Cystic fibrosis (CF) is the most common severe inherited disease in Caucasians, affecting approximately 1/2,500 live births. It is associated with a multisystem disorder affecting the respiratory, gastrointestinal, and genital tracts.
Chronic malnutrition is a well-known complication of CF. Undernutrition and weight retardation are crucial factors affecting the long-term survival and wellbeing of patients (1,2). A variety of mechanisms including anorexia, poor dietary intake, maldigestion or absorption, chronic respiratory infection, and persistent cough contribute to the malnutrition seen in CF patients. Total energy expenditure and basal metabolic rate were found to be increased in CF patients compared to age and sex-matched healthy controls. Moreover, nutritional status and pulmonary function are inversely correlated with energy expenditure and metabolic rate in these patients (3-5). Some patients with malnutrition fail to respond even with optimal multidisciplinary approaches such as appropriate education, dietary advice, optimization of pancreatic enzyme replacement, and intensive treatment of pulmonary exacerbations (6). In these patients, the U.S. CF Foundation consensus recommends early intervention with aggressive treatment (7,8) including the use of total parenteral nutrition (9,10), nasogastric feeding (11), and percutaneous endoscopic gastrostomy feeding (PEG) (12).
Several studies evaluated the effect of gastrostomy feeding in CF patients (8,9,12,13,16,17,19,20). However, only two previous papers studied gastrostomy feeding for more than 1 year (8,13). Rosenfeld et. al. demonstrated a significant improvement in the nutritional status and linear growth of CF patients during 4 years of gastrotomy therapy, however changes in pulmonary function were not evaluated. Recently, Oliver et al (13) demonstrated a decrease in weight for age z-score over 2 years following gastrostomy insertion. Moreover, the same group observed a high mortality rate (30%) during this period.
The aims of this study were to asses the effect of nutritional supplementation via gastrostomy on nutritional parameters, pulmonary function tests, and clinical outcome, and to identify predicting factors for success of long-term nutritional rehabilitation in these patients.
All CF patients in Israel who underwent gastrostomy insertion (n = 25), from 1992 to 2001, comprising 6.25% of all CF patients in Israel, were included in this retrospective multicenter study, which was approved by the medical center's ethical committee. The diagnosis of CF was made by the presence of typical respiratory disease or pancreatic insufficiency together with abnormal sweat test (chloride > 60 mmol/L) or the presence of two CFTR mutations.
Indications for gastrostomy tube insertion were identical in the 4 CF centres involved. All centres adopted the guidelines for nutritional intervention suggested by Ramsey et al (7). The indication for gastrostomy placement included weight/height index consistently below 85% of ideal body weight in 15 patients, and weight loss for more than three consecutive months in 6 patients (patients 4, 5, 10, 18, 19, 20).
Four patients were excluded from the study: two in which the tube was inserted after lung transplantation, 1 because of poor compliance and discontinuation of PEG therapy shortly after PEG insertion, and one because of missing data.
Anthropometric and clinical data including height, weight, complications of gastrostomy placement, number of hospitalizations, and respiratory status as reflected by pulmonary function tests, were obtained for each patient over the following time periods: 0−12 months before, and 6−12 months and 18−24 months following gastrostomy insertion.
In order to assess the effect of compliance on the success of gastrostomy therapy, we divided the patients into two groups - compliers and noncompliers. Compliance was defined based on the patients' compliance with the routine CF care (regular clinic visits, inhalations and other medications, physiotherapy, etc.) prior to gastrostomy placement as reported by the treating physician's report in each center.
For each patient, mean values of height and weight calculated for the following time periods: 0−12 months before placement of gastrostomy, and 6−12 months and 18−24 months following gastrostomy insertion. Changes in the nutritional status were evaluated based on the changes in the body mass index (BMI), calculated as weight in kilograms divided by stature in meters.
Standard deviation scores (SDS), or z-scores, for height, weight, and BMI were calculated on the basis of data on growth in a reference population from the National Center for Health Statistics (NCHS) (Centers for Disease Control and Prevention, Atlanta, GA). The use of SDS for growth status allows for comparison of data obtained at different ages. A z-score of zero corresponds to the 50th percentile, and a z-score of −1.0 indicates 1 SD below the mean, which corresponds to approximately the 15th percentile of the reference population. A positive deviation of the z-score indicates an accelerated weight or height gain (increased growth), while a negative deviation of the weight or BMI z-score indicates a deterioration of the subject's nutritional status.
Percent of height-appropriate body weight was calculated as: measured weight ÷ ideal body weight (IBW) × 100, where ideal body weight was defined as the 50th percentile weight corresponding to the age at which the child's height was the 50th percentile height (14).
