Intestinal failure is defined as a reduction in the functioning of gut mass below the minimum amount necessary for adequate digestion and absorption of nutrients to achieve and maintain normal nutritional status (1,2). Home parenteral nutrition (PN) represents the main medical treatment of this condition (1), although further therapeutic options, such as pharmacological treatments and enteral nutrition, can be used depending on the cause of the intestinal failure.
The therapeutic strategies available for the management of intestinal failure lead to satisfactory intestinal adaptation in most of these patients. Different limits of time of intestinal adaptation (3–6) have been reported in previous pediatric studies and have been assessed at 2 (6), 5 (5), and 10 years (3,4), respectively.
However, some intestinal failure patients, notably if they have a short remaining bowel, a congenital epithelium disease, or extended aganglionosis, cannot achieve satisfactory intestinal autonomy and become definitively dependent on PN (3–20). These patients, dependent on PN for years, are considered to have permanent or irreversible intestinal failure and are candidates for intestinal transplantation.
Advances in knowledge of the outcome and potential complications of intestinal failure, especially in children, for whom only a few data are available, should lead not only to planning the therapeutic options best able to guarantee progress toward optimal intestinal autonomy but also to assessing the factors that can predict the development of definitive dependence on PN.
In the past 15 years, there have been several reports on children receiving home PN (2,7–9). By contrast, few studies (1,3,8) have evaluated the outcome of intestinal failure. Notably, most of them have evaluated the clinical outcome and complications of intestinal failure having a single cause (11–20) without comparing them.
This article describes a large cohort of children receiving PN because of intestinal failure, treated in a single specialized center, and reports the outcome and complications of intestinal failure in relation to the underlying disease. The aim is to analyze for each subgroup the survival, potential for bowel adaptation, and likelihood of complications.
PATIENTS AND METHODS
Selection of Participants
All patients requiring PN treatment, younger than 18 years, whose conditions were diagnosed between January 1, 1989 and December 31, 2006, were retrospectively enrolled in our study. All of the patients were recruited consecutively at the gastroenterology and nutrition unit of our hospital, where they were admitted because of their primary disease associated with growth and nutritional status impairment assessed by reference growth charts (21). In all, 218 patients with intestinal failure were thereby identified. Many of them, however, underwent brief courses of PN and rapidly started an oral or enteral nutrition regimen by nasogastric tube. In the selection of intestinal failure patients, the following inclusion criteria were used: a primary intestinal disease needing PN, providing at least 50% of total energy for not less than 3 months (9). Exclusion criteria from our study were oncological diseases, primary or secondary immune deficiencies, established extraintestinal causes, and inflammatory bowel diseases.
The patients were divided into three major groups in relation to the cause of intestinal failure: short bowel syndrome (SBS); motility disorders (MD), including total aganglionosis and chronic intestinal pseudo-obstruction syndrome; and severe protracted diarrhea (SPD, defined as severe diarrhea occurring within the first 2 years of life and requiring PN (19). The SPD group included patients with congenital mucosal diseases, autoimmune enteropathy, and severe food allergy (SFA). Autoimmune enteropathy was based on minimal changes at histological evaluation and on the presence of antienterocyte antibodies with or without associated autoimmune disorders (22). The SFA group included patients with diarrhea caused by the lack of enteric pathogens or other specific intestinal causes, whose conditions were worse with milk formulas or elemental diets (23).
Data were collected from our patients' medical records and included demographic characteristics (age and sex), primary diagnosis of intestinal failure, length of remaining small bowel and persistence of ileocecal valve for SBS patients, type of vascular access, dates of beginning PN and weaning from PN, date and cause of death, date of intestinal and bone marrow transplantation, and complications developed during PN treatment.
The following complications were included:
- Catheter-related infections demonstrated by positive blood culture from the infected central venous catheter (CVC), supported by another culture from a peripheral vessel positive for the same pathogen (24,25)
- Thrombotic catheter occlusions diagnosed by Doppler ultrasound (25)
- CVC mechanical complications, including catheter displacement, breakage, occlusion (24,25)
- Intestinal failure–associated liver disease (IFALD), defined as a value at least 1.5 times the upper limit of normal on 2 of 3 liver function measures: levels of serum conjugated bilirubin alkaline phosphatase and γ-glutamyl transferase, persisting for at least 6 months (26). In patients with IFALD, the liver functionality was followed by blood tests, including coagulation test, and by ultrasonography and echo Doppler, all performed every 4 months. In the presence of splenomegaly and portal hypertension, periodic gastrointestinal endoscopies were also performed.
Statistical analyses were performed with the SPSS version 10.1 for Windows (SPPS Inc, Chicago, IL). Quantitative variables were expressed as mean ± SD in case of Gaussian distribution and as median and range in case of non-Gaussian distribution. The Mann-Whitney test was used to compare values with non-Gaussian distribution.
