained PN dependent, 4 (6%) underwent transplant, and 8 (13%) died while on PN. Excluding patients who underwent transplant or died, the median (IQR) small intestinal length was 55.0 (28.0, 75.0) cm in weaned and 26.0 (14.0, 41.0) cm in PN-dependent patients (P = .006), with 40 of 51 (78%) weaned by study end. The cumulative probability of wean for patients with at least 50 cm of small intestine was 88% after 12 and 96% after 24 months. Patients with less than 50 cm of small intestine had a cumulative probability of wean of 23% after 12, 38% after 24, and 71% after 57 months. Small intestinal length was found to be the primary predictor of wean. Notable predictors of time to wean included the amount of small intestine remaining (hazard ratio, 1.94 [95% CI, 1.45-2.58] per 20 cm of intestine; P < .001), entirety of care within our institution (3.27 [1.59-6.72]; P = .001), and intestinal lengthening procedure (0.19 [0.04-0.84]; P = .03). CONCLUSIONS AND RELEVANCE The majority of patients will wean from PN despite short intestinal length, likely as a result of new management strategies combined with a multidisciplinary team approach.

Bacterial variants: etiologic agent in Crohn's disease?

Bacterial variants of Pseudomonas maltophilia and Pseudomonas-like bacteria were recovered from tissues removed during the surgical treatment of three successive patients with Crohns disease and from one patient with clinical and pathological features of both Crohns disease and chronic ulcerative colitis. Bacterial variants were not cultured from colonic specimens of one patient with classical features of chronic ulcerative colitis and two patients with adenocarcinoma of the colon. The findings suggest that a relationship exists between variant bacteria and the pathogenesis of Crohns disease.

Risk Factors for Parenteral Nutrition–associated Liver Disease Following Surgical Therapy for Necrotizing Enterocolitis

Objective:The aim of the study was to prospectively determine risk factors for the development of parenteral nutrition–associated liver disease (PNALD) in infants who underwent surgery for necrotizing enterocolitis (NEC), the most common cause of intestinal failure in children. Patients and Methods:From February 2004 to February 2007, we diagnosed 464 infants with NEC, of whom 180 had surgery. One hundred twenty-seven patients were available for full analysis. PNALD was defined as serum direct bilirubin ≥2 mg/dL or ALT ≥2 × the upper limit of normal in the absence of sepsis after ≥14 days of exposure to PN. Results:Median gestational age was 26 weeks and 68% were boys. Seventy percent of the cohort developed PNALD and the incidence of PNALD varied significantly across the 6 study sites, ranging from 56% to 85% (P = 0.05). Multivariable logistic regression analysis identified small-bowel resection or creation of jejunostomy (odds ratio [OR] 4.96, 95% confidence interval [CI] 1.97–12.51, P = 0.0007) and duration of PN in weeks (OR 2.37, 95% CI 1.56–3.60, P < 0.0001) as independent risk factors for PNALD. Preoperative exposure to PN was also associated with the development of PNALD; the risk of PNALD was 2.6 (95% CI 1.5–4.7; P = 0.001) times greater in patients with ≥4 weeks of preoperative PN compared with those with less preoperative PN use. Breast milk feedings, episodes of infection, and gestational age were not related to the development of PNALD. Conclusions:The incidence of PNALD is high in infants with NEC undergoing surgical treatment. Risk factors for PNALD are related to signs of NEC severity, including the need for small-bowel resection or proximal jejunostomy, as well as longer exposure to PN. Identification of these and other risk factors can help in the design of clinical trials for the prevention and treatment of PNALD and for clinical assessment of patients with NEC and prolonged PN dependence.

Changes in Gastric and Lung Microflora With Acid Suppression Acid Suppression and Bacterial Growth

IMPORTANCE The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs. OBJECTIVES To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux. DESIGN, SETTING, AND PARTICIPANTS A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review. MAIN OUTCOMES AND MEASURES Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test. RESULTS Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37, P = .008), and Capnocytophagia (r = 0.37, P = .008). CONCLUSIONS AND RELEVANCE Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression-related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.