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Original Article: Nutrition

Pediatric Intestinal Pseudo-obstruction: Impact of Neonatal and Later Onset on Clinical and Nutritional Outcomes

Diamanti, Antonella; Fusaro, Fabio; Caldaro, Tamara; Capriati, Teresa; Candusso, Manila§; Nobili, Valerio§; Borrelli, Osvaldo||

Author Information
Journal of Pediatric Gastroenterology and Nutrition: August 2019 - Volume 69 - Issue 2 - p 212-217
doi: 10.1097/MPG.0000000000002373

Abstract

What Is Known

  • The majority of pediatric intestinal pseudo-obstruction occurs at neonatal period.
  • Nutritional strategies tailored to the single patient enable one to reach enteral autonomy in several cases.
  • Severe liver disease, recurrent episodes of venous thrombosis and central line-associated infections indicate intestinal transplantation.

What Is New

  • New case series of pediatric intestinal pseudo-obstruction should be ordered as primary, secondary, and idiopathic.
  • Neurodisability and severe intestinal dysmotility can be combined in idiopathic pediatric intestinal pseudo-obstruction.
  • Neonatal onset pediatric intestinal pseudo-obstruction has more gastrointestinal involvement and more need for long-term parenteral nutrition but less extradigestive comorbidities than later onset pediatric intestinal pseudo-obstruction.

Severe motility disorders are important causes of intestinal failure (IF) in childhood (1). Due to gastrointestinal symptoms triggered by food ingestion and inadequate caloric intake, children with motility disorders are often unable to achieve normal growth, hence requiring long-term PN in order to improve their nutritional status and preserve both growth and development (2). A recent Italian pediatric series reported that motility disorders account for about 20% of all the indications to home parenteral nutrition (HPN) programs and that Italian data parallels those from other European surveys (1). Recently, the French group showed that severe motility disorders contributed for 19% to all HPN programs, with 9% of the cases involving chronic intestinal pseudo-obstruction (CIPO) and 10% long-segment Hirschsprung's disease (3). In UK, the prevalence of patients with motility disorders on HPN ranges between 17% and 21% (4,5). As long-term PN is associated with a high risk of life-threatening complications, maintaining patients on maximally tolerated enteral nutrition (EN) is strongly encouraged (6,7). Potentially life-threatening complications of HPN are intestinal-failure-associated liver disease (IFALD), recurrent episodes of venous thrombosis (BVT) and central line-associated bloodstream infections (CLABSIs) (7).

Severe complications of long-term of PN in IF patients identify the so-called “nutritional failure,” which becomes indication to intestinal transplantation (8).

The prevalence of patients with motility disorders among transplanted patients seems to be higher than that observed in HPN series, so confirming the clinical severity of motility disorders during childhood (1,3–5,9,10).

Among the severe motility disorders, CIPO represents a marked disorder of intestinal propulsive motility mimicking mechanical obstruction, without signs of any organic injury occluding the gut lumen (11). The diagnosis is based on typical clinical manifestations and radiological signs of intestinal mechanical occlusion without any organic obstruction of the gut lumen (11).

New ESPGHAN guidelines have been recently published with revised classification and diagnostic criteria in order to assist the diagnosis and pave a more uniform and appropriate clinical management (6). Noteworthy, the authors have highlighted the distinctive clinical features between typical adult and pediatric forms of CIPO, thus introducing the term of Pediatric Intestinal Pseudo-obstruction (PIPO) (6). The inability to maintain adequate nutritional status and growth without PN or EN is a frequent characteristic of PIPO, and it is currently considered as one of the prerequisite for the diagnosis (6). Hence, in children with PIPO, a careful nutritional management plays a key role in the clinical course, and requires strategies tailored to the single patient, which combine specialized oral feeding (OF), EN, and PN (6).

In children, the majority of PIPO cases occurs at neonatal period, although some of them may develop also later in life (6). However, until recently, only limited data exists about potential distinctive features of neonatal-onset PIPO (NO-PIPO) and later-onset PIPO (LO-PIPO).

The present study revised the cohort of patients, followed in the last 30 years (1988–2018) in our Institution, affected by PIPO according to the new ESPGHAN diagnostic criteria (6). The main purpose of the study was to evaluate long-term nutritional outcomes and clinical characteristics of patients with NO-PIPO and LO-PIPO.