We also evaluated by Kaplan-Meier curves the probability of survival and weaning from PN in relation to the cause of intestinal failure and, in SBS patients, in relation to residual small bowel length and to the presence of an ileocecal valve. Distributions were compared by use of the Mantel-Henzel log rank test. On the basis of Kaplan-Meier curves we assessed when the intestinal failure patients became definitively dependent on PN; in our study these patients were considered affected by irreversible intestinal failure. Differences in survival rate, weaning from PN, continuing PN, and prevalence of irreversible intestinal failure in relation to the cause of intestinal failure and, in SBS patients, in relation to the remaining small bowel length and to the persistence of the ileocecal valve, were evaluated by contingency table (Fisher exact test). All of the tests were 2-sided. In SBS patients, duration of PN was correlated with length of remaining small bowel by Spearman correlation.
The incidence of complications was reported as number of complications per 1000 CVC days, except for patients with IFALD, reported as percentage of the total number of patients. Differences in complication rate in relation to the cause of intestinal failure were evaluated by contingency table (Fisher exact test). P ≤ 0.05 were considered significant.
Ethical Approval and Consent
Ethical approval was obtained from the ethical committee of our hospital.
Cause of Intestinal Failure and PN Characteristics
At the end of the study period, 96 patients (61 male, 35 female), all white, met the inclusion criteria and were therefore included in our study. The whole cohort included 48 SBS patients, 39 SPD patients, and 9 MD patients (Table 1). In the SBS patients, the median value of the remaining small bowel length was 30 cm (range 1–100 cm). Among SBS patients, 59% (n = 28) had residual small bowel less than 40 cm, and 61% (n = 29) had a preserved ileocecal valve. Vascular access was by a Broviac-type catheter in 89 patients (92%) and a port-a-cath in 7 (8%). In the SPD group, the 2 patients with glucose-galactose malabsorption were siblings and of Arab origin; their parents were also consanguineous (first-degree). In the SBS group, 18 (38%) of the patients were premature, with a mean gestational age of 34.6 weeks (range 30.7–35.9 weeks). The total PN duration was 71,080 days. PN was started at neonatal age in 65 patients (68%). The causes of intestinal failure and the underlying disease are detailed in Table 1. Figure 1 shows the duration of PN in relation to the cause of intestinal failure.
Probabilities of survival and weaning from PN in relation to the cause of intestinal failure are shown in Fig. 2. The survival rate was significantly different in SBS patients (81%) from that in the other 2 groups (70% in SPD, 71% in MD). All of the deaths in SPD patients occurred within the first year of life. Significant differences were also found in the percentage of patients remaining definitively dependent on PN: 10% (n = 5) in SBS patients after 39 months of treatment, 9% (n = 4) in SPD patients after 37 months, and 56% (n = 5) in MD patients after 26 months.
In SBS patients, the probabilities of survival and of weaning from PN in relation to length of residual bowel and presence of ileocecal valve, respectively, are shown in Fig. 3. The duration of PN was significantly correlated with length of residual gut (P < 0.03).
As indicated in Fig. 3, the survival rate was 100% in patients whose remaining small bowel length was >40 cm and 74% in patients whose remaining small bowel length was <40 cm (P NS). The residual small bowel significantly influences the dependence on PN: none of the patients with small bowel length >40 cm was definitively dependent on PN, whereas 18% (n = 5) of patients with small bowel length <40 cm remained definitively dependent on PN after 39 months of treatment (P < 0.01).
Regarding ileocecal valve persistence, no significant differences in survival rate or in weaning from PN were found between patients with or without an ileocecal valve. In SBS patients with an ileocecal valve, survival rate and percentage of definitive dependence on PN were 100% and 10%, respectively, after 33 months of treatment; in SBS patients without an ileocecal valve, they were 92% and 17% after 40 months of treatment.
At the study update (December 31, 2006), 22 patients (23%) of the total intestinal failure cohort were still receiving PN. Sixteen (17%) patients had died (direct causes of death are shown in Table 2), 1 patient (1%) had undergone a combined liver/intestinal transplantation, 2 patients (2%) had undergone bone marrow transplantation, and 55 patients (57%) gradually suspended PN within 15 to 30 days and had their oral or enteral feeding increased according to their digestive tolerance and weight gain. Patients weaned from PN were receiving normal oral feeding, except for 2, who were still receiving home enteral nutrition. Among the 22 patients still receiving PN, 10 had been receiving home PN for more than 4 years and 4 for more than 8 years, and they can therefore be considered to have irreversible intestinal failure. In this group, 1 patient with autoimmune enteropathy, who had been receiving PN for more than 4 years, was on a waiting list for bone marrow transplantation. Therefore, 9 of these patients can be considered definitively dependent on PN. The 8 remaining patients had all received PN for less than 4 years. Two of them, both affected by SBS, had been receiving PN for 28 and 31 months, respectively, and had a residual bowel length <20 cm without an ileocecal valve and could therefore be considered definitively dependent on PN. The remaining 6 patients (4 SBS and 2 SPD) were in the process of weaning from PN. Therefore, at the study update, in our series 15 of the 96 intestinal failure patients (16%) were affected by irreversible intestinal failure; of those, 7 had SBS, 3 had SPD, and 5 had MD. PN was provided at least 75% of the total energy units in all patients with irreversible intestinal failure. All of these data are given in Table 1.
In our series we observed a total of 133 complications (1.87/1000 CVC days, mean 0.08/patient/year). The prevalence of catheter-related infections was 0.84/1000 CVC days, and catheter colonization developed in only 3 patients. We observed 10 fungal infections that required catheter removal. The prevalence of thrombosis was 0.25/1000 CVC days. The prevalence of mechanical complications was 0.42/1000 CVC days. Indeed, IFALD was seen in 25 of 96 patients (26%): 11 of 25 patients (44%) resolved liver disease while continuing to receive PN; 8 of 25 patients (32%) died; 1 of 25 patients (4%) underwent a combined liver-small bowel transplantation; 5 of 25 patients (20%) are still affected by liver disease. Over time, all of these patients showed splenomegaly, and 3 of them had portal hypertension diagnosed by ultrasound and echo Doppler. Esophageal varices did not develop in any of them, but 2 of them had gastric bleeding. Among SBS patients, 19 experienced liver complications, with a consequent prevalence of IFALD significantly higher than in the 2 other groups, as shown in Table 1. In this group, liver complications were seen in 15 patients with residual bowel length <40 cm but in only 4 patients with small bowel length >40 cm (P < 0.04; OR 0.2167, CI 0.05765–0.8143).
Although long-term PN is a life-saving treatment for patients with chronic intestinal failure (1,4), many therapeutic options are available to treat and achieve complete intestinal autonomy in these patients, depending on the underlying disease.
In our series, SBS patients received, in association with PN, enteral nutrition with a low-osmolarity solution as soon as their clinical conditions allowed it. (4,27). Pharmacological treatments included broad-spectrum antibiotics, ranitidine, or proton pump inhibitors and oral ursodeoxycholic acid. In autoimmune enteropathy patients, further management options included enteral nutrition with elemental diets and drugs (steroids, immunosuppressors, and antibiotics), sometimes administered in combination. In SFA patients, PN was gradually suspended and oral or enteral feeding with a protein hydrolysate or amino acids solutions was increased according to their digestive tolerance and weight gain. Congenital epithelial diseases and intestinal fibrosis did not require other treatments except for PN, whereas patients with glucose-galactose malabsorption received, after a brief period of exclusive PN, a diet based on fructose, calcium caseinate, and corn oil with vitamin supplementation. The treatment of patients with chronic intestinal pseudo-obstruction consisted of brief periods of enteral nutrition by semielemental diets, antibiotics for the control of intestinal bacterial overgrowth and for the prophylaxis for urinary tract infection if the urinary tract was involved, ranitidine or proton pump inhibitors, and oral ursodeoxycholic acid.
Despite all management strategies, a few of our intestinal failure patients did not achieve intestinal autonomy and remained definitively dependent on PN. In these patients, considered to have irreversible intestinal failure, intestinal transplantation represents the final therapeutic option (1,4). In our study, SBS was the main cause of intestinal failure but not of irreversible intestinal failure, although SBS was worsened by the higher number of liver complications. SPD was the most aggressive cause of intestinal failure in terms of survival rate, and MD was the main contributing cause of irreversible IF.
In SBS patients, morbidity, mortality, and lack of intestinal autonomy are determined by factors including length of remaining small bowel, loss of ileocecal valve, sepsis, and development of IFALD (1,3,4,6,28–33). In our experience, remaining small bowel was a strong predictor of intestinal adaptation, in agreement with previous studies (12,13,28).
Conversely, we did not find that ileocecal valve preservation significantly influenced survival rate and weaning from PN. The relevance of ileocecal valve maintenance on the outcome of intestinal failure is indeed debated. Some studies report that survival and adaptation are more likely to occur in children with an ileocecal valve (3,4,13), although not all studies are in agreement with this (12,28). Also in children with intestinal failure who were referred for intestinal transplantation, the ileocecal valve did not affect survival (9).
In our study, septic complications and IFALD in SBS patients were higher than in the other 2 groups, although statistical significance was not reached for septic complications. The higher number of septic complications could represent a possible cofactor in the etiopathogenesis of IFALD in our SBS patients. The cause of IFALD in intestinal failure patients is multifactorial; important mechanisms in infants include prematurity, length of remaining bowel, and recurrent sepsis (26,34,35); these conditions are often associated with SBS.
In our series, the prevalence of IFALD was 26% in total but 41% in the SBS group, and strongly associated with residual small bowel length. Previous studies of children with intestinal failure have reported a prevalence of cholestasis ranging from 40% to 60% and of chronic abnormalities on liver function tests ranging from 15% to 85% (7,26,36). Some previous reports, in agreement with ours, have described a higher prevalence of IFALD in SBS patients in comparison with other causes of intestinal failure and have concluded that liver disease is less frequently associated with medical causes of intestinal failure than with surgical causes, probably because IFALD is related to gut disease (prematurity and residual small bowel length) rather than to PN management. Unlike our results, a recent article (6) reported a higher prevalence of IFALD in patients with intractable diarrhea than in SBS patients. Differences in SBS selection, such as a higher number of premature infants and a lower average remaining small bowel in our series (36 cm), and differences in the study period evaluated, could justify this discrepancy.
According to previous reports (3,19) and our study, SPD, although associated with brief PN courses in many cases, represented the most aggressive intestinal failure category in terms of death. SPD in infancy is heterogeneous and includes several diseases with different causes, sometimes severe and only partially responding to bowel rest and PN treatment (19). The same survey (19) reported a mortality rate higher than the one indicated in our study in a large series of patients with intractable diarrhea. However, that series (19) selected all of the patients who did not respond clinically to bowel rest and PN treatment and whose cases, therefore, were more severe than ours. In fact, our series included many patients with severe food intolerance who recovered with bowel rest and PN treatment, not only patients with intractable diarrhea, as described in the above-mentioned work (19). In our series, only 1 SPD patient with severe food allergy died, but this patient was also affected by heart failure secondary to heart transplantation.
In our series, MD was the main reason for long-term PN and therefore for irreversible IF. These patients were indeed at major and earlier risk for permanent dependency on PN. We found that in this group the number of patients who did not achieve intestinal autonomy was higher than that indicated in a previous report, which nevertheless considered only patients with chronic intestinal pseudo-obstruction (15). The small sample size of MD patients may represent a limitation in comparing this group of patients with intestinal failure, both with the other 2 groups in our study and with other case series.
With regard to the prevalence of infectious complications, our experience indicates that it is similar to that reported in adult patients, in whom the incidence of infections ranged from 0.3 to 1.3 episodes per 1000 CVC days and, in children, an incidence of septic catheter-related complications varying from 1 to 4 per 1000 CVC days (25). The number of septic complications in our study was lower than that in many pediatric series, which, however, reported the results from a previous study period (3,7,8,28). We can hypothesize that the continuous treatment of these patients has improved their CVC management, lowering the incidence of septic complications. Comparison of different studies is also complicated by the different criteria for classifying CVC sepsis (7,8,12).
Thrombotic CVC occlusions and CVC mechanical complications occurred more frequently in patients with SBS than in patients with intestinal failure from other causes, although the differences were not significant. Complications of intestinal failure required immediate suspension of PN and candidacy for intestinal transplantation in only 1 case, in which a patient had a residual small bowel length of 1 cm and severe liver failure. In all of the remaining patients with intestinal failure, CVC-related complications and liver complications did not require sudden PN suspension and immediate referral for intestinal transplantation.
Some patients in our series showed an evolution toward irreversible intestinal failure that reached a prevalence of 16%. A previous North American survey of patients receiving long-term home PN estimated that approximately 15% to 20% have irreversible intestinal failure (37). As reported in 2 previous pediatric studies (1,3), irreversible intestinal failure, and therefore candidacy for intestinal transplantation, is due also in our experience to medical causes rather than to surgical causes. Only a few patients with intestinal failure from surgical causes remain definitively dependent on PN. Previous data have reported that children with SBS who will remain definitively dependent on PN may represent 10% to 15% of the total (5), in agreement with our results. Our experience also suggests, unlike previously reported data by another Italian group from pediatric patients (6), that intestinal autonomy can be reached in SBS within 3 years of PN from the beginning of the study. Therefore, this period seems to be the limit for defining irreversible intestinal failure in SBS patients.
In conclusion, our study suggests that SPD is different from other causes of intestinal failure in terms of survival and severity of disease, notably during the first year of life. Therefore, it requires careful clinical surveillance because of its potential for early death. The primary disease may predict the probability of weaning from PN. The potential for bowel adaptation is indeed higher in surgical than in medical causes of intestinal failure and does not seem to be influenced by complications of intestinal failure complications. Indeed, SBS, although worsened by the greater number of complications, was not shown to be the main contributing cause of irreversible IF.
The authors thank Prof Oliver Goelet, Director, Gastroenterology Unit of Hospital Necker Enfantes-Malades, and his collaborators for support in the clinical evaluation of the children requiring intestinal transplantation, and Ms Andreina Santoro for help in writing the manuscript.
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