Infants and children with IF are at risk for myriad complications as well as death. Large societal and financial costs of this relatively small sub-group of patients underlie the importance of understanding the natural history and outcomes of IF. The rarity of the condition combined with changing care practices make single center prospective studies that are adequately powered difficult to perform.
For 272 infants with IF, the cumulative percentage who achieved enteral autonomy (with death and intestinal transplantation as competing risks) was almost 50% at 3 years and achievement of enteral autonomy continued through 60 months of study. Our findings along with others(18
) suggest infants with IF can hope to achieve enteral autonomy even after many years on PN, which is in sharp contrast to adults who rarely achieve enteral autonomy beyond 2 years on PN.(19
) However, the path to enteral autonomy is not linear as a few children fell back to PN dependency before achieving enteral autonomy a second time. The cumulative percentage of children who died was 27%, and the cumulative percentage receiving ITx was 26%. Mortality and morbidity remain high in this population, and is similar to other reports.(20
) Nearly all of the deaths occurred within 2 years after study entry. Therefore, improvements in the early management of infants with IF may improve outcomes.
We found greater heterogeneity among the diagnostic categories than previously described as 26% had complex intestinal anomalies or insults, which can be associated with unique medical and surgical challenges.(21
) Recording of residual bowel length varied between sites. Reasons to account for these differences include the potential the infant was too sick for detailed measurements, inability to measure due to multiple adhesions, or clinical judgment that knowledge of the bowel length would not impact management. The relative importance of the residual bowel length is also dependent upon other factors that include gestational age, presence of an ileal segment and/or ileo-cecal valve, and colon length. Therefore, a standard approach to measuring technique as well as documentation of important co-variables should be incorporated into future prospective studies.
For those patients in whom the presence or absence of cholestasis could be assessed, we demonstrated that cholestatic disease is associated with a significant decrease in the probability of survival. The preponderance of our data were collected prior to initiation of lipid management strategies to prevent or treat cholestasis. An omega-3 fish oil-based parenteral emulsion was first introduced at one PIFCon site in 2004 and their findings were reported after completion of our data collection.(22
) No other sites were able to access the omega-3 intravenous lipid preparation at any time during the study. A lipid reduction protocol to treat or prevent cholestasis was not initiated until 2007 at another PIFCon site.(23
) Therefore, the impact on our data set by the evolving changes in clinical practice related to lipid management is likely small. Whether these strategies prevent PN-related liver disease or just improve cholestasis remains in question.(24
) Newer lipid formulations containing medium-chain triglycerides, olive oil in addition to soy and fish oil may be available in the future.(25
) The impact of alternative lipid components or reduced lipid infusions upon neurocognitive development, neuronal maturation, or cellular membrane composition in seriously ill neonates and infants is not known. Future studies will need to address these concerns.
Catheter-related blood stream infections (CRBSIs) were common, consistent with prior reports.(26
) Sepsis was the second leading cause of death among those who died without an ITx, making infectious complications associated with IF a leading cause of morbidity and mortality in this population. Ethanol lock therapy to prevent CRBSIs in selected patients has recently been advocated, but adequately powered trials to support its use are lacking in pediatric populations.(27
) New technologies related to impregnating central catheters with molecules to prevent adherence of biofilm or bacteria to the catheter may provide future options to prevent or reduce CRBSIs.(29
) Antibiotic lock therapy has been used to salvage the central catheter following some CRBSIs and was used in 41 (15%) patients in our study; this likely represents an evolving change in clinical practice. Lock therapy with antibiotics is now recommended for catheter salvage (30
), thus the frequency of antibiotic lock therapy has likely increased since 2006.
Infants with IF are exposed to multiple medications, none of which have been subjected to an adequately powered, prospective, randomized study in this population.(32
) Although the prevalence and clinical relevance of bacterial overgrowth in SBS is unknown(33
), 76% of children in our study were given oral antibiotics for presumed bacterial overgrowth with regimens that differed widely among the centers. Random manipulation of the gut microbiota with oral antibiotics may negatively impact energy absorption and intestinal secretion.(34
) Ranitidine may reduce gastric acid secretion in patients with SBS (35
), but the impact of prolonged use of more potent proton pump inhibitors alone or in combination with other histamine 2 antagonists is unknown.(36
) Likewise, the use of pro- or anti-motility agents was noted in over 40% of our cohort with little evidence of safety or efficacy in this population. Alterations in enteral drug absorption and metabolism in the setting of SBS is an additional confounding variable that impacts a rational use of oral medications.(38
Enteral feeding is essential for intestinal adaptation. Breast milk has been associated with decreased duration of PN in IF patients.(7
) The beneficial effects of breast milk are attributable to its immunoprotective properties, effect on postnatal development of intestinal flora, and its nutrient composition that includes long chain triglycerides, free amino acids, nucleotides, and growth factors as well as complex protein and fat.(39
) Only 52/272 (19%) of infants were reported to have received breast milk. Variations in practice regarding the choice of enteral formulas were considerable between and within the 14 sites. Opportunities to improve oral and enteral feeding strategies aimed to enhance intestinal adaptation should be addressed in future studies.
One limitation of this study is the gaps in data collected that can occur with retrospective studies. Reasons for missing data include absence of an electronic medical record, miss-filed or un-retrievable paper records of these frequently hospitalized children and incomplete records from the patients’ home institution. A second limitation is the variation in clinical practice between and within PIFCon sites. Although not unexpected, identification of practice variations provide opportunities to pursue comparative effectiveness strategies that will establish a “best practice” within the consortium. Development of a prospective, multi-center study would enhance the completeness, consistency and accuracy of the data and its analysis.
Enteral autonomy can be achieved in this high risk population, but physicians and families must be patient and vigilant as it may require many years. Current management strategies are imperfect as many are not evidence-based. Emerging strategies to prevent or treat cholestasis and CRBSIs will likely improve outcomes for children with IF. Comprehensive, multi-center, prospective studies will be required to design adequately powered clinical trials to assess medical, nutritional, and surgical interventions in children with IF that will reduce time on PN, morbidity, mortality and need for transplantation.