Vidigal, Maria V.M.*; Leite, Heitor P.†; Nogueira, Paulo C.K.‡
Significant developments in enteral formulas during the last several years have made enteral tube feeding the most common method of nutrition support for critically ill patients (1). Nevertheless, the increasing variety of available enteral formulas may increase the risk of inadequate use of these products, especially those conceived for particular situations. Nutritional support with disease-specific formulas may increase the costs 3-fold in an intensive care unit (ICU) (2). It is our observation that in pediatrics, peptide-based formulas are frequently used as an alternative to polymeric ones, despite the absence of scientific evidence of clinical advantages of its use. This replacement is based on theoretical reasons, postulating that there is better absorption of partially digested nutrients under conditions of pathophysiological changes that are common in inflammatory diseases, which are assumed to modify digestive and absorption functions, impairing the use of intact proteins, carbohydrates, and lipids (3,4).
Studies addressing the clinical advantages of using peptide-based formulas in critical illness were carried out in adult patients and the results are controversial (5,6). No recommendations are available on the use of polymeric or peptide-based formulas for pediatric, critically ill patients and, to our knowledge, no pediatric studies on this issue have been conducted. On the basis of the premise that peptide-based formulas are frequently used in critically ill children, the present study aimed to identify the factors that are associated with the choice of these formulas as the first enteral tube feeding prescription in a pediatric ICU (PICU) and to compare the direct costs of the polymeric and peptide-based formulas used.
This was a prospective cohort study carried out in patients admitted from July 2007 to January 2009 to a university-teaching hospital ICU with 8 beds. The study was approved by the research ethics committee of the institution. Patients admitted to the ICU and receiving enteral tube feeding for at least 48 hours were eligible for inclusion. In this ICU, enteral nutrition is initiated in all hemodynamically stable children with an intact gastrointestinal tract, and the patients are studied by a multidisciplinary team composed of pediatric intensivists, dietitians, and physicians specializing in nutrition (7).
For nutritional state classification, the weight-for-age z score was used as the anthropometric indicator for children younger than 2 years, whereas the body mass index was used for children older than 2 years. The data were compared against the reference curve of the World Health Organization 2006/2007. Children with a z score of <−2 of expected weight for age or body mass index were considered malnourished (8,9).
Standard infant formulas and whole-protein pediatric enteral formulas were considered polymeric formulas, whereas infant or pediatric semielemental (peptide-based) and elemental (free amino acid) formulas were considered hydrolyzed formulas (10).
The choice of a peptide-based formula as the first nutritional prescription was considered as the primary outcome variable. Changes in the nutrition prescriptions of each patient were registered throughout the ICU stay.
The following potential exposure variables for the choice of a peptide-based formula as the first nutritional prescription were analyzed: age, sex, nutritional status at admission, medical diagnosis of sepsis and/or septic shock, fasting period before first diet prescription, use of dopamine ≥10 μg · kg−1 · min−1 and/or norepinephrin before initiating first diet, and clinical severity by the revised Pediatric Index of Mortality (PIM2) (11).
The total cost (in 2011 US dollar values) of both polymeric and peptide-based formulas used was compared considering the prices provided by the dietetics and nutrition service of the hospital. Only patients receiving the same type of diet throughout the ICU stay were included in the diet cost comparison.
Sample size was estimated based on the frequency of peptide-based formulas use verified in a pilot study performed in our ICU involving 90 patients. In the pilot sample, we observed 40% peptide-based formula use, and adopting 95% confidence and 80% power, we estimated that 270 patients would be necessary to reveal associations between the independent variables and the outcome. The Mann-Whitney test was used to compare polymeric and peptide-fed group patients. The χ2 test was used for comparison of proportions, and the variables with P < 0.10 in the bivariate analysis were included in a multiple logistic regression model using the stepwise method. In the multivariate analysis, a P value of 5% (P < 0.05) was adopted for rejection of the null hypothesis. Data were expressed as median, maximum, and minimum values. The results are presented as odds ratio (OR) and respective confidence intervals (CI). Statistical analyses were performed using the SPSS for Windows software (version 13.0; SPSS Inc, Chicago, IL).
Of the 552 children admitted to the ICU during the study period, 167 were fasting or received enteral nutrition for <48 hours, 72 received oral feedings only, and 22 were excluded because of incomplete data, giving a total sample of 291 patients. Enteral nutrition was initiated within 2 days of admission for 171 (58.8%) patients. Hydrolyzed formulas were used as the first diet choice for 85 patients (29.21%), 82 of whom were given peptide-based formula with 3 patients receiving free amino acid formula. Patients’ characteristics are shown in Table 1.
The originally prescribed enteral nutrition formula was changed during the ICU stay for 48 patients. Polymeric formulas were replaced by hydrolyzed ones in 32 patients during the course of the ICU stay, and the factors associated were the use of α-adrenergic drugs in 21 patients, abdominal bloating in 5, and diarrhea in 4 patients.
The variables found to be associated with the use of hydrolyzed formulas as the first nutritional prescription in the bivariate analysis were malnutrition, age younger than 11 months, fasting period ≥2 days before first enteral nutrition, PIM2 >5% use of α-adrenergic drugs, and sepsis or septic shock at admission. In the adjusted model of multiple logistic regression, the predictive factors for hydrolyzed formulas prescription were malnutrition, fasting period ≥2 days, and the use of α-adrenergic agents before initiating first diet (Table 2).
The use of hydrolyzed formulas in the first nutritional prescription was associated with higher mortality (OR 3.19, 95% CI 1.54–6.61; P = 0.002), length of ventilation (OR 2.19; 95% CI 1.31–3.68; P = 0.003), and length of ICU stay (OR 1.99, 95% CI 1.19–3.33; P = 0.008) in the univariate analysis. Meanwhile, the frequency of diarrhea was lower for this group of patients. The main characteristics of polymeric versus peptide-based formula-fed patients are shown in Table 3.