PATIENTS AND METHODS

Study Design

Medical records of all children treated in our institution for motility disorders were retrospectively reviewed. These patients are followed by a multidisciplinary team consisting of pediatric gastroenterologists, pediatric surgeons, nurses specialized in caring for patients requiring nutritional supports and central venous catheter (CVC), radiologists, dietitians, psychologists, pharmacists, and social workers. The team is responsible for overall planning, managing, and revising the tailored intestinal rehabilitation programs. Other specialists are available for consultation, including neonatologists, pediatric intensive care physicians, and nurses specialized in the care of ostomies. In Table 1 we summarize our nutritional protocol that has been progressively implemented since 2009, according to the literature indications (12–15).

TABLE 1
TABLE 1:
Protocol for nutritional management of pediatric intestinal pseudo-obstruction

Inclusion criteria were: diagnosis/follow-up starting between January 1, 1988 and June 2018; age at disease onset 0 to 18 years; diagnostic criteria fulfilling at least 2 out of 4 following criteria: objective measurements of small intestinal neuromuscular involvement (manometry, histopathology, transit); recurrent and/or persistently dilated loops of small intestine with air fluid levels; genetic and/or metabolic abnormalities definitively associated with PIPO and inability to maintain adequate nutrition and/or growth on OF (needing specialized EN and/or PN support) (2).

For each patient, we collected the following features: sex (M/F); etiology of PIPO subdivided as primary, secondary and idiopathic; symptoms at disease onset; histopathology; urinary tract involvement; pancreatobiliary system involvement; comorbidity; need for surgery, including enterostomy placements, gut resections, and transplantations.

Nutritional outcomes reviewed at the last follow-up were the following: survival; enteral autonomy identified by the weaning off PN without need for re-initiation for at least 1 year or for periodic fluids and electrolyte support (3). In patients with enteral autonomy at the last follow-up, we evaluated prevalence of OF, EN by gastric route (GEN) or jejunal route (JEN); number of patients needing PN and HPN during the study-period; rate of the major complications: prevalence of liver disease (LD), considered as persisting abnormal liver function tests (LFTs) (plasma aminotransferases, ASAT and ALAT, and gamma-glutamyltransferase) for more than 2 months, and IFALD, defined by the combination of LFTs with total bilirubin >100 mmol/L or direct bilirubin >20 mmol/L for at least 2 to 4 weeks (16,17); rate of CLABSIs, diagnosed according to the Center for Disease Control and Prevention (CDC) (18) and reported as rate over 1000 CVC days; rate of BVT, diagnosed according to the ESPEN guidelines (13) and were reported as rate over 1000 CVC days; growth course. Growth measurements that were weight (W) z-score, height (H) z-score, and BMI z-score have been assessed for each patient at the end of the follow-up. CDC (19) and WHO (20) growth charts were used as reference in patients ages more and less than 5 years, respectively.

Our primary endpoint was to revise the nutritional outcomes over the 30-year period. To better define the outcomes, we subdivided the series into 3 groups according to the decades: 1988 to 1997; 1998 to 2007; and 2008 to 2018. The secondary end-point was to compare clinical features and nutritional outcomes between NO-PIPO and LO-PIPO patients.

Statistical Analysis

Categorical variables were summarized as percentage, and continuous variables as median and range or as mean ± SD. Overall survival and cumulative risk of remaining on PN were evaluated by Kaplan-Meier method with Mantel-Cox log-rank test. NO-PIPO and LO-PIPO were compared as follows: differences in categorical variables by Fisher exact and odds ratio (OR) with 95% confidence interval (95% CI); differences in growth measures by unpaired t-test; differences in PN length, CLABSIs and BVT by Mann-Whitney U-test. P value <0.05 was considered statistically significant. Statistical evaluation and figures were performed using Graph Pad 6 for Windows.

Ethics

The Research and Development Office of “Bambino Gesù” Hospital approved the review of the clinical records for the research proposed in this study.

