This document represents the first collaboration between two organizations, American Society of Parenteral and Enteral Nutrition (ASPEN) and the Society of Critical Care Medicine (SCCM), to describe best practices in nutrition therapy in critically ill children.
Guideline Limitations.These SCCM-ASPEN Clinical Guidelines are based on general consensus among a group of professionals who, in developing such guidelines, have examined the available literature on the subject and balanced potential benefits of nutrition practices against risks inherent with such therapy. A task force of multidisciplinary experts in clinical nutrition composed of physicians, nurses, pharmacists, dietitians, and statisticians was jointly convened by the two societies. These individuals participated in the development of the guidelines and authored this document. These practice guidelines are not intended as absolute policy statements. Use of these practice guidelines does not in any way guarantee any specific benefit in outcome or survival. The professional judgment of the attending health professionals is the primary component of quality medical care delivery. Since guidelines cannot account for every variation in circumstances, practitioners must always exercise professional judgment when applying these recommendations to individual patients. These Clinical Guidelines are intended to supplement, but not replace, professional training and judgment.
The current guidelines represent an expanded body of literature since the publication of the first guidelines in 2009 (1). The guidelines offer basic recommendations that are supported by review and analysis of the current literature and a blend of expert opinion and clinical practicality. Current literature has limitations that include variability in study design, small sample size, patient heterogeneity, variability in disease severity, lack of information on baseline nutritional status, and insufficient statistical power for analysis. The authors of these guidelines acknowledge the scarcity of high-level evidence for nutrition practices in the PICU environment. Most questions addressed in this guideline do not have enough homogeneous, high-quality trials and therefore do not lend themselves to any statistical analyses. A combination of cohort studies and trials, where available, has been summarized and used to develop practical recommendations by consensus. Where randomized controlled trials (RCTs) were not available, observational studies formed the main evidence. Their quality was critically reviewed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology and guided the consensus-derived recommendations (2).
Definitions. Nutrition support therapy refers specifically to the provision of either enteral nutrition (EN) by enteral access device and/or parenteral nutrition (PN). Standard therapy refers to provision of IV fluids, no EN or PN, and advancement to oral diet as tolerated.
Target Patient Population for Guideline. The target of these guidelines is intended to be the pediatric (> 1 mo and < 18 yr) critically ill patient expected to require a length of stay (LOS) greater than 2 or 3 days in a PICU admitting medical, surgical, and cardiac patients. These guidelines are not intended for neonates or adult patients. We believe that neonates are different physiologically from older children, and therefore, these guidelines specifically do not include them. These guidelines are not intended for patients with specific diagnoses such as burn injuries. These guidelines are directed toward generalized patient populations but, like any other management strategy in the PICU, nutrition therapy should be tailored to the individual patient.
Target Audience. These guidelines are intended for use by all healthcare providers involved in nutrition therapy of the critically ill child, primarily physicians, nurses, dietitians, and pharmacists.
The GRADE process was used to develop the key questions and to plan data acquisition and conflation for these guidelines (2). The task force of experts defined keywords to be used for the literature search, developed key questions that address major practice themes at the bedside, and determined the time frame for the literature search, target population, and the specific outcomes to be addressed. Ultimately, questions related to eight major practice areas were developed, which were reviewed and approved by the ASPEN and SCCM boards. These questions and the recommendations are summarized in Table 1. Due to a dearth of well-designed RCTs, many studies addressing these questions and relevant outcomes are either prospective or retrospective observational reports of clinical outcomes associated with a strategy. In some cases, these interventions were protocolized. The evidence provided by these observational studies was strengthened, however, when the effects shown were strong, when the sample size was large, or when there was a dose-response relationship. We used the GRADE criteria to adjust the evidence grade based on assessment of the quality of study design and execution. The GRADE process distinctly separates the body of evidence from the recommendation statements. This separation enables incorporation of the weight of the risks versus the benefits that occur from adopting the recommendation. Thus, a recommendation may be “strong” despite comparatively weak published evidence if the net benefits outweigh the harms from its adoption. Recommendations based mainly on expert opinion were deemed weak. Table 2 describes the standard language and rationale for the grade assigned to a recommendation.
A rigorous search of the Medline/PubMed and EMBASE databases was performed spanning January 1995 through March 2016 for citations relevant to nutrition support in the critically ill pediatric population using the techniques outlined in a recent publication (3). For the Medline portion of the search, Medical Subject Heading (MeSH) folders for “Critical Illness,” “Intensive Care,” and “Critical Care” were searched for relevant citations. To meet our search criteria, these citations had to also be indexed in MeSH folders for “Nutritional Support,” “Malnutrition,” “Nutrition Assessment,” “Energy Intake,” “Energy Metabolism,” or “Dietary Proteins.” To further restrict citations to our chosen population, the terms were cross-referenced in the MeSH folders for “Pediatrics,” “Infant,” “Child,” “Adolescent,” or “Young Adult.” Alternatively, we also accepted citations that had the terms pediatric*, paediatric*, infan*, adolescen*, or child* in at least one of their PubMed/Medline subject fields. Finally, all citations had to be cross-referenced in the “Humans” MeSH folder. The PubMed (non-Medline) database was then searched using text-based terms (Fig. 1). As an added protection against MeSH miscategorization of citations, this text-based search was then used to search the Medline database restricting the search to only yield citations carrying those terms in their title or abstract. For the clinical trials search, the Medline portion was restricted to those citations categorized according to the publication type “Clinical Trials.” For the cohort search, the Medline portion was restricted to those studies cross-referenced in the “Cohort” MeSH folder, whereas the text-based portion was restricted to only those citations that were not indexed according to the publication types “Clinical Trial,” “Review,” “Case Reports,” or “Commentary.” An analogous search strategy focusing only on EMBASE-indexed non-Medline clinical trials was created and implemented for the EMBASE database.