The cost of polymeric formulas ranged from US$2.36 to US$18.70/L. In comparison, peptide-based formulas were more expensive: semielemental and elemental formulas costs per liter were US$30.59 and US$92.00, respectively. Overall, the costs of peptide-based formulas were up to 10 times higher than for polymeric formulas.
Peptide-based formulas were prescribed as first enteral nutrition for 29.2% of patients in the present study. The use of peptide-based formulas as the first enteral nutrition prescription was associated with malnutrition at ICU admission, fasting period >48 hours, and the use of α-adrenergic drugs before initiating enteral tube feeding. Late in the ICU stay, prescriptions of polymeric formulas decreased, whereas prescriptions of hydrolyzed formulas increased. This change for hydrolyzed formula was associated with hemodynamic instability of the patients, requiring α-adrenergic drugs, the occurrence of abdominal bloating, and diarrhea. Critically ill malnourished children have higher risk of developing physiological instability, with impairment of digestive function. Thus, in such situations, there is a greater tendency toward intolerance to intact nutrients because intestinal mucosa permeability is increased. A pediatric study has shown that permeability of the intestinal mucosa may be 3 times greater in severely malnourished noncritically ill patients (12); however, there are no studies comparing the efficacy of using intact and hydrolyzed nutrients for malnourished critically ill children.
With regard to the fasting period before initiating nutritional support, it is accepted that the faster the enteral nutrition is initiated, the greater the chances of preventing intestinal permeability changes. Patients with head injuries receiving nutritional support in the first 48 hours of admission have shown better recovery, regardless of the type of formula used (13). During the first 48 hours of admission, treating hemodynamic instability, abdominal bloating, and decreasing α-adrenergic drugs may allow the initiation of enteral nutritional support (14). The use of α-adrenergic drugs may cause intolerance to enteral formula because of changes in gastrointestinal pH and blood flow and in intestinal motility, but the studies that aimed at clarifying this relation have presented different conclusions (15,16). A study in pediatric patients showed that the use of dopamine at doses greater or less than 6 μg · kg−1 · min−1 was not associated with feeding intolerance (17).
Comparison between polymeric and peptide-based formula-fed groups of patients showed that mortality, length of ventilation, and length of ICU stay were higher in the second group of patients. These results are probably related to the greatest clinical severity of the peptide-based formula-fed patients. Diarrhea was less frequent, most likely because with the use of predigested nutrients, little or no digestion is required and the stimulation of bile and pancreatic secretions is minimal. Studies comparing the tolerance to polymeric and hydrolyzed formulas for critically ill adult patients showed that groups of hypoalbuminemic patients receiving hydrolyzed or intact nutrients have shown no differences in feeding intolerance (18). No benefits were verified for adult critically ill patients receiving hydrolyzed formulas composed of amino acids or peptides (19,20). Therefore, in critically ill adult patients, with regard to specific clinical situations, there is a consensus on starting nutritional support with whole-protein formulas because the benefits of peptide-based formulas for such patients are not yet well established (21–23).
Studies on the use of peptide-based formulas in ICUs have been carried out only in adult patients. There is no evidence-based consensus on the use of peptide-based formulas for critically ill children. Nutrition support guidelines for critically ill children have not addressed this specific issue (24). A recent European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition report stated that oligopeptide feeds and elemental feeds may be useful in certain circumstances (eg, in patients with food intolerance or impaired intestinal absorption and/or digestion); however, claims of benefit as opposed to polymeric formulas should be evaluated critically (25). Hence, the rationale is based on the physiopathology of disease.
In the present study, the costs of enteral nutrition with peptide-based formulas were up to 10 times higher than those of polymeric formulas. Feeding critically ill patients with peptide-based or free amino acid formulas may not be efficient, especially considering the substantially higher costs involved compared with the costs of whole-protein formulas. A cost-effective approach is required to make an appropriate choice.
The present study has several limitations. It was a single-center study; therefore, the enteral diet usage pattern could have been different if other ICUs had been included. It is our observation that a similar prescribing pattern is found in PICUs of public teaching hospitals in Brazil, where malnutrition is more common. We have not found data available on the extent to which peptide-based formulas are used in the PICU setting in different countries. Given the prevalence of malnutrition in our ICU, the results cannot be generalized to all ICUs. Therefore, the role of this factor on prescription of peptide-based formulas should be studied in other PICUs in which high prevalence of malnutrition is not expected. As a cohort study, it was not designed to compare different types of diets in terms of tolerance and clinical outcome. This would require a randomized trial with homogenous groups of patients and controlled for variables other than used in the present study; however, to our knowledge, this is the first pediatric study that reinforces the need of establishing criteria for selecting enteral diets in different clinical conditions, which may help toward reducing hospital costs. Our aim was to contribute with an initial diagnosis of this problem and highlight the need to establish specific criteria and guidelines for the use of disease-specific enteral formulations in critically ill children.
In conclusion, the study showed that the choice of peptide-based formulas is associated with the greater severity of patients’ clinical status during the ICU stay. Hydrolyzed diets are prescribed for children receiving α-adrenergic drugs, those who were malnourished and with longer fasting periods. The application of such criteria may help the work of multidisciplinary teams in charge of providing nutrition support for critically ill patients. Nevertheless, it should be emphasized that criteria for indication of peptide-based diets in critically ill children should be substantiated by studies assessing the degree of impairment of intestinal permeability in different clinical conditions. More important, the findings of the present study should indicate the need for prospective randomized controlled trials to test the hypothesis that peptide or amino acid–based formulas have any potential advantages over polymeric diets in critically ill children.
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