Gastrostomy Insertion and Feeding
All procedures were performed in the pediatric intensive care unit or operating room. PEG tube was inserted using a standard pull-through technique (15). Enteral feeding started 24 hours after insertion, the feed was individualized to the patient's requirements and usually provided 40−60% of the recommended daily energy intake. Supplemental feeding was performed overnight, while continuing normal oral nutrition during the day. Most subjects consumed polymeric formulas (Pulmocare, Abbott laboratories, Columbus, OH; Neocate, SHS, Israel; Scandishake, Scandipharm, Israel) that provide 45% of calories from fat, 40% of calories from carbohydrates, and 15% of calories from protein, and some of them used elemental formulas (Neocate, L-Elemental, SHS, Israel). Pancreatic enzyme supplements were administered before night feeding and at the end of the feeding.
Standard CF therapy such as pancreatic enzyme supplementation during the day, vitamins, and antibiotics was not altered.
Nutritional parameters (height, weight, BMI, and their respective z-scores, and percent of IBW) and pulmonary function tests at the three time periods were compared using the paired t-test.
To assess the effect of the degree of compliance on the response to gastrostomy therapy (i.e., changes in height, weight, and BMI), we used the nonparametric Spearman's correlation test.
The effect of age on the response to gastrostomy feeding (i.e. changes in height, weight, and BMI) was studied using the Pearson's correlation test.
Results were considered as significant if the two-sided P value was less than 0.05. Calculations were performed using SPSS 11.0, a software analytical package.
Nutritional and Clinical Characteristics at Gastrostomy Placement
Twenty-one CF patients (11 female), aged 8 months to 20 years, who underwent insertion of a gastrostomy tube were included in this study. Four patients underwent a surgical gastrostomy, while 17 underwent percutaneous endoscopic gastrostomy (PEG) insertion. Patients' characteristics are depicted in Table 1.
The follow-up period following insertion of gastrostomy ranged from 1 to 8 years. However, only data for the first 2 years following gastrostomy placement were analyzed. All subjects were followed for a minimum of 12 months after gastrostomy placement, while 14 subjects were followed for 24 months or longer.
One patient died 18 months following gastrostomy insertion because of end-stage lung disease.
All patients were pancreatic insufficient. Nineteen patients carried severe mutations, while in two patients CFTR mutations were not identified. Specifically, three patients were homozygous to W1282X and 10 were compound heterozygotes for this mutation (Table 1).
At the initiation of gastrostomy feeding, patients were mildly to moderately malnourished: mean weight as a percent of ideal body weight was 84.6% (range: 65% to 105%). Mean height z-score was −1.94 (corresponding to the 3rd percentile), with a range of −4 to 0.72.
Four patients underwent gastrostomy insertion during infancy. One patient (pt. 21) had short bowel syndrome secondary to intestinal resection due to meconium ileus. In the three other patients (patients 11, 13, 14) nutritional failure was initially treated with nasogastric tube feeding, however, because of severe anorexia, long-term treatment was needed, and gastrostomy was inserted.
Pulmonary Function Tests
Fifteen of 16 patients who were capable of performing pulmonary function tests (5 patients were too young) showed moderate to severe obstructive pulmonary defect prior to insertion of gastrostomy. The mean percent-of-predicted forced expiratory volume in 1 second (FEV1) decreased significantly (P = 0.05) during the first year of gastrostomy feeding, from 44.2% (range 25−77%) to 41% (25−67%) (Table 2). However, during the second year of gastrostomy feeding, there was a trend toward improvement in FEV1 from 39.4% (23−62%) to 41.1% (16−65%) (Table 3 and Fig. 1).
Nutritional Effects of Gastrostomy Feeding (Tables 2, 3 and Fig. 1)
Nutritional parameters were expressed as median weight z-score, height z-score, weight as percentage of ideal body weight, and BMI z-score.
Compared with the values recorded during the year preceding gastrostomy placement, weight z-score increased significantly (P = 0.013) during the first year after initiation of gastrostomy feeds, (from −3.05 to −2.52). The patients for whom data was available for 2 years showed a significant (P = 0.026) improvement in weight z-score during the second year as well.
Height z-score for age decreased during the first year of gastrostomy feeding from −1.94 to −2.1 (P = NS) (Table 2). However, a trend toward improvement was observed during the second year of therapy (P = 0.09). The pattern of decrease in height z-score during the first year of therapy followed by a substantial improvement during the second year was even more pronounced in the patients who underwent gastrostomy insertion during infancy (Table 4); however the small number of patients precluded statistical analysis of this subgroup.
BMI z-score increased significantly (P = 0.001) during the first year (from −2.11 to −1.23), with minimal change during the second year. BMI z-score was still significantly (P = 0.006) increased at the end of the second year of therapy in comparison with the baseline.
Similarly, percentage of IBW increased significantly (P = 0.003) during gastrostomy therapy, from 85.8% to 96.5%.
A significant correlation was found between the change in weight z-score and height z-score during both the first (r = 0.488, P = 0.016) and the second (r = 0.825, P < 0.001) year of gastrostomy feedings.
Despite the improvement in the nutritional status of the whole group, there was no difference in the mean number of hospitalizations per year during gastrostomy feeding (2.5 ± 1.3) compared to the year preceding the tube insertion (3.2 ± 1.8).
Predictors of Success of Gastrostomy Feedings
One of our aims was to identify predictors of success of gastrostomy feedings. We hypothesized that better compliance with the therapeutic regimen (regarding medications, clinic visits, physiotherapy, etc.) prior to gastrostomy placement and younger age at the time of gastrostomy placement would be associated with a better nutritional outcome. To test the first hypothesis, we divided the patients into two groups - compliers and noncompliers - based on the treating physician's report. There was no difference between the two patient groups regarding height, weight, and BMI either before the initiation of gastrostomy feedings or after one year of therapy. When we analyzed the effect of age at insertion of gastrostomy, we found a significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016), indicating, in contrast to our hypothesis, a better improvement in height z-score when gastrostomy was inserted at a more advanced age.
Eight of our patients had cystic fibrosis related diabetes (CFRD) (patients 5-8, 10, 16, 19, 20). In two of them (patient 7 and patient 20), CFRD ensued during gastrostomy therapy. There was no difference between diabetics and nondiabetics regarding improvement in either FEV1 values or height, weight, and BMI z-scores during gastrostomy feeding.
There was no difference between males and females in the response to therapy (change in height, weight, BMI, or pulmonary function tests).
Complications of Gastrostomy and Tube Feedings
No major complications were observed in our patients. Four patients (20%), all of whom underwent PEG insertion, had minor complications including local infection (n = 2), abdominal pain (n = 1), and rupture of the gastrostomy tube (n = 1).
New-onset cystic fibrosis related diabetes was observed in 2 patients during the follow-up period.
In the current study, we describe the effect of long-term enteral feeding via gastrostomy tube in 21 Israeli CF patients on respiratory and nutritional parameters. Improving the nutritional status and the course of pulmonary disease in CF patients is extremely important. Previous studies have shown that aggressive nutritional rehabilitation improves (12,16), stabilizes, or slows the rate of pulmonary deterioration (17-20). In the current study, we observed a significant decline in FEV1 (from 44% to 41% of predicted values) during the first year following tube insertion, however, a trend toward improvement in FEV1 was observed during the second year of gastrostomy feeding.
We hypothesize that, since most of our patients showed moderate to severe obstructive ventilatory defect prior to gastrostomy insertion, indicating a marked destruction of lung tissue, their ability to respond to improvement in nutritional status was limited. Furthermore, even during gastrostomy therapy, most of our patients showed recurrent pulmonary exacerbations, which have a large negative impact on FEV1 values (21). During the first year of gastrostomy feeding, there was a 3.2% decrease in mean FEV1, which is somewhat higher than the expected 1.9% decrease per year (22). We hypothesize that this reflects the severity of lung disease in the study population. However, the initial decrease in FEV1 was not accompanied by an increase in the number of hospitalizations or pulmonary exacerbations. In fact, there was a trend toward a decrease in the number of hospitalizations during gastrostomy feeding (2.5 ± 1.3 compared to 3.2 ± 1.8 in the year preceding the tube insertion). Overall, pulmonary function (as reflected by FEV1) was stabilized during 2 years of gastrostomy therapy. Stabilization of FEV1 values indicates an improvement over the natural history of the lung disease in our patients (22). Moreover, because pulmonary function tests improved during the second year of therapy, it is possible that over a longer observation period a further improvement in FEV1 values would be observed.
Studies of protein turnover suggest that malnourished patients are in a chronic catabolic state, which negatively affects the lean body mass and causes a deterioration of respiratory muscle function (23). Lean body mass is the factor that most strongly correlates with FEV1. However, nutritional rehabilitation with weight gain initially increases body fat mass, which has little impact on respiratory muscle function and FEV1 (24,25). This may explain the lack of improvement in pulmonary function tests during the first year of gastrostomy feeding, while the improvement in FEV1 during the second year of therapy may reflect a delayed increase in lean body mass.
Unlike Oliver et al (13) who observed a high mortality rate over 2 years following gastrostomy tube insertion, all but one of our patients survived for at least 2 years following gastrostomy placement, despite similar FEV1 values.
More than half of all CF patients are malnourished (26). Ramsey et al, in a consensus report, stated that there is no reason to accept nutritional failure or impaired growth in any CF patient (7).
During a long observation and treatment period of up to 2 years, we demonstrated a significant improvement in the nutritional status of our patients. Weight z-score increased significantly during both years of follow-up from -3.05 to -2.5. An important finding is the trend toward decrease in the height z-score during the first year of therapy, from -1.94 to -2.1. However, a trend toward improvement in height z-score was observed during the second year of enteral feeding. Furthermore, a positive correlation between weight-gain and height gain was observed during both first and second year of gastrostomy feeding. This is in accordance with previous studies that showed that improvement in weight of CF patients preceded improvement in height percentile for age (8), similar to children with poverty related malnutrition (27,28).
BMI z-score increased significantly during the first year of therapy from -2.1 to -1.23 as well as during the second year. Similarly, weight percentage of IBW increased significantly from 85.8% to 96.5%. BMI has been recommended as the single most useful measure for weight status for healthy adult patients (29). There is a correlation between BMI values and morbidity and mortality in the general population. Poor nutritional status, low BMI, and lean body mass depletion, are important risk factors for morbidity and mortality, especially when accompanying end-stage lung disease, and during the waiting period to lung transplantation (30,31). Furthermore, BMI below the 25th percentile or <17 kg/m2 was found to be a risk factor for mortality during the first 90 days following lung transplantation (32,33).
Despite a specific genotype seen in our patients (W1282X in 48% of our patients) which is associated with pancreatic insufficiency and severe malnutrition, we observed a good response to aggressive nutritional intervention.
One of our aims was to identify predicting factors for success in rehabilitative feeding interventions. We hypothesized that better compliance with the therapeutic regimen (regarding medications, clinic visits, physiotherapy, etc.) prior to gastrostomy placement and younger age at the time of gastrostomy placement would be associated with better nutritional outcome. To test the first hypothesis, we divided the patients into two groups - compliers and noncompliers - based on the treating physician's report. We did not find any difference between the two patient groups in relation to anthropometric measurements either before or following the first or second years of feeding intervention. Patients who were noncompliers prior to gastrostomy placement showed the same degree of improvement in nutritional status compared to compliers. When we analyzed the effect of age at insertion of gastrostomy, we found a significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016), indicating, in contrast to our hypothesis, a better improvement in height z-score when gastrostomy was inserted at a more advanced age. We speculate that since malnutrition is associated with delayed puberty, nutritional rehabilitation in the older patients was associated with induction of puberty, resulting in a growth spurt exceeding the catch-up growth observed in younger patients.
Eight of our patients had CFRD. In two of them, CFRD ensued during gastrostomy therapy. We believe that in these two patients, supplemental feeding might have unmasked a pre-existing carbohydrate intolerance. There was no difference between diabetics and nondiabetics regarding improvement in either FEV1 values or height, weight, and BMI z-scores during gastrostomy feeding.
No major complications of gastrostomy placement were observed in our patients. Four patients (20%) showed minor complications that did not necessitate discontinuation of enteral feeding.
There are several limitations to our study. First, the follow-up period was up to 2 years, which is not sufficient to fully evaluate the effect on linear growth, pulmonary function, and survival, especially in the younger patients. Second, there is a vast variability in patients' ages, which could influence the results. Third, because most of the patients that met the guidelines for gastrostomy placement (7) were treated accordingly, an adequate number of children of the same age, gender, genotype, and weight and height percentiles could not be identified to form a control group. Therefore, our patients were used as their own control. Finally, we did not assess the effect of enteral feeding on quality of life. However, a recent paper showed that patients with CF who underwent PEG reported that they were healthier (77%), and had more energy (59%) after PEG placement, suggesting an improvement in the quality of life (36).
In conclusion, we observed a trend toward improvement in pulmonary disease during the second year following gastrostomy insertion as demonstrated by the pulmonary function tests. Furthermore, a significant improvement was seen in weight, height, and BMI z-scores as well as in the weight percent of IBW. Neither compliance nor young age prior to tube insertion were predictors of success in nutritional rehabilitation.
Aggressive nutritional intervention should be planned individually in correlation to the age, and pulmonary function, and the decision to place the gastrostomy tube should be made on a case by case basis. However, in patients with advanced lung disease who are candidates for lung transplantation, the threshold for gastrostomy tube insertion should probably be lower since maintenance of optimal nutritional status with enteral feeding is imperative in these patients (32-35).
Prolonged, multicenter controlled trials are required to assess the effect of enteral feeding on survival, quality of life, and severity of pulmonary disease before end-stage lung disease develops.
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