In total, 2,032 citations were scanned for relevance. The PubMed/Medline search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1,661 citations. In total, the search for clinical trials yielded 1,107 citations, whereas the cohort search yielded 925. Each citation was reviewed by at least two reviewers to examine eligibility for inclusion in guideline development. After careful review, 16 RCTs and 37 cohort studies appeared to answer one of the eight preidentified question groups for this guideline. These studies were then reviewed, and the relevant data were abstracted by the authors using a standardized form. After review of the abstracted data, evidence tables were generated for each question. Based on the evidence tables, the authors used an iterative process to develop practical recommendations for each question using the GRADE methodology where applicable and by consensus. The recommendations for questions are summarized in Table 1. The rationale for the GRADE and the language for the recommendations are described in Table 2. Tables 3–10 summarize the evidence in the form of trials and cohort studies related to each of the guideline questions. Each table is followed by a discussion on the rationale for the recommendation(s) and suggested areas for future investigation for the question(s).
The role of nutrition in contributing to the outcomes of patients with critical illness is being increasingly recognized. Since the first pediatric critical care nutrition guidelines (ASPEN) published in 2009, there has been a substantial increase in research and publications related to this subject. The impact of nutritional status and nutrient delivery during critical illness has been demonstrated on clinical outcomes such as mortality, infectious complications, and LOS (4–10). Thus, careful planning and monitoring of nutrient delivery at the bedside is attempted in most ICUs. As more information becomes available from higher quality studies, the field will eventually move toward uniform evidence-based strategies for most nutrition practices in the PICU. However, at present, many questions remain unanswered, and practices are widely variable between institutions and among providers. RCTs, while providing definitive evidence, require tremendous time and resources to complete. Hence, there is a scarcity of RCTs in the pediatric critical care nutrition literature. Furthermore, results of single RCTs in the adult population have often not been replicated in subsequent studies (10–13). Despite these limitations, there have been a number of both small and large studies published over the past decade. Observational cohort and case-controlled studies have provided meaningful information and helped develop hypotheses that can be tested by clinical trials with more robust study designs. Prospective or retrospective cohorts allow measurement of disease occurrence and its association with an exposure by offering a temporal dimension. These studies are described in more detail in relevant sections of this article.
The PICU is unique in terms of the heterogeneity of patients in relation to age, disease type, interventions, comorbid conditions, and presenting nutritional status. It is therefore overly simplistic to expect that one strategy will be applicable to all patients. Nutritional support must be individualized based on the baseline nutritional status and vulnerabilities of patients, anticipated time to volitional feeding, and the risk-to-benefit ratio of intended nutritional therapies. Therefore, the recommendations provided here are useful starting points on which to build customized nutritional therapy for individual patients.
Question 1A. What Is the Impact of Nutritional Status on Outcomes in Critically Ill Children?
Based on observational studies, malnutrition, including obesity, is associated with adverse clinical outcomes including longer periods of ventilation, higher risk of hospital-acquired infection, longer PICU and hospital stay, and increased mortality. We recommend that patients in the PICU undergo detailed nutritional assessment within 48 hours of admission.
Furthermore, as patients are at risk of nutritional deterioration during hospitalization, which can adversely affect clinical outcomes, we suggest that the nutritional status of patients be re-evaluated at least weekly throughout hospitalization.
Quality of Evidence.
Question 1B. What Are the Best Practices to Screen and Identify Patients With Malnutrition or Those at Risk of Nutritional Deterioration in the PICU?
Based on observational studies and expert consensus, we recommend that weight and height/length be measured at admission to the PICU, and z scores for body mass index (BMI)-for-age (weight-for-length, < 2 yr) or weight-for-age (if accurate, height is not available) be used to screen for patients at extremes of these values. In children under 36 months old, head circumference must be documented.
Validated screening methods for the PICU population to identify patients at risk of malnutrition must be developed. Screening methods might allow limited resources to be directed to high-risk patients who are most likely to benefit from early nutritional interventions.
Quality of Evidence.
Malnutrition is prevalent in children admitted to the PICU (6,7,14,15). Although variables used to define malnutrition are inconsistent across reports, both underweight and overweight status have been associated with worse morbidity and mortality (4–6,10). More recently, guidelines to define pediatric malnutrition have become available to facilitate early identification of individuals at risk (16). A uniform approach to define pediatric malnutrition may allow determination of thresholds for interventions aimed at ameliorating nutritional deterioration (17). A large portion of children admitted to PICU is at risk for nutritional deterioration; therefore, periodic nutritional re-evaluation is essential (15,18). Nutritional assessment must include a dietary history, detection of changes in anthropometry, functional status, and nutrition-focused physical examination. A nutrition-focused physical examination in this cohort allows for determination of individualized nutrient needs, interventions, and monitoring to optimize nutrient intake during illness. The subjective global nutrition assessment is correlated with anthropometric variables in one study but has not been shown to predict outcomes in critically ill children (19).
In a limited resource setting, timely and detailed nutritional assessment of every patient in the PICU may not be feasible. A validated method to screen critically ill children for malnutrition risk may help allocate resources to high-risk patients. However, such a screening method is not currently available. The Pediatric Yorkhill Malnutrition Score, the Screening Tool for the Assessment of Malnutrition in Pediatrics, and the Screening Tool for Risk of Impaired Nutritional Status and Growth (STRONGKids) were recently evaluated in 2,567 patients from multiple centers in Europe (20). These screens varied significantly in their ability to identify and classify malnutrition risk and were unable to detect a significant proportion of children with abnormal anthropometrics. The authors concluded that none of these screens could be recommended for use in clinical practice. Admission weight-for-age and BMI-for-age (or weight-for-length in children, < 2 yr) z scores of individual patients in relation to population reference standards have been used to classify patients as undernourished or obese. Admission BMI z scores predicted mortality in a large multicenter cohort of mechanically ventilated children (4). Due to their consistent associations with LOS, duration of mechanical ventilation, and mortality, BMI z scores may be useful to screen for patients at risk of poor outcomes in the PICU (17). Despite the inherent challenges of obtaining accurate anthropometric measurements at admission to PICU, the routine evaluation of weight-for-age and BMI-for-age or weight-for-length z scores must be prioritized. Indeed, in a majority of tertiary centers, documentation of anthropometric measurements at admission is seen as the standard of care.
A validated nutrition screen for timely and accurate identification of malnourished PICU patients is needed. This tool will facilitate allocation of resources, early interventions, and close monitoring of nutritional status in high-risk patients. A uniform definition of malnutrition must be employed, and validated methods for nutritional assessment must be developed and implemented in the PICU. Subsequently, the impact of malnutrition on clinical outcomes in the PICU population should be examined.
Question 2A. What Is the Recommended Energy Requirement for Critically Ill Children?
Based on observational cohort studies, we suggest that measured energy expenditure by indirect calorimetry (IC) be used to determine energy requirements and guide prescription of the daily energy goal.
Quality of Evidence.
Question 2B. How Should Energy Requirement Be Determined in the Absence of IC?
If IC measurement of resting energy expenditure (REE) is not feasible, we suggest that the Schofield or Food Agriculture Organization/World Health Organization (WHO)/United Nations University equations may be used “without” the addition of stress factors to estimate energy expenditure. Multiple cohort studies have demonstrated that most published predictive equations are inaccurate and lead to unintended overfeeding or underfeeding. The Harris-Benedict equations and the Recommended Daily Allowances (RDAs), which are suggested by the Dietary Reference Intakes, should not be used to determine energy requirements in critically ill children.
Quality of Evidence.
Question 2C. What Is the Target Energy Intake in Critically Ill Children?
Based on observational cohort studies, we suggest achieving delivery of at least two thirds of the prescribed daily energy requirement by the end of the first week in the PICU. Cumulative energy deficits during the first week of critical illness may be associated with poor clinical and nutritional outcomes. Based on expert consensus, we suggest attentiveness to individualized energy requirements, timely initiation and attainment of energy targets, and energy balance to prevent unintended cumulative caloric deficit or excesses.
Quality of Evidence.
Metabolic alterations are common in critical illness and patients present with a variety of metabolic states that cannot be predicted, including hypometabolism (measured resting energy expenditure [MREE], < 90% of predicted), normal metabolism (MREE, 90–110% predicted), and hypermetabolism (MREE, > 110% predicted) (21–25). Currently available equations fail to estimate energy expenditure within ± 10% of MREE in a majority of critically ill children; IC is the only available method to accurately determine energy requirements for this population (21,28–33). Energy expenditure measured by IC in critically ill children is independent of nutritional status, initial diagnosis, or severity of the acute illness (30–32,34). MREE may be decreased during deep sedation and neuromuscular blockade, severe hypothyroidism, or increased with temperature greater than 38°C and prolonged PICU LOS (16,30). In cohort studies, MREE did not significantly vary within the same patient over time (21,28,35). After the baseline, MREE is performed (ideally during the first week of critical illness); repeat measurements may be obtained in patients with significant changes in clinical status (27,35). Patients at high risk for metabolic alterations are appropriate candidates for targeted MREE with IC, especially if this resource is limited (Appendix 1).
If IC is not feasible, the Schofield weight-height or weight equations or the WHO equations may be used to estimate energy expenditure (37–39). However, stress factors must be used selectively with caution, as their routine use might result in unintended overfeeding. In recent studies, hypometabolism has been demonstrated in patients after major cardiac surgery, and following hematopoietic stem cell transplantation (25,40,41). When using an equation to estimate energy requirements, it is essential to vigilantly monitor for potential signs of overfeeding (hyperglycemia, hypertriglyceridemia, increased Co2 production, increased arm circumference, and rapid or excessive weight gain) and underfeeding (weight loss, decreased arm circumference, malnutrition, prolonged dependency on mechanical ventilation, and increased length of PICU stay). In particular, equations such as the Harris-Benedict and the RDAs developed for healthy adults and growing children, respectively, over-predict energy requirements and should not be used to determine energy requirements in critically ill children. Because IC is not widely available clinically, and predictive equations are consistently inaccurate, innovative efforts must focus on discovering more accessible surrogates of MREE. A simplified equation based on measured volumetric Co2 (VCo2) was recently developed in mechanically ventilated children and was found to be more accurate than equation-estimated energy expenditure (42,43). The increased use of devices that provide bedside VCo2 measurement in the PICU may allow this equation to replace the Schofield or WHO equations for determination of energy requirement in mechanically ventilated patients.
Observational data suggest a positive association between adequacy of energy intake and improved outcomes in the PICU population (8,36,44). Intake of greater than two thirds of estimated energy goal in a large, multicenter, prospective cohort and greater than 80% of estimated energy goal in a smaller, single-center, retrospective cohort was significantly associated with reduced mortality in mechanically ventilated, critically ill children (8,44). Higher energy intake of 54–58 kcal/kg/d is positively correlated with achieving protein balance and anabolism (36,45). Based on hypometabolic states described in a variety of pediatric illnesses and reduced mortality associated with intake of greater than two thirds of energy goal, achievement of 100% of estimated energy requirement may not be necessary in all patients (8,22,24,40,41).
Future studies must examine the optimal energy dose that is associated with improved nutritional and clinical outcomes in critically ill children. The impact of route of nutrition delivery must be examined when discussing this dose-outcome relationship.
Question 3A. What Is the Minimum Recommended Protein Requirement for Critically Ill Children?
Based on evidence from RCTs and supported by observational cohort studies, we recommend a minimum protein intake of 1.5 g/kg/d. Protein intake higher than this threshold has been shown to prevent cumulative negative protein balance in RCTs. In critically ill infants and young children, the optimal protein intake required to attain a positive protein balance may be much higher than this minimum threshold. Negative protein balance may result in loss of lean muscle mass, which has been associated with poor outcomes in critically ill children. Based on a large observational study, higher protein intake may be associated with lower 60-day mortality in mechanically ventilated children.
Quality of Evidence.
Question 3B. What Is the Optimal Protein Delivery Strategy in the PICU?
Based on results of randomized trials, we suggest provision of protein early in the course of critical illness to attain protein delivery goals and promote positive nitrogen balance. Delivery of a higher proportion of the protein goal has been associated with positive clinical outcomes in observational studies.
Quality of Evidence.
Question 3C. How Should Protein Delivery Goals Be Determined in Critically Ill Children?
The optimal protein dose associated with improved clinical outcomes is not known. We do not recommend the use of RDA values to guide protein prescription in critically ill children. These values were developed for healthy children and often underestimate the protein needs during critical illness.
Quality of Evidence.
Randomized clinical trials of protein supplementation have included small sample sizes, heterogeneous patient populations, use of the enteral, parenteral, or combined routes, and varied protein doses (0.7–5 g/kg/d) in the experimental group. Higher protein doses were associated with positive nitrogen balance, a surrogate for protein balance. These studies evaluated protein turnover and balance by stable isotope-labeled amino acid methods or with urinary urea nitrogen to obtain nitrogen balance (46–53). Variation in the methods used to assess protein balance further limits the interpretation of absolute values. These studies indicate an association between higher protein dose and positive protein balance. In a systematic review of studies in mechanically ventilated PICU patients, a minimum protein intake of 1.5 g/kg/d and a minimum energy intake of 54 kcal/kg/d were associated with achievement of positive nitrogen balance (45). In another cohort study of 76 mechanically ventilated children, a minimum daily threshold delivery of 1.5 g/kg protein and 58 kcal/kg energy was required to achieve a positive nitrogen and energy balance (36). In a recent large, prospective, international, multicenter (n = 59), observational study of 1,245 mechanically ventilated children from 15 countries, a total of 985 subjects received EN; delivery of greater than 60% of prescribed enteral protein goal was significantly associated with decreased 60-day mortality (< 20% vs > 60%; odds ratio, 0.14 [0.04–0.52]; p = 0.003) after adjustment for disease severity, site, PICU days, and energy intake (9). Hence, at the very minimum, a protein intake of 1.5 g/kg/d must be ensured to avoid cumulative protein deficits in critically ill children. The optimal protein intake threshold for infants and young children is likely to be higher than this value. Specific subgroups, such as infants and young children admitted with bronchiolitis or other causes of respiratory failure requiring mechanical ventilation, require 2.5–3 g/kg protein daily to improve protein balance (46,48,51). Protein intake was well tolerated in the above studies. However, the safety of protein intake greater than 3 g/kg/d in children more than 1 month old has not been adequately demonstrated and may be associated with increased blood urea nitrogen. The effect of the route of protein delivery, enteral versus parenteral, on clinical outcomes is unclear. In particular, the role of early parenteral protein intake has not been shown, and most studies demonstrating the benefits of higher protein intake have utilized the enteral route.
Current evidence for increased protein dosing in critically ill children exceeds RDA recommendations and recommendations from WHO. These recommendations are calculated estimates from derived equations of protein deposition in healthy children and do not account for the increased protein breakdown that occurs during critical illness (9,36,39). The use of RDA recommendations to guide protein intake during critical illness may lead to unintended negative protein balance. The determination of protein requirements for obese patients in the PICU may be challenging. The recommendation of a minimum of 1.5 g/kg/d should also be applied to this population, using their ideal body weight. This population is at risk of undetected lean body mass erosion. A reliable method to monitor the body composition for the critically ill pediatric population, particularly obese children, is needed to better address their optimal macronutrient needs.
Future studies are needed to determine the optimal dose of protein that improves protein balance, nutritional status (e.g., muscle mass and function), and relevant clinical outcomes (e.g., duration of mechanical ventilation, PICU LOS, and mortality). Future studies must also examine the effect of specific protein sources and the route of delivery on outcomes.
Question 4A. Is EN Feasible in Critically Ill Children?
Based on observational studies, we recommend EN as the preferred mode of nutrient delivery to the critically ill child. Observational studies support the feasibility of EN, which can be safely delivered to critically ill children with medical and surgical diagnoses, and to those receiving vasoactive medications. Common barriers to EN in the PICU include delayed initiation, interruptions due to perceived intolerance, and prolonged fasting around procedures. Based on observational studies, we suggest that interruptions to EN be minimized in an effort to achieve nutrient delivery goals by the enteral route.
Quality of Evidence.
Question 4B. What Is the Benefit of EN in This Group?
Although the optimal dose of macronutrients is unclear, some amount of nutrient delivered as EN has been beneficial for gastrointestinal mucosal integrity and motility. Based on large cohort studies, early initiation of EN (within 24–48 hr of PICU admission) and achievement of up to two thirds of the nutrient goal in the first week of critical illness has been associated with improved clinical outcomes.
Quality of Evidence.
The enteral route is the preferred modality to provide nutrition support to adults and children. Animal studies have demonstrated the beneficial effects of EN on gut-associated lymphoid tissue, mucosal immunity, and improved survival after Escherichia coli–induced peritonitis and brief intestinal ischemia (56–60). Early initiation of EN is preferred in most PICUs. However, a variety of challenges impedes early initiation and maintenance of EN in children during critical illness (61,63). Many of these perceived barriers to EN may be avoidable (61). In large cohorts of patients on vasoactive medications in the PICU, EN was administered without any significant adverse events (64,65). Although the physician decision to start EN in patients may have been biased by the clinical condition of the patient, gastrointestinal complications (vomiting, diarrhea, bleeding, and abdominal distension), other severe feeding-related complications, or mortality were not increased in the group who received vasoactive medications (65).
Cohort studies of children admitted to the PICU have reported improved survival with optimal nutrient intake by the enteral route. In two large international prospective cohort studies of mechanically ventilated children, enteral delivery of greater than two thirds of the energy goal and greater than 60% of the protein goal was significantly associated with lower 60-day mortality (8,9). These benefits were not seen for nutrients delivered via the parenteral route. In a large, retrospective, multicenter study of 5,105 patients from 12 centers, the provision of one-fourth goal calories enterally over the first 48 hours of admission was associated with reduced PICU mortality (66). In another retrospective cohort of 107 children with acute respiratory distress syndrome, enteral delivery of adequate calories (≥ 80% estimated goal) and protein (≥ 1.5 g/kg/d) was associated with a reduction in ICU mortality (44). Hence, EN is feasible during acute critical illness and must be prioritized as the preferred route for nutrient delivery.
Future studies evaluating the feasibility of EN in critically ill children should examine its impact on well-defined outcomes. Higher quality randomized study designs should evaluate the benefits of providing adequate EN with predefined energy and protein goals.
Question 5A. What Is the Optimum Method for Advancing EN in the PICU Population?
Based on observational studies, we suggest the use of a stepwise algorithmic approach to advance EN in children admitted to the PICU. The stepwise algorithm must include bedside support to guide the detection and management of EN intolerance and the optimal rate of increase in EN delivery.
Quality of Evidence.
Question 5B. What Is the Role of a Nutrition Support Team or a Dedicated Dietitian in Optimizing Nutrition Therapy?
Based on observational studies, we suggest a multidisciplinary nutrition support team, including a dedicated dietitian, be available on the PICU team, to facilitate timely nutritional assessment, and optimal nutrient delivery and adjustment to the patients
Quality of Evidence.
Despite the preference for the enteral route for nutrition delivery and benefits reported by many authors, the practice of providing EN to critically ill children is variable. There is no uniform approach to initiate and advance EN. A stepwise protocol/algorithm is expected to address barriers to EN such as prolonged interruptions due to procedures, lack of a clear definition of feeding intolerance, and management of mechanical issues with feeding tubes, among others. The use of feeding protocols is considered safe and in individual centers has been effective in optimizing nutrient delivery without increasing the risk of other complications (70–72). In an international multicenter cohort study, nine of the 31 participating PICUs reported the use of an EN algorithm (73). These algorithms defined the rate of EN advancement, recommended nutrition screening and fasting guidelines, and most centers defined intolerance by some threshold of increased gastric residual volume (GRV). Despite being commonly measured in many PICUs, the accuracy of GRV as a marker of delayed gastric emptying has been recently challenged in both adult and pediatric intensive care populations (55, 74). Measurement of GRV has not been correlated with risk of aspiration in adult studies, and it is no longer recommended in the recent adult critical care nutrition guidelines (75,76). In a recent single-center study of children eligible for EN initiation in the PICU, measured GRV did not correlate with delayed gastric emptying or with the ability to rapidly advance EN (55). The threshold volume used to define increased GRV in the PICU is variable (73,77). In the absence of pediatric trials, we cannot recommend discontinuing GRV measurement in the PICU, but the role of this practice is not clear and might impede EN advancement. Several studies have reported rapid advancement of EN and achievement of nutrient delivery goals by a stepwise algorithmic approach (70,71,78). The use of EN algorithms/protocols has been associated with decreased time to initiation of EN, increased EN delivery and decreased reliance on PN, and increased likelihood of achieving nutrient delivery goals (70,72,79).
Presence of a dedicated multidisciplinary nutrition team in the ICU guides the timely initiation and management of nutrition support. It is suggested that the composition of the team includes personnel knowledgeable and experienced in pediatric critical care, pediatric nutrition, and nutrition support therapy. Dedicated dietitians support sound nutritional practices such as timely assessment and documentation of nutritional status, development of an optimal nutritional prescription, serial follow-up, and monitoring for safe nutrient delivery are some of the responsibilities of a PICU dietitian (80). In a multicenter, observational cohort study of 31 PICUs, a majority of the centers (93%) reported presence of a dedicated dietitian for an average of 0.4 full time equivalents per 10 beds (8). In a subsequent larger multicenter study of 59 PICUs, presence of a dedicated dietitian was a significant and independent predictor of adequate enteral protein intake (9). Hence, dietitians are essential members of the multidisciplinary care team in the PICU. It is important to develop a seamless transition of nutrition care plan as patients move across the continuum of pediatric ward to the ICU and back.
Future studies must clarify the evidence to inform stepwise decision making in the EN algorithms. These steps include selection of gastric versus postpyloric tube feeding, clear and practical definitions of feeding intolerance (e.g., reflux, vomiting, constipation, diarrhea, and malabsorption), and the role of adjuncts such as prokinetic, antiemetic, antidiarrheal, acid suppressive, and laxative medications. In particular, the practice of measuring GRV as a marker of EN intolerance in the PICU population must be challenged. Future studies examining the role or the optimal threshold of GRV to guide EN delivery are desirable. In addition, prospective trials are needed to show the benefit of algorithmic EN advancement and dietitian interventions on important nutritional and clinical outcomes.
Question 6A. What is the Best Site for EN Delivery - Gastric or Small Bowel?
Existing data are insufficient to make universal recommendations regarding the optimal site to deliver EN to critically ill children. Based on observational studies, we suggest the gastric route be the preferred site for EN in patients in the PICU. The postpyloric or small intestinal route for EN may be used in patients unable to tolerate gastric feeding or those at high risk for aspiration. Existing data are insufficient to make recommendations regarding the use of continuous versus intermittent gastric feeding.
Quality of Evidence.
Question 6B. When Should EN Be Initiated?
Based on expert opinion, we suggest that EN be initiated in all critically ill children, unless it is contraindicated. Based on observational studies, we suggest early initiation of EN, within the first 24–48 hours after admission to the PICU, in eligible patients. We suggest the use of institutional EN guidelines and stepwise algorithms that include criteria for eligibility for EN, timing of initiation, and rate of increase.
Quality of Evidence.
Gastric feeding is physiologic and is the preferred EN route for critically ill children, unless the child has perceived or demonstrated risks of aspiration of gastric contents into the tracheobronchial tree. The use of small intestinal (postpyloric) feeding in two small RCTs did not demonstrate reduced aspiration when compared with gastric feeding (81,82). The postpyloric route was associated with higher proportion of goal nutrition delivery in one study (82), but a delay in the initiation of nutrition via the postpyloric route in a second study (81). The provision of EN into the small bowel requires the placement of a feeding tube past the pylorus. This can be accomplished by several methods but requires time and expertise and incurs higher costs. In a single-center study, mechanical problems with postpyloric tubes led to frequent EN interruptions and failure to achieve delivery of goal nutrients (61). In centers with the necessary expertise and resources to successfully place postpyloric feeding tubes, this route may be used with caution to improve nutrient delivery. Gastric feeding has been administered to critically ill children either as a continuous or intermittent modality. In two RCTs comparing continuous versus intermittent gastric feeding, authors reported no differences in EN tolerance (77,83). Single-center, observational studies have demonstrated the feasibility of postpyloric EN in cohorts of critically ill children with a higher prevalence of EN intolerance such as those with shock and acute kidney injury (84,85).
Wide variability in the definition of early EN in the critically ill child has been reported in the published literature. A majority of the studies have described initiation as early as 6 hours and as late as 48 hours after admission to the PICU (66,71,89). In a multicenter study of nutrient delivery in the PICU, early EN, defined as delivery of one quarter of cumulative goal enteral energy over the first 48 hours, was associated with a survival benefit (66). In a multicenter retrospective examination of EN initiation in the PICU, feeding was delayed more than 48 hours from admission in 20% of the patients (89). Positive-pressure invasive and noninvasive ventilation, procedures, and gastrointestinal disturbances were common risk factors associated with delayed EN. The use of stepwise protocols or guidelines for EN delivery in the PICU has been associated with significant reductions in the time to start EN (71,78).
Future, large-scale RCTs should evaluate the benefits of gastric versus small bowel feeding, early compared with delayed EN (< 24 vs ≥ 48 hr), and bolus/intermittent versus continuous gastric feeding. These studies must have clear definitions of EN delivery targets and intolerance and must include important clinical outcomes including hospital-acquired complications, PICU and hospital LOS, and duration of mechanical ventilation.
Question 7A. Is There a Role for Early PN Initiation in Critically Ill Children?
Based on a single RCT, we do not recommend the initiation of PN within 24 hours of PICU admission.
Quality of Evidence.
Question 7B. What Is the Role and Optimal Timing of PN Initiation as a Supplement to Inadequate EN?
In children tolerating EN, we suggest stepwise advancement of nutrient delivery via the enteral route and delaying commencement of PN. Based on current evidence, the role of supplemental PN to reach a specific goal for nutrient delivery is not known. The time when PN should be initiated to supplement insufficient EN is also unknown. The threshold for and timing of PN initiation should be individualized.
Based on a single RCT, supplemental PN should be delayed until 1 week after PICU admission in patients with normal baseline nutritional state and low risk of nutritional deterioration. Based on expert consensus, we suggest PN supplementation in children who are unable to receive any EN during the first week in the PICU. In patients who are severely malnourished or at risk of nutritional deterioration, PN may be supplemented in the first week if they are unable to advance past low volumes of EN.
Quality of Evidence.
As previously discussed, EN is the preferred route of nutrition support in the critically ill child; however, PN should be considered when EN is not feasible or is contraindicated. The use of PN as a supplement to EN, timing of supplemental PN initiation, and the targeted macronutrient goal are key questions that will require an evidence-based approach. Unfortunately, there is little evidence to guide these practices. In a recent three-center RCT (PEPaNIC trial) addressing timing of supplemental PN in critically ill children, the group with late initiation of PN (on day 8) demonstrated better outcomes (fewer new infections and shorter length of PICU stay) compared with the early PN group (receiving PN within 24 hr of admission) (90). Also, the late PN group was likely to have an earlier live discharge from the PICU, shorter duration of mechanical ventilation, and lower odds of renal replacement therapy.
The finding that can be strongly generalizable from this study is that PN should not be started within 24 hours of PICU admission. For reasons outlined below, we recommend caution in broadly applying the delayed PN strategy (8 d until initiation) used in the control group of this study. Children in this study received significant enteral calories: mean of 30 kcal/kg/d (300 kcal/d) by day 4. It is possible that most of these children could have been sustained enterally using a robust EN protocol (70,71). Children in this study were discharged at rates that are standard in most PICUs: 50% left the PICU by day 4 and 74% by day 8. As only 24% of the late PN cohort was exposed to PN, the intervention arm of the trial was more representative of a “no PN” strategy. Again, this supports the conclusion that initiation of PN within the first 24 hours of admission is not advisable as a general strategy in the PICU.
Our expert consensus is that PN should not be withheld until day 8 as a universal strategy in critically ill children. Because most children were receiving significant amounts of EN, the results of the PEPaNIC trial should not be extrapolated to children receiving no EN. The proportion of severely malnourished children in the study is unclear and likely to be low. The nutritional assessment/screening tool used in the study (STRONGkids) has not been validated in critically ill children, and its accuracy in hospitalized children has been questioned (20). Also, BMI z scores of patients in the study suggest that most children were well nourished at PICU admission. Therefore, the results cannot be extrapolated to severely malnourished children or those at risk of malnutrition who may not tolerate a week of cumulative nutrient deficit accrued by the late PN strategy. Finally, other vulnerable groups such as children admitted to the PICU with contraindications to EN, intestinal failure, or requiring extracorporeal membrane oxygenation often rely on PN to meet nutrient needs. In these subgroups, the optimal timing of PN to supplement or replace EN as the mode of nutrient delivery will need to be determined by future trials.
The PEPaNIC investigators chose an EN energy delivery threshold of less than 80% goal, to trigger supplemental PN at the two time points. A majority of children in this study had energy expenditure estimated using equations that have been discredited in critically ill children (refer to Recommendations and Rationale for Question 2B). Hence, it is possible that a significant portion of children in the early PN arm of this study were over-fed. In addition, glycemic control protocols were different in each of the three centers. Multiple problems exist with one of the primary outcomes in this study, new infections acquired during the ICU stay. The investigators used nonstandard definitions of acquired infections such as ventilator-associated pneumonia and catheter-related blood stream infection (BSI). The presence of indwelling devices such as central venous catheters in the two groups was not reported. It is not clear how the investigators distinguished between an infection present at baseline from a new infection.
The role of PN initiated from 2 to 7 days in the PICU cannot be determined by this study, and the findings of this study need to be confirmed by future RCTs. Until then, EN should be initiated and actively advanced in eligible children in the PICU. The optimal timing of supplemental PN in children failing to meet their nutrient delivery goals enterally must be individualized based on the nutritional and clinical status of the patient, and anticipated nutrient deficits during the course of illness.
Future studies should focus on determining the optimal timing for PN supplementation in cases where EN is insufficient to meet the nutritional requirements during the first week of critical illness. These trials must account for the varying baseline nutritional status of patients and their individualized energy and protein goals.
Question 8. What Is the Role of Immunonutrition in Critically Ill Children?
Based on available evidence, we do not recommend the use of immunonutrition in critically ill children.
Quality of Evidence.
Several dietary components, including glutamine, arginine, nucleotides, omega-3 fatty acids, fiber, antioxidants, selenium, copper, and zinc, have been used in various combinations to modulate dysregulated immune responses induced by critical illness, injury, and surgery. The aim is to achieve a therapeutic benefit, such as to attenuate inflammation or provide nutrients depleted by stress. Terms used to describe this therapy include immunonutrition, immunonutrients, immunonutrient-enhanced diet, immune-enhancing nutrition, immune-modulating nutrition, pharmaconutrition, pharmaconutrients, and pharmaceutical nutrients. RCTs comparing immunonutrition to standard nutrition in critically ill children have used a variety of nutrients, delivered using the enteral or parenteral route, in heterogeneous populations, and using different methods to estimate energy needs. In some studies, a combination of interventions has been studied; therefore, the impact of any single immunonutrient is difficult to interpret. In one pilot RCT and one retrospective cohort, investigators examined the use of an enteral formula containing omega-3 fatty acids, gamma-linolenic acid, and antioxidants in critically ill children with acute respiratory distress syndrome (91,92). Although the specialty formulae were feasible and tolerated in these studies, neither study was powered to show difference in outcomes. Other small, single-center studies randomizing critically ill children with respiratory failure, septic shock, and traumatic brain injury to an enteral formula containing glutamine, arginine, antioxidants, fiber, and omega-3 fatty acids, or a standard pediatric formula were also underpowered and unable to demonstrate outcome differences (93,94). In two studies, infants requiring PN were randomized to receive IV lipid emulsion as omega-3 fatty acids, either alone or in combination with medium- and long-chain (omega-6) fats, or a 100% soybean oil-based lipid (omega-6) (95,96). These studies were designed to evaluate the effects of the two lipid formulations on inflammatory biomarkers; relevant clinical outcomes for critically ill children were not evaluated. Lipids containing omega-3 versus 100% omega-6 fatty acids were associated with lower plasma pro-inflammatory cytokines and potential for reduced ICU LOS (97). Clinical outcomes of critically ill children requiring PN randomized to receive parenteral glutamine did not differ from those administered standard PN (98). In a comparative effectiveness trial, critically ill children requiring mechanical ventilation and EN were randomized to receive enteral supplementation of a combination of glutamine, zinc, selenium, and metoclopramide, or whey protein (100). The study was terminated for futility at a planned interim analysis after enrollment of 293 patients. No differences in PICU LOS, duration of mechanical ventilation, infections, or mortality were demonstrated. However, in a small subgroup of immunocompromised children, a significant reduction in nosocomial infections was seen with the study intervention compared with whey protein (1.57 vs 6.09; p = 0.011). No two trials of immunonutrients in children are similar, and none demonstrated superiority of immunonutrition versus standard nutrition in critically ill children in terms of clinical outcomes.
Prior studies in critically ill adults have demonstrated reduced hospital LOS and mortality with glutamine-supplemented PN (101). Based on these observations, in a recent large multicenter two-by-two factorial trial of mechanically ventilated, critically ill adults with multiple organ failure, patients were randomized to glutamine, antioxidants, both, or placebo (102). A significant increase in hospital and 6-month mortality and a trend toward increased 28-day mortality were seen in the group receiving glutamine. A subsequent multicenter trial of critically ill mechanically ventilated adults showed no infectious benefits and possibility of harm with a significantly higher 6-month mortality in medical patients randomized to a formula containing glutamine, omega-3 fatty acids, and antioxidants versus a standard high-protein formula (103). Arginine supplementation has been considered to improve immune function and wound healing in critically ill patients but has demonstrated increased mortality in septic patients (104). The 2016 critically ill adult nutrition support therapy guidelines recommend that immunonutrition not be used in critically ill septic or medical patients but may be considered in those who are perioperative, or have traumatic injuries (75). Due to the potential harm of glutamine and arginine supplementation in adults and the paucity of pediatric data, immunonutrition cannot be currently recommended in critically ill children.
Future trials should examine the role of immunonutrition in select populations, such as immunocompromised and malnourished critically ill children, with standardized clinical interventions and therapies to avoid confounding results. These studies need to define immunonutrition and specific populations where it might be tested. In addition, studies are needed to identify the optimal route of immunonutrient delivery.
In this article, we have provided guidelines for some of the important steps in the provision of optimal nutrition to the critically ill child. We selected key questions for this version of the guidelines, but we are aware that some of these and several other questions remain unanswered and will require systematic investigation. A majority of the recommendations in these guidelines are driven by consensus or low-level evidence. We hope that our systematic search strategy, followed by meticulous data abstraction, has allowed us to capture all the relevant studies. The process of converting a broad variety of evidence levels to meaningful and practically applicable recommendations is challenging. These recommendations provide a starting point from where the nutritional strategy for individual patients can be customized. The guidelines reiterate the importance of nutritional assessment, particularly the detection of malnourished patients who are most vulnerable and therefore potentially may benefit from timely nutritional intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to cumulative energy imbalance. IC must be used to guide energy prescription, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended in its absence. Optimal protein dose and its correlation with clinical outcomes is an area of great interest. The optimal route and timing of nutrient delivery is an area of intense debate and investigations. EN remains the preferred route for nutrient delivery. Several strategies to optimize EN during critical illness have emerged. The role of supplemental PN has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualize nutrition support with the aim of improving clinical outcomes is necessary. We have summarized key areas for future investigations, which will guide us in developing the next level of evidence-based nutrition therapy in the future. Until then, multidisciplinary collaborative efforts must continue to prioritize and highlight the unique and dynamic nutritional needs of the critically ill child in the complex PICU environment.
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APPENDIX 1. Targeted Indirect Calorimetry (31)
Children who are at high risk for metabolic alterations are suggested candidates for targeted measurement of resting energy expenditure using indirect calorimetry (IC) in the PICU:
- Underweight, overweight, or obese
- Children with more than 10% weight change during ICU stay
- Failure to consistently meet prescribed energy goals
- Failure to wean or need to escalate respiratory support
- Neurologic trauma (traumatic, hypoxic, and/or ischemic)
- Oncologic diagnoses (including children with stem cell or bone marrow transplant)
- Children with thermal injuries or amputations
- Children requiring mechanical ventilatory support for more than 3 days
- Children suspected to be severely hypermetabolic (status epilepticus, hyperthermia, systemic inflammatory response syndrome, dysautonomic storms, etc.) or hypometabolic (hypothermia, hypothyroidism, pentobarbital or midazolam coma, etc.)
Any patient with ICU stay more than 4 weeks may benefit from IC to assess adequacy of energy intake.