RESULTS

Overall, 54 patients with PIPO were considered eligible for the study, whilst 5 patients have been excluded because of either lack of data or fulfilling the diagnostic criteria required by the guidelines (2). Median follow-up length was 17.5 years (1–30 years). Every patient on HPN in the cohort had the last follow-up in 2018. Out of the 49 patients included in the analysis, 44 were still alive at the end of the study-period. In Table 2, we detail etiology and diagnostic criteria for PIPO. Five patients, all on PN, died during the 30-year period because of progressive worsening of underlying disease in 2 patients with mitochondrial diseases and to multiorgan failure complicating severe sepsis in 3 patients with NO-PIPO. Four out of the 5 dead patients had developed IFALD, that was never the primary cause of death but it was significantly associated to mortality (P < 0.0001, OR 267.0, 95% CI 9.4–757.3). In Supplemental Figure 1 (Supplemental Digital Content, https://links.lww.com/MPG/B636), we report the cumulative 30-year survival that was 93.5% (CI 79–98) at 10 years, 89% (CI 73–96) at 20 years, and 84% (CI 64–93) at the end of the follow-up. The overall anthropometric assessment at the last follow-up showed weight-z-score—1.192 ± 1.197 height z score −1.444 ± 0.8758 and BMI z-score −0.8268 ± 1.306.

TABLE 2
TABLE 2:
Etiology and diagnostic features

Out of the 44 surviving patients, 25 (57%) achieved enteral autonomy; 18 (41%) remained on HPN, and 1 still requires periodic fluid administration at the end of the follow-up. In our series, no patients needing PN during the study gained enteral autonomy 7 years after PN beginning: thus in the present series, patients who needed PN had a probability of being on PN of 55% (CI 34–70) at 10 years, which remained unchanged until the end of the follow-up.

Tables 3 and 4 summarize demographic and clinical characteristics as well as outcomes according to each decade. Jejunostomy placements were significantly more common during the third decade than in the previous period (11/30 vs 13/19, P = 0.0290). Median HPN length, 5840 day (range 125–8760), 2738 (438–5110), and 1460 (range 180–2555) during first, second, and third decades, respectively, increased significantly in the second in comparison with the third decade (P = 0.015).

TABLE 3
TABLE 3:
Demographics and baseline disease characteristics of the patients included in the study
TABLE 4
TABLE 4:
Outcomes at the end of the follow-up

Patients enrolled during the third decade are all alive and none out of them developed IFALD. Furthermore, there were overall 68 episodes of CLABSI (0.98/1000 CVC days), 60 in the first 2 decades and 8 in the third decade (P = 0.0060), and 11 thrombotic events (0.15/1000 CVC days), of which 9 in the first 2 decades, and 2 in the third decade (P = NS).

Neonatal-onset Pediatric Intestinal Pseudo-obstruction Versus Later-onset Pediatric Intestinal Pseudo-obstruction

Several clinical features and outcomes significantly differed between NO-PIPO and LO-PIPO.

Clinical Features

Regarding the symptoms of presentation, the combination of vomiting, abdominal distention, and intestinal occlusion was significantly more frequent in NO-PIPO [P = 0.0035, OR 16.9 (CI 1.8–152.9)]; whereas abdominal pain in LO-PIPO [P = 0.0061, OR 23.1 (CI 1.2–447.6)]. Urinary involvement was significantly associated with NO-PIPO [P = 0.0167, OR 10.4 (CI 1.2–89.1)] and comorbidity not for malrotation with LO-PIPO [P = 0.0074722, OR 5.5 (1.5–20.7)], respectively.

Surgery

NO-PIPO received more gastrostomy [P = 0.0284, OR 4.4 (CI 1.2–15.8) and ileostomy [P = 0.0014, OR 18 (CI 2.1–152.6)] placements and complex gastrointestinal surgery [P = 0.0120, OR 7.4 (CI 1.5–38.0) than LO-PIPO.

Nutritional Outcomes and Complications of Parenteral Nutrition

Overall, less NO-PIPO patients achieved enteral autonomy, needing, therefore, more PN programs than LO-PIPO. NO-PIPO patients developed more liver diseases defined as abnormal LFTs.

Growth

LO-PIPO were more malnourished than NO-PIPO as shown by the significantly lower BMI z score [−1.920 ± 0.2596 and −0.6 ± 1.3, respectively (P = 0.0457)].

DISCUSSION

Children affected by PIPO require very complex nutritional and clinical management, that should be maximized by the presence of a skilled multidisciplinary team in order to pave the best clinical outcome (2,21). Nevertheless, the multidisciplinary management in our survey allowed to reduce the incidence of life-threatening HPN complications, but it did not impact on the probability to achieve enteral autonomy, which clearly parallels the disease severity. Specifically, we found a significantly reduced incidence of CLABSIs and a trend toward reduced mortality, IFALD, and BVT during the third decade.

The occurrence of CLABSIs is probably related to the underlying condition, being the patients more prone to bacterial overgrowth and translocation (21). In the present series, 8 out of the 36 patients (22%) who needed PN during the study period had more than 2 episodes of CLABSI, whilst 4 patients (11%) had major thrombotic events in 2 central veins. Remarkably, 7 out of 12 children with major catheter-related complications were followed up initially in other centers at low volume of treated patients, hence highlighting how the clinical experience and the availability of a multidisciplinary team might have an impact on disease outcomes.

In the second and in the third decade of the study period, the number of patients who gained enteral autonomy was similar but it was slightly lower than in the first decade. Furthermore, the number of patients who required PN and HPN was similar over time; during the third decade, more patients were found on HPN than in the previous decades but, nevertheless, this result could be biased in the shorter follow-up period. Unlike the follow-up length, we interestingly found that no patients had been weaned from PN after 7 years. Therefore, in our experience this can be considered as the cut off to identify PIPO patients potentially permanently dependent on HPN.

This is the first systematic report on PIPO according to the new guidelines (6). We identified 3 cases of mitochondrial diseases as cause of primary PIPO. One of these cases has never been related to PIPO. We also found 3 patients with profound neurodisability who developed intestinal dysmotility and hence based on the current guidelines were classified as idiopathic (6). It has been previously shown that in children with severe neurodisability and feeding intolerance, the incidence of foregut dysmotility is noticeably more common than generally acknowledged (22). Moreover, in the last years, it is being increasingly recognized that these patients represent an unnoticed indication to PN (23). Therefore, considering the new diagnostic criteria also, children with severe neurodisability and IF can be labeled as having PIPO. Of note, in our previous series, 1 quarter of the patients with nonprimary digestive IF had an underlying neurological disease (1). Finally, we identified 1 case of fabricated or induced illness (FFI) previously known as Munchausen syndrome by proxy, because of chronic administration of diuretics by the mother, supporting that in infants and children with suspected enteric neuromuscular disorders, FFI should always be ruled out (24). The guidelines also recommend that CIPO occurring in infants and children should be considered as a separate entity from that in adults, and therefore, it has been proposed to define as PIPO all the forms of CIPO occurring during pediatric age (6). In our study, we aimed to identify differences between CIPO at neonatal onset and cases of later occurrence. We have found that many features of LO-PIPO resemble those reported in adults. In particular, we found that abdominal pain was the symptom of onset in a quarter of cases, urological involvement and intestinal malrotation were rarely seen, the need for PN to prevent malnutrition was significantly lower than in NO-PIPO and similar to that reported in adults (47% in PIPO and 20–50% in adults); finally the rate of surgery was much less frequently required in LO-PIPO than in NO-PIPO, similarly to adult-onset CIPO. In our experience, impaired growth trend and comorbidities, but not malrotation, were more commonly detected in LO-PIPO children. On the basis on our data, it could be suggested that NO-PIPO might have a limited, although more severe enteric neuromuscular involvement associated with IF, which can be managed by accurate nutritional programs, whilst LO-PIPO might be related to complex diseases involving not only the gastrointestinal tract but also other organic functions as shown by the several comorbidities. The complex underlying disease in LO-PIPO may also justify the more severe malnutrition, as demonstrated by the BMI z score, despite the nutritional interventions.

In conclusion, in our study, we have reported nutritional outcomes and clinical characteristics of a cohort of children with PIPO over a 30-year period from a tertiary referral center, showing that about 20% of patients develop a condition of irreversible IF requiring life-long PN. Nutritional and clinical outcomes seem to be influenced by the onset time of the disease as the neonatal form of PIPO has greater gastrointestinal involvement, higher rate of surgery, and higher rate of long-term PN programs. Prospective multicenter studies are highly warranted to confirm our findings as well as to understand whether the nutritional outcomes might be affected by surgical decisions.

Acknowledgment

We acknowledge Lorenzo Guglielmi for the English editing.

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Keywords:

children; enteral nutrition; intestinal pseudo-obstruction; parenteral nutrition

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Copyright © 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition