Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review

Clinical Nutrition ESPEN xxx (2017) e1ee8

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Review

Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review Mervin Loi a, *, Justin Wang b, Chengsi Ong c, Jan Hau Lee d, e a

Pediatric Intensive Care Unit, Bristol Royal Hospital for Children, Paul O'Gorman Building, Upper Maudlin Street, Bristol BS2 8BJ, United Kingdom Pediatric Intensive Care Unit, Birmingham Children's Hospital NHS Trust, Steelhouse Lane, Birmingham B4 6NH, United Kingdom c Department of Nutrition and Dietetics, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore d Children's Intensive Care Unit, Department of Pediatric Subspecialties, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore e Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore b

a r t i c l e i n f o

s u m m a r y

Article history: Received 28 January 2017 Accepted 7 February 2017

Acute Respiratory Distress Syndrome (ARDS) continues to be associated with significant morbidity and mortality. Optimization of nutrition remains a significant challenge in these patients. The role of nutrition in supporting convalescence and modulating the disease process has attracted much research attention. While there are similarities in ARDS phenotype between children and adults, there are also significant differences in causation, metabolic responses and outcomes. This review aims to critically evaluate the available evidence for various nutritional practices in managing children and adults with ARDS, and to summarize and compare the recommendations by expert bodies. There is conflicting evidence regarding the target caloric intake in ARDS. The use of predictive equations for the estimation of resting energy expenditure in ARDS patients remains inadequate. The gold standard of indirect calorimetry is costly and labor intensive, and may not be as accurate in intubated patients with high oxygen requirements. Whilst overfeeding should be avoided, early enteral feeding should be encouraged. There is no evidence of benefit in early commencement of parenteral nutrition in children and adults with ARDS. Further studies are needed to inform nutritional practice in patients with ARDS, particularly in children, where there remains a paucity of clinical studies. Crown Copyright © 2017 Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Respiratory distress syndrome Acute lung injury Nutrition support Immunonutrition Critical illness

1. Introduction Originally described by Ashbaugh et al. in 1967, acute respiratory distress syndrome (ARDS) continues to be a significant healthcare burden in critically ill patients [1,2]. Despite interventions such as low tidal volume ventilation and improved supportive management strategies, mortality remains high from the condition [3]. Malnutrition is prevalent in both critically ill adults [4] and children [5]. Poor nutrition is associated with worse respiratory muscle function [6], increased susceptibility to infections [7] and mortality [8]. Consequently, there has been much interest in investigating whether optimizing nutrition in ARDS might lead to improvement in clinical outcomes. * Corresponding author. Bristol Royal Hospital for Children, Paul O'Gorman Building, Upper Maudlin Street, Bristol BS2 8BJ, United Kingdom. E-mail address: [email protected] (M. Loi).

In this review, we critically evaluate the available evidence for caloric targets, protein provision, as well as enteral and parenteral nutrition (PN) in patients with ARDS. In addition, we consider the physiological differences between children and adults, and relate this to why nutritional strategies should be tailored to different patient groups. Where available, we therefore also compare the current consensus recommendations by specialist nutrition societies. The topics of immunonutrition and specialized formulas/ nutrition additives are beyond the scope of this review and we refer the reader to other excellent reviews in these topics [9
14].

2. Methods We searched for publications in PubMed using the following MeSH headings: “nutritional status” OR “nutrition” OR “nutritional sciences” AND “acute respiratory distress syndrome” OR “acute

http://dx.doi.org/10.1016/j.clnesp.2017.02.005 2405-4577/Crown Copyright © 2017 Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

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lung injury”. We did not limit our search by publication type, but limited our search to English publications and human studies. We hand-searched review articles on ARDS to include additional publications not captured in the initial search. The most recent recommendations by the following specialist groups were compared: American Society for Parenteral and Enteral Nutrition (ASPEN, 2009, 2016), Society of Critical Care Medicine (SCCM, 2016) the European Society for Clinical Nutrition and Metabolism (ESPEN, 2006, 2009); European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN, 2005); the Pediatric Acute Lung Injury Consensus Conference (PALICC, 2015); and the Canadian Critical Care Practice Guidelines (CCPGs, 2015). 2.1. How the acute metabolic response and pathophysiology of ARDS differs between children and adults The pathophysiology of ARDS, though not completely clear, is associated with the presence of pro-inflammatory cytokines and apoptosis activators, which are thought to play a role in alveolar epithelial damage [15,16]. The diagnosis, progression and outcomes of ARDS in adults are different from children, suggesting differences in pathophysiology and response to the illness [17]. Indeed, adults and children appear to differ in their metabolic response to critical illness. During acute critical illness, adults have been shown to undergo a brief hypometabolic “ebb” phase, followed by a hypermetabolic “flow” phase after fluid resuscitation [18]. The “flow” phase, which typically occurs around day 2 of injury, is characterized by the production of inflammatory cytokines, and a rise in body temperature and respiratory rate [19]. A more detailed review of this metabolic response has been published elsewhere [20]. Briefly, rapid catabolism occurs and energy expenditure increases proportionally to the degree of inflammation [21], although this may be altered by the use of interventions such as cooling [22,23]. Protein catabolism appears to be significant in critical illness in adults, resulting in acute skeletal muscle wasting [24]. It is hypothesized that rapid breakdown of skeletal muscle occurs to provide substrates for production of inflammatory cytokines and gluconeogenesis [25]. Resistance to anabolic hormones such as insulin also occurs, and together with increased gluconeogenesis, often results in stress hyperglycemia [20]. In adults with ARDS, muscle catabolism leads to muscle wasting that eventually results in prolonged functional impairment in survivors [26]. Children, on the other hand, appear to have a different metabolic response during critical illness. Healthy children, unlike adults, have a significant energy and protein requirement for growth and tissue deposition. During critical illness, it is hypothesized that energy for growth is redirected for tissue repair and sustaining organ function [27]. As a result, children who are sedated and supported on mechanical ventilation (MV) do not necessarily demonstrate increased energy requirements [28]. However, like in adults, protein catabolism has shown to be elevated in critically ill compared to healthy children. Whole body protein turnover studies using isotope tracers demonstrated increased protein turnover and a net negative balance in critically ill children compared to healthy controls [29]. Notably, these studies were not specific to children with ARDS, and the catabolic effects of ARDS on functional outcomes have not yet been well described in children. Nevertheless, the presence of different metabolic states indicates the need for nutrition therapy to be tailored to each phase. One difficulty, however, lies in the identification of which phase a patient is in, and when the transition between phases occurs. 2.2. Caloric intake and protein provision Caloric and protein malnutrition is common in critically ill patients [4,5]. Inadequate energy intake has previously been shown to

be associated with increased mortality [8,30], and respiratory muscle dysfunction [6], leading to prolonged dependence on MV and increased susceptibility to infection [7]. This association between malnutrition and increased morbidity [31] and risk-adjusted mortality [32] has also been observed in critically ill children. Nutritional management in critical care has therefore been traditionally centered on ensuring that patients are kept as nutritionally replete as possible. However, more recent studies have called these assumptions into question [33,34]. 2.3. Adults Energy requirements of patients in the intensive care unit (ICU) are traditionally estimated by standard equations. A review evaluating 7 predictive equations concluded that calculated requirements are seldom within 10% of measured energy expenditure, with no consensus as to which standard equation is most accurate [35]. A more accurate method of deriving the Resting Energy Expenditure (REE) is by indirect calorimetry (IC) [36]. This has potential utility in the ICU setting, where some patients confound traditional predictive equations by exhibiting hypometabolism [37]. IC is also particularly useful in patients at the extremes of body mass index (BMI), where predictive equations are increasingly inaccurate [37]. However, IC is costly, requires trained personnel, and is less accurate at high concentrations of inspired oxygen, thereby potentially limiting its use in the ARDS population [36]. Also, while it is the gold standard technique in eligible patients, IC as a technique, is not always accurate [38]. Finally, a practical limitation exists in that IC measurement is not currently widely available in many ICUs [39]. The inflammatory process in ARDS leads to increased protein catabolism and energy expenditure. Adults with ARDS are estimated to have an energy expenditure that is approximately 30% higher than REE [40]. A multi-center cluster randomized trial was conducted to evaluate the clinical effects of evidence-based feeding guidelines, implemented using Browman's Clinical Practice Guideline Development Cycle [41]. However, despite the intervention group achieving caloric goals more often (6.10 vs. 5.02 mean days fed per 10 fed patient-days; difference, 1.07 [95% CI, 0.12e2.22]; p ¼ 0.03), there was no statistically significant difference in hospital discharge mortality, or hospital and ICU length of stay (LOS). Furthermore, studies investigating early supplementation of PN have been demonstrated to be associated with adverse clinical outcomes [33,34]. While evidence remains equivocal regarding the benefits of supplementing nutrition early in the disease course of critically ill adults, there are deleterious effects associated with overfeeding. One of the earlier pieces of research into the interaction between nutrition and ARDS was in the area of carbon dioxide (CO2) production [42]. This was based on the theory that a high carbohydrate intake might increase CO2 production, thereby possibly adversely affecting weaning of MV. A subsequent study of 20 stable mechanically ventilated patients, who received PN comprising varying amounts of calories (60% carbohydrate at 1.0, 1.5 and 2.0 times the calculated REE) and proportions of carbohydrate (40%, 60% and 75% of total calorie intake) demonstrated that a higher proportion of calories and not carbohydrate was significantly associated with higher CO2 production [43]. It may therefore be important to avoid overfeeding in ARDS patients to limit CO2 production and its potential impact on duration of MV. Furthermore, overfeeding has also been shown to have adverse effects on liver function [44], glycemic control [45] and infection risk [46]. There is emerging evidence to suggest that some measure of caloric underfeeding may possibly confer benefit. In a prospective cohort study of adult medical ICU patients, underfeeding at

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

M. Loi et al. / Clinical Nutrition ESPEN xxx (2017) e1ee8

approximately 33%e65% of American College of Chest Physician (ACCP) targets was associated with a significantly greater likelihood of achieving spontaneous ventilation prior to ICU discharge [47]. One possible reason for this might be the suppression of autophagy with hypercaloric feeding, and in particular, the amount of amino acids provided [48]. The EDEN study randomized 1000 adult patients with ARDS to either trophic feeding for 6 days, or full enteral feeding [49]. The group receiving trophic feeds showed no significant difference in number of ventilator free days (14.9 [95% CI: 13.9, 15.8] vs 15.0 [95% CI: 14.1, 15.9]; p ¼ 0.89), or 60-day mortality (23.2% [95% CI: 19.6%, 26.9%] vs 22.2% [95% CI: 18.5%, 25.8%]; p ¼ 0.77) compared to full feeding. The ideal target for caloric delivery relative to REE therefore remains a controversial area. Similar to recommendations on caloric targets, the subject of protein requirements in ARDS is complex and nuanced. Critical illness is associated with increased protein turnover [50]. This is due in part to the increased amino acid requirements for the synthesis of so-called central proteins, which are involved in the immunological and inflammatory response, tissue repair, and acute phase proteins among other functions [51]. There are theoretical benefits to providing sufficient exogenous protein in order to support this synthetic activity [52], as well as to prevent the breakdown of muscle if these needs are not met [53]. Certainly, the role of protein provision has been gaining increasing recognition, and has been shown in a prospective cohort study to have a more important association with reduced mortality than caloric provision alone [54]. In another prospective observational cohort study of 886 mechanically ventilated adult patients in a mixed medicalesurgical ICU, achieving protein (at least 1.2 g/kg protein provided) and energy targets was associated with a 50% reduction in 28-day mortality, with no significant decrease in mortality when energy targets alone were met [55]. A systematic review concluded that increasing protein provision up to 2.5 g/kg/day results in improved nitrogen balance [56]. 2.4. Recommendations for adult caloric intake and protein provision Total caloric target for adult ARDS patients remains controversial, with no clear consensus amongst the various societies on this (Table 1). However, there is overall agreement that overfeeding is undesirable. In their 2015 update, the CCPGs recommend considering intentional underfeeding in patients at low nutrition-risk [57]. This is based on 3 randomized controlled trials suggesting trends towards reduced ICU and hospital mortality, and dependence on MV. In these studies, the caloric supply in the hypocaloric

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group as a proportion of daily energy expenditure was 50% [58,59] and 40e60% [60]. ASPEN/SCCM and ESPEN both make recommendations on protein delivery. For the enteral route, the ESPEN guidelines are given in the context of early enteral nutrition, with no separate recommendation for enteral protein provision per se. The ASPEN/SCCM document highlights the difficulty of determining protein requirement in critically ill patients, with simplistic weight-based equations remaining the mainstay [61]. There is an urgent need for robust trials to determine the optimal amount and type of protein and amino acid provision, as well as the clinical outcomes [62]. 2.5. Children There is a paucity of clinical studies examining caloric requirements in children with ARDS. An observational study of 107 children with ARDS found that delivery of adequate calories (80% of predicted REE) and protein (1.5 g/kg/day) were associated with a reduction in ICU mortality [63]. Meeting the predicted protein requirements was also associated with an increase in median ventilator-free days (12 [IQR: 3.0e19.0] vs 0 [IQR: 0.0e14.8] days) [63]. Given the limited data in this aspect in pediatric ARDS, clinicians would have to extrapolate findings from other critically ill children in tailoring nutritional practices in pediatric ARDS. In an international, prospective cohort study of patients in pediatric intensive care units (PICUs) requiring longer than 48 h of MV, Mehta et al. corroborated previous findings of inadequacy of enteral nutrition (EN) in critically ill patients. Of the 500 children included in the analysis, the mean percentage daily enteral nutritional intake compared to prescribed goals was 38% for energy and 43% for protein. Mortality was significantly lower in patients with enteral energy intake 33.3%e66.6% (OR 0.27 [95% CI: 0.11, 0.67]) and in those with >66.7% of their prescribed goals (OR 0.14 [95% CI: 0.03, 0.61]), when compared to those who had intake from EN <33.3% of prescribed goals. This finding remained significant even after correcting for severity of illness scores, nutrition days, and PICU site [64]. It is challenging to determine what would constitute adequate caloric intake in critically ill children. Firstly, there is conflicting evidence regarding actual energy requirements in critically ill children relative to REE calculated with the Schofield formula [65]. A study of mechanically ventilated children fed according to existing local guidelines showed that a significant proportion of these patients were overfed, when compared to IC measurements [66]. The hypermetabolic response seen in critically ill adults is not observed in children [67]. Therefore, the traditional application of

Table 1 Guidelines for caloric requirements in critically ill adults. ASPEN/SCCM [61]

ESPEN [96,105]

CCPGs [57]

Indirect calorimetry

Recommended

Recommended

Caloric target (Enteral)

100% of goal calories

Insufficient data to recommend on indirect calorimetry vs predictive equations Intentional underfeeding of calories (not protein) should be considered in patients at low nutrition-risk.

During acute illness, the aim should be to provide energy as close as possible to the measured energy expenditure in order to decrease negative energy balance. An exogenous energy supply in excess of 20 e25 kcal/kg body weight/day may be associated with less favorable outcome. Early enteral nutrition should comprise a Insufficient data to make a recommendation standard high-protein formula regarding high protein vs low protein composition in enteral nutrition.

Protein provision (Enteral) Sufficient (high-dose) protein should be provided (enteral). Protein requirements are expected to be in the range of 1.2 e2.0 g/kg actual body weight per day.

ASPEN, American Society for Parenteral and Enteral Nutrition; CCPG, Canadian Clinical Practice Guidelines; ESPEN, European Society for Clinical Nutrition and Metabolism; SCCM, Society of Critical Care Medicine.

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

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stress factors to predictive equations for energy are no longer routinely recommended by some clinicians, as it may lead to a significant overestimate [27,68,69]. Energy requirements in critically children also have the propensity to being highly variable in being either hypometabolic or hypermetabolic, and may fluctuate as the clinical condition progresses [70] although when these stages occur is difficult to determine. Predictive equations that are commonly used are the WHO [71], Schofield [72] and HarriseBenedict [73] equations. There is growing evidence that these equations are not an adequate substitute for IC in determining energy requirements in critically ill children [67], with a high risk of underfeeding or overfeeding [70]. However, similar to the situation in adults, IC measurements are not widely available in PICUs. Protein requirements are increased in acutely ill children [74]. A study of 18 children with burns averaging 60% of total surface area showed a poorer opsonic index in the normal protein group, compared to the high protein group (diet supplemented with milk whey protein) [75]. A prospective randomized controlled trial in 51 critically ill children was carried out where patients received either a standard diet, or a protein-enriched diet (1.1 g protein/100 ml feeding formula) [76]. The group that received the protein-enriched diet showed significantly higher levels of retinol-binding protein, and a trend towards positive nitrogen balance, prealbumin, transferrin and total protein.

2.6. Recommendations for pediatric caloric intake and protein provision The paucity of robust evidence makes it difficult to make definitive recommendations on target caloric intake in pediatric ARDS. A Cochrane review on nutritional support for critically ill children only found one small randomized controlled trial (RCT) that met their inclusion criteria, and could not draw any firm conclusions regarding timing and forms of nutrition [77]. ESPEN/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines on pediatric PN recommend using WHO and especially Schofield equations for calculating REE in children <10 years old [70]. In children 10 years old, the Harris-Benedict, WHO and Schofield equations can be used (Grade B). Although IC may be used to measure REE in selected patients, they concluded that there was lack of data to recommend general use (Grade D). Finally, they recommend that energy intake be adapted to take into account disease states that may increase REE (Grade B), but suggest that predictive equations be used without the routine addition of ‘stress factors’ in critically ill children. The ESPEN/ESPGHAN guidelines for nutrition in critically ill children [69] recommended assessment of energy expenditure throughout the course of illness, and recognized that estimates using available standard equations are often unreliable (Grade D). They also recommended using IC in a subgroup of patients with suspected metabolic alterations or malnutrition (Grade E). Regarding macronutrient intake, they concluded that there is insufficient data to make evidence-based recommendations (Grade E). The Pediatric Acute Lung Injury Consensus Conference (PALICC) [78] recommends that ‘periodic metabolic assessments of nutritional adequacy and balance of nutritional delivery and metabolic utilization of substrates’ be performed. They suggested that ‘assessment of the respiratory quotient and energy expenditure measured by a validated method such as IC would be preferable’. For protein delivery, ASPEN guidelines recommend a range of targets according to age group: 2e3 g/kg/day (0e2 years); 1.5e2 g/ kg/day (2e13 years); and 1.5 g/kg/day (13e18 years) [27]. Further

studies are needed to elucidate protein delivery targets, as well as its impact on clinically relevant outcomes. 2.7. Enteral and parenteral nutrition The preferential use of enteral feeds to supply patients' nutritional needs, compared to the parenteral route, is well-established practice in critical care. The provision of EN in critically ill patients provides the beneficial effect of preserving mucosal integrity of the gastrointestinal tract [79], thereby reducing bacterial translocation [80]. Enteral feeding has also been shown to preserve gut mass [81], reduce liver injury in the face of hemorrhagic shock [82], and maintains mucosal immunity [83,84]. However, obstacles to the delivery of EN in the critically ill are common. Studies have demonstrated frequent EN interruptions for reasons such as interventional procedures, perceived gastrointestinal intolerances [85], and hypotension [86]. 2.8. Adults A challenge in drawing conclusions about when to commence EN is the different definitions used by researchers to describe ‘early EN’. An analysis of 4049 adult patients on MV showed an association of early feeding with reduced mortality, with the effects most profound in the sickest patients [87]. A systematic review concluded that early initiation of EN (within 36 h of hospital admission or surgery) in acutely ill patients was associated with lower incidence of infections and reduced hospital LOS [88]. There is conflicting data about how much calories should be supplied during initial stages of illness. A prospective controlled trial of 150 mechanically ventilated patients found that aggressive early enteral feeding (providing total nutritional requirements on day 1) was associated with increased infectious complications and LOS, when compared to the group of patients who only received 20% of their daily requirements during the first 4 days of MV [89]. In contrast, the EDEN study mentioned above [49] showed no statistically significant difference in clinical outcomes between the group receiving trophic-feeding initially, and the full enteral feeding group. There is similar uncertainty regarding the amount of EN that ARDS patients should be receiving beyond the ‘early EN’ period. In an RCT of 240 patients at a mixed medical-surgical ICU [53], there was a trend towards lower 28-day all-cause mortality in the group receiving permissive enteral underfeeding (caloric goal 60e70% of calculated requirement) compared to the group receiving full EN (relative risk 0.79; 95% CI: 0.48, 1.29; p ¼ 0.34). The INTACT study [90] compared an ‘intensive medical nutrition intervention’ (IMNT) with ‘standard care’ (SC) in adults with ARDS. IMNT involved close monitoring and provision of EN at >75% of patients' estimated daily energy and protein needs, commencing at the time of diagnosis of ARDS and continuing to hospital discharge. The study was stopped early due to a significant increase in mortality in the group receiving IMNT, with unadjusted analysis revealing a 2.65 times higher hazard of death compared to the SC group. Of note, there was no significant difference in delivery of PN in both groups. There has been controversy regarding the timing of commencing PN in critically ill patients who do not tolerate feeding via the enteral route. A meta-analysis comparing patients in ICUs who could not receive EN, showed that initiating PN within the first 24 h of ICU admission was associated with lower mortality rates compared to those without PN initiation [91]. A multi-center, randomized single-blind trial of 1372 patients, similarly showed that early PN in patients who had short term relative contraindications to EN was associated with fewer days of mechanical ventilation [92].

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

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Other studies further examined patients who were able to receive both enteral and parenteral nutrition, and compared the different routes of delivery. For example, the CALORIES trial that randomized 2388 patients to receive early nutritional support (commencement of nutrition within 36 h of ICU admission, and continued for up to 5 days), via either the enteral or parenteral route, did not showed any difference in 30-day mortality [93]. The findings of 2 meta-analyses cast further doubt on the benefits of early PN. Heyland et al. [94] evaluated RCTs that compared PN with standard care (conventional oral diet with intravenous dextrose), and found a significant reduction in mortality and complication rates in the standard care group, when compared to the PN group. Similarly, a meta-analysis by Braunschweig et al. [95] showed lower risk of infection in the tube-fed and standard care group, compared to critically ill patients who received PN. The landmark EPaNIC study [34] compared supplementing enteral intake with PN on day 3 to prevent a caloric deficit, with delaying PN for 1 week. These two intervention arms reflected the respective guidelines of ESPEN [96], which recommended considering initiating PN within 2 days of ICU admission, and the American and Canadian guidelines, which suggest delaying PN for 1 week [97,98]. The primary outcome showed that patients in the late-initiation group had a median stay in ICU that was 1 day shorter than in the early-initiation group, with a consequent increase of 6.3% in likelihood of earlier discharge from ICU (hazard ratio 1.06, 95% CI: 1, 1.13, p ¼ 0.04). Late initiation of PN was also associated with fewer new infections in the ICU, and shorter duration of MV and renal replacement therapy. 2.9. Recommendations for enteral and parenteral nutrition e adults Current consensus statements recommend commencing early EN, however there is still uncertainty regarding amount of calories that need to be provided, as well as rate of advancement (Table 2). 2.10. Children There are only a limited number of pediatric studies investigating the effects of early EN on clinically relevant outcomes.

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Commencing EN early upon PICU admission seems to be safe and achievable [99,100]. Mikhailov et al. [101] showed that after adjusting for propensity score, PIM2 score, age and center, early EN (provision of 25% of prescribed calories enterally within 48 h of admission) was associated with lower mortality (odds ratio 0.51; 95% CI: 0.34, 0.76; p ¼ 0.001). Another study, an international prospective cohort study found that increased provision of prescribed energy goal via EN was associated with improved survival in mechanically ventilated children [64]. The study also found that PICUs that used protocols for the initiation and advancement of EN had fewer reported acquired infections. Many PICUs have the practice of beginning supplementary PN early in critically ill children who are unable to meet their nutritional requirements enterally, in order to support the presumed increased macronutrient needs associated with growth [102]. The recently concluded PEPaNIC (Pediatric Early versus Late Parenteral Nutrition in the Intensive Care Unit) trial randomized 1440 critically ill children to receive either early (initiated within 24 h of PICU admission) or late (withheld till the morning of day 8 in PICU) PN [33]. The primary outcomes of the trial showed that the group receiving late PN had fewer new infections (adjusted odds ratio 0.48; 95% CI: 0.35, 0.66) and shorter PICU stays by a mean of 2.7 days (95% CI: 1.3, 4.3). Additionally, delaying PN was associated with shorter duration of MV (p ¼ 0.001), and fewer patients requiring renal replacement therapy (p ¼ 0.04). These results mirror those of the adult EPaNIC study described above [34].

2.11. Recommendations for enteral and parenteral nutrition e children Current ESPEN/ESPGHAN guidelines recommend that ‘in critically ill children with a functioning gastrointestinal tract, EN should be the preferred mode of nutrient provision, if tolerated (Grade C) [69]. The PALICC statement also recommends with strong agreement, that ‘EN, when tolerated, should be used in preference to PN’ [78]. While there is some evidence for commencing ‘early EN’ in children, there is uncertainty regarding the amount of feeds required that would confer clinical benefit. Further work needs to

Table 2 Enteral and parenteral feeding in critically ill adults consensus statements. ASPEN/SCCM [61]

ESPEN [96,105]

CCPGs [57]

Early enteral feeding Dosage of enteral feeds

Enteral feeding should be started within the first 24e48 h following admission Efforts to provide >80% of goal energy within 48 e72 h should be made (24e48 h for patients at high nutrition risk) Either trophic or full enteral nutrition are appropriate for patients with ARDS

Recommend feeding early (<24 h)

Timing of PN

Exclusive PN should be withheld in the first 7 days following ICU admission in low nutrition risk patients. Exclusive PN should be initiated as soon as possible in high nutrition risk patients

All patients who are not expected to be on normal nutrition within 3 days should receive PN within 24e48 h if EN is contraindicated or not tolerated

Supplemental PN should be considered after 7 e10 days if unable to meet >60% energy and protein requirements enterally Consider hypocaloric PN dosing (20 kcal/kg/ d or 80% of estimated energy needs) Adequate protein (1.2 g protein/kg/d) in high risk patients

Consider supplemental PN in all patients receiving less than their targeted enteral feeding after 2 days Aim to provide energy as close as possible to measured energy expenditure (25 kcal/kg/day) A balanced amino acid mixture should be infused at approximately 1.3e1.5 g/kg ideal body weight per day

Early enteral nutrition (within 24e48 h following admission to ICU) is recommended Intentional underfeeding of calories (not protein) should be considered in patients at low nutrition risk. In patients with ALI, an initial strategy of trophic feeding (compared to full enteral feeds) should not be considered. Insufficient data to put forward recommendation regarding timing of PN in patients not tolerating adequate EN. Consider early PN in nutritionally high risk patients with relative contraindication to early EN Strongly recommend that early supplemental PN not be used in unselected critically ill patients (low risk patients with short ICU stay) No specific recommendation

Dosage of PN Protein in PN

No specific guidance

No specific recommendation

ALI, Acute Lung Injury; ARDS, Acute Respiratory Distress Syndrome; ASPEN, American Society for Parenteral and Enteral Nutrition; CCPG, Canadian Clinical Practice Guidelines; ESPEN, European Society for Clinical Nutrition and Metabolism; IC, Indirect calorimetry; ICU, intensive care unit; PN, Parenteral Nutrition; SCCM, Society of Critical Care Medicine.

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

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be done to inform clinicians about the effects of post-pyloric feeding and antacids in seeking to optimize enteral feeds, and whether gastric residual volumes are reliable markers of feed intolerance [103]. There is probably some advantage in the use of feeding protocols for the initiation and advancement of EN [64]. To date, there is no expert consensus on the optimal timing to commence PN in those patients for whom the enteral route is not feasible. We believe the findings of the PEPaNIC trial are compelling, and on the available evidence, we would recommend delaying the introduction of PN till the second week of PICU admission [33]. We hope the upcoming guidelines will issue consensus recommendations on this question. 3. Conclusion There continues to be significant morbidity and mortality associated with a diagnosis of ARDS in critically ill children and adults. Malnutrition is prevalent in these patients, and nutritional assessment and support are important in mediating clinical outcomes. The provision of nutrition must be weighed against the risk of generating a positive fluid balance, which has been shown to have an important detrimental impact on clinical outcomes in ARDS [104]. Recent studies have been helpful in further informing our approach to nutritional support in this vulnerable patient population, including timing of PN supplementation, and the role of using protocol-based strategies for advancing feeds. There are still no definitive answers to some fundamental questions, such as the caloric requirement of ARDS patients, the best way of estimating or measuring this, and what proportion of this we should be aiming to provide to patients with ARDS. There has been much work done in the field of so-called immunutrition, evaluating the role of various micronutrients and lipids. However, this is beyond the scope of this review. While similarities exist between children and adults with ARDS, there remain important physiological and metabolic differences. It is therefore imperative that further studies are performed to inform best nutritional practices in children with ARDS. Competing interests None declared. References [1] Erickson S, Schibler A, Numa A, Nuthall G, Yung M, Pascoe E, et al. Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8(4): 317e23. [2] Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353(16): 1685e93. [3] Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, et al. Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review. Am J Respir Crit Care Med 2009;179(3):220e7. [4] Giner M, Laviano A, Meguid MM, Gleason JR. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Nutrition 1996;12(1):23e9. [5] Hulst J, Joosten K, Zimmermann L, Hop W, van Buuren S, Büller H, et al. Malnutrition in critically ill children: from admission to 6 months after discharge. Clin Nutr 2004;23(2):223e32. [6] Pingleton SK, Harmon GS. Nutritional management in acute respiratory failure. JAMA 1987;257(22):3094e9. [7] Rubinson L, Diette GB, Song X, Brower RG, Krishnan JA. Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit. Crit Care Med 2004;32(2):350e7. [8] Khalid I, Doshi P, DiGiovine B. Early enteral nutrition and outcomes of critically ill patients treated with vasopressors and mechanical ventilation. Am J Crit Care 2010;19(3):261e8. [9] Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J. Benefit of an enteral diet enriched with eicosapentaenoic acid and gamma-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006;34(4): 1033e8.

[10] Manzanares W, Dhaliwal R, Jiang X, Murch L, Heyland DK. Antioxidant micronutrients in the critically ill: a systematic review and meta-analysis. Crit Care 2012;16(2):R66. [11] Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011;306(14):1574e81. [12] DeMichele SJ, Wood SM, Wennberg AK. A nutritional strategy to improve oxygenation and decrease morbidity in patients who have acute respiratory distress syndrome. Respir Care Clin N Am 2006;12(4):547e66. vi. [13] Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med 2006;34(9):2325e33. [14] Hamilton LA, Trobaugh KA. Acute respiratory distress syndrome: use of specialized nutrients in pediatric patients and infants. Nutr Clin Pract 2011;26(1):26e30. [15] Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342(18):1334e49. [16] Galani V, Tatsaki E, Bai M, Kitsoulis P, Lekka M, Nakos G, et al. The role of apoptosis in the pathophysiology of acute respiratory distress syndrome (ARDS): an up-to-date cell-specific review. Pathol Res Pract 2010;206(3): 145e50. [17] Pediatric Acute Lung Injury Consensus Conference G. Pediatric acute respiratory distress syndrome: consensus recommendations from the pediatric acute lung injury consensus conference. Pediatr Crit Care Med 2015;16(5): 428e39. [18] Cuthbertson DP, Angeles Valero Zanuy MA, Leon Sanz ML. Post-shock metabolic response. 1942. Nutr Hosp 2001;16(5):176e82. [discussion 175e176]. [19] Cuthbertson DP. Second annual Jonathan E. Rhoads lecture. The metabolic response to injury and its nutritional implications: retrospect and prospect. JPEN J Parenter Enteral Nutr 1979;3(3):108e29. [20] Preiser JC, Ichai C, Orban JC, Groeneveld AB. Metabolic response to the stress of critical illness. Br J Anaesth 2014;113(6):945e54. [21] Moriyama S, Okamoto K, Tabira Y, Kikuta K, Kukita I, Hamaguchi M, et al. Evaluation of oxygen consumption and resting energy expenditure in critically ill patients with systemic inflammatory response syndrome. Crit Care Med 1999;27(10):2133e6. [22] Faisy C, Guerot E, Diehl JL, Labrousse J, Fagon JY. Assessment of resting energy expenditure in mechanically ventilated patients. Am J Clin Nutr 2003;78(2):241e9. [23] Bruder N, Raynal M, Pellissier D, Courtinat C, Francois G. Influence of body temperature, with or without sedation, on energy expenditure in severe head-injured patients. Crit Care Med 1998;26(3):568e72. [24] Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, Chan P, et al. Acute skeletal muscle wasting in critical illness. JAMA 2013;310(15): 1591e600. [25] Lecker SH, Solomon V, Mitch WE, Goldberg AL. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 1999;129(1S Suppl.):227Se37S.  A, Tomlinson G, Diaz-Granados N, Cooper A, [26] Herridge MS, Tansey CM, Matte et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364(14):1293e304. [27] Mehta NM, Compher C, Directors ASPENBo. A.S.P.E.N. clinical guidelines: nutrition support of the critically ill child. JPEN J Parenter Enteral Nutr 2009;33(3):260e76. [28] Mehta NM, Bechard LJ, Dolan M, Ariagno K, Jiang H, Duggan C. Energy imbalance and the risk of overfeeding in critically ill children. Pediatr Crit Care Med 2011;12(4):398e405. [29] Cogo PE, Carnielli VP, Rosso F, Cesarone A, Giordano G, Faggian D, et al. Protein turnover, lipolysis, and endogenous hormonal secretion in critically ill children. Crit Care Med 2002;30(1):65e70. [30] Tsai JR, Chang WT, Sheu CC, Wu YJ, Sheu YH, Liu PL, et al. Inadequate energy delivery during early critical illness correlates with increased risk of mortality in patients who survive at least seven days: a retrospective study. Clin Nutr 2011;30(2):209e14. [31] Pollack MM, Ruttimann UE, Wiley JS. Nutritional depletions in critically ill children: associations with physiologic instability and increased quantity of care. JPEN J Parenter Enteral Nutr 1985;9(3):309e13. [32] Numa A, McAweeney J, Williams G, Awad J, Ravindranathan H. Extremes of weight centile are associated with increased risk of mortality in pediatric intensive care. Crit Care 2011;15(2):R106. [33] Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016;374(12):1111e22. [34] Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365(6):506e17. [35] Walker RN, Heuberger RA. Predictive equations for energy needs for the critically ill. Respir Care 2009;54(4):509e21. [36] Flancbaum L, Choban PS, Sambucco S, Verducci J, Burge JC. Comparison of indirect calorimetry, the Fick method, and prediction equations in estimating the energy requirements of critically ill patients. Am J Clin Nutr 1999;69(3): 461e6.

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

M. Loi et al. / Clinical Nutrition ESPEN xxx (2017) e1ee8 [37] McClave SA, Martindale RG, Kiraly L. The use of indirect calorimetry in the intensive care unit. Curr Opin Clin Nutr Metab Care 2013;16(2):202e8. [38] Lev S, Cohen J, Singer P. Indirect calorimetry measurements in the ventilated critically ill patient: facts and controversiesethe heat is on. Crit Care Clin 2010;26(4):e1e9. [39] Stapleton RD, Jones N, Heyland DK. Feeding critically ill patients: what is the optimal amount of energy? Crit Care Med 2007;35(9 Suppl.):S535e40. [40] Kiiski R, Takala J. Hypermetabolism and efficiency of CO2 removal in acute respiratory failure. Chest 1994;105(4):1198e203. [41] Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I, et al. Effect of evidence-based feeding guidelines on mortality of critically ill adults: a cluster randomized controlled trial. JAMA 2008;300(23):2731e41. [42] al-Saady NM, Blackmore CM, Bennett ED. High fat, low carbohydrate, enteral feeding lowers PaCO2 and reduces the period of ventilation in artificially ventilated patients. Intensive Care Med 1989;15(5):290e5. [43] Talpers SS, Romberger DJ, Bunce SB, Pingleton SK. Nutritionally associated increased carbon dioxide production. Excess total calories vs high proportion of carbohydrate calories. Chest 1992;102(2):551e5.  M, Acosta JA, et al. Liver dysfunction [44] Grau T, Bonet A, Rubio M, Mateo D, Farre associated with artificial nutrition in critically ill patients. Crit Care 2007;11(1):R10. [45] Ahrens CL, Barletta JF, Kanji S, Tyburski JG, Wilson RF, Janisse JJ, et al. Effect of low-calorie parenteral nutrition on the incidence and severity of hyperglycemia in surgical patients: a randomized, controlled trial. Crit Care Med 2005;33(11):2507e12. [46] Dissanaike S, Shelton M, Warner K, O'Keefe GE. The risk for bloodstream infections is associated with increased parenteral caloric intake in patients receiving parenteral nutrition. Crit Care 2007;11(5):R114. [47] Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric intake in medical ICU patients: consistency of care with guidelines and relationship to clinical outcomes. Chest 2003;124(1):297e305. [48] Derde S, Vanhorebeek I, Güiza F, Derese I, Gunst J, Fahrenkrog B, et al. Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits. Endocrinology 2012;153(5):2267e76. [49] National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307(8): 795e803. [50] Rooyackers O, Kouchek-Zadeh R, Tjader I, Norberg A, Klaude M, Wernerman J. Whole body protein turnover in critically ill patients with multiple organ failure. Clin Nutr 2015;34(1):95e100. [51] Radrizzani D, Iapichino G, Cambisano M, Bonetti G, Ronzoni G, Colombo A. Peripheral, visceral and body nitrogen balance of catabolic patients, without and with parenteral nutrition. Intensive Care Med 1988;14(3):212e6. [52] Burke PA, Young LS, Bistrian BR. Metabolic vs nutrition support: a hypothesis. JPEN J Parenter Enteral Nutr 2010;34(5):546e8. [53] Reid CL. Nutritional requirements of surgical and critically-ill patients: do we really know what they need? Proc Nutr Soc 2004;63(3):467e72. [54] Allingstrup MJ, Esmailzadeh N, Wilkens Knudsen A, Espersen K, Hartvig Jensen T, Wiis J, et al. Provision of protein and energy in relation to measured requirements in intensive care patients. Clin Nutr 2012;31(4):462e8. [55] Weijs PJ, Stapel SN, de Groot SD, Driessen RH, de Jong E, Girbes AR, et al. Optimal protein and energy nutrition decreases mortality in mechanically ventilated, critically ill patients: a prospective observational cohort study. JPEN J Parenter Enteral Nutr 2012;36(1):60e8. [56] Hoffer LJ, Bistrian BR. Appropriate protein provision in critical illness: a systematic and narrative review. Am J Clin Nutr 2012;96(3):591e600. [57] Nutrition CC. http://www.criticalcarenutrition.com/cpgs; 2016. [Accessed 5 November 2016]. [58] Petros S, Horbach M, Seidel F, Weidhase L. Hypocaloric vs normocaloric nutrition in critically ill patients: a prospective randomized pilot trial. JPEN J Parenter Enteral Nutr 2016;40(2):242e9. [59] Charles EJ, Petroze RT, Metzger R, Hranjec T, Rosenberger LH, Riccio LM, et al. Hypocaloric compared with eucaloric nutritional support and its effect on infection rates in a surgical intensive care unit: a randomized controlled trial. Am J Clin Nutr 2014;100(5):1337e43. [60] Arabi YM, Aldawood AS, Haddad SH, Al-Dorzi HM, Tamim HM, Jones G, et al. Permissive underfeeding or standard enteral feeding in critically ill adults. N Engl J Med 2015;372(25):2398e408. [61] McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2016;40(2):159e211. [62] Plank LD. Protein for the critically ill patient e what and when? Eur J Clin Nutr 2013;67(5):565e8. [63] Wong JJ, Han WM, Sultana R, Loh TF, Lee JH. Nutrition delivery affects outcomes in pediatric acute respiratory distress syndrome. JPEN J Parenter Enteral Nutr 2016. http://dx.doi.org/10.1177/0148607116637937. [64] Mehta NM, Bechard LJ, Cahill N, Wang M, Day A, Duggan CP, et al. Nutritional practices and their relationship to clinical outcomes in critically ill children e an international multicenter cohort study. Crit Care Med 2012;40(7): 2204e11.

e7

[65] van der Kuip M, de Meer K, Westerterp KR, Gemke RJ. Physical activity as a determinant of total energy expenditure in critically ill children. Clin Nutr 2007;26(6):744e51. [66] Kerklaan D, Hulst JM, Verhoeven JJ, Verbruggen SC, Joosten KF. Use of indirect calorimetry to detect overfeeding in critically ill children: finding the appropriate definition. J Pediatr Gastroenterol Nutr 2016;63(4):445e50. [67] Framson CM, LeLeiko NS, Dallal GE, Roubenoff R, Snelling LK, Dwyer JT. Energy expenditure in critically ill children. Pediatr Crit Care Med 2007;8(3): 264e7. [68] Briassoulis G, Venkataraman S, Thompson AE. Energy expenditure in critically ill children. Crit Care Med 2000;28(4):1166e72. [69] Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. 1. Guidelines on paediatric parenteral nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr 2005;41(Suppl. 2): S1e87. [70] Mehta NM, Bechard LJ, Leavitt K, Duggan C. Cumulative energy imbalance in the pediatric intensive care unit: role of targeted indirect calorimetry. JPEN J Parenter Enteral Nutr 2009;33(3):336e44. [71] Joint FAO/WHO/UNU Expert Consultation on Energy and Protein Requirements. Energy and protein requirements: report of a joint FAO/WHO/ UNU expert consultation. Geneva: World Health Organization; 1985. [72] Schofield WN. Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 1985;39(Suppl. 1):5e41. [73] Harris JA, Benedict FG. A biometric study of basal metabolism in man. Washington: Carnegie Institution of Washington; 1919. [74] American Academy of Pediatrics. Committee on nutrition. In: Barness LA, editor. Pediatric nutrition handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. [75] Alexander JW, MacMillan BG, Stinnett JD, Ogle CK, Bozian RC, Fischer JE, et al. Beneficial effects of aggressive protein feeding in severely burned children. Ann Surg 1980;192(4):505e17. [76] Botran M, Lopez-Herce J, Mencia S, Urbano J, Solana MJ, Garcia A. Enteral nutrition in the critically ill child: comparison of standard and proteinenriched diets. J Pediatr 2011;159(1):27e32. e21. [77] Joffe A, Anton N, Lequier L, Vandermeer B, Tjosvold L, Larsen B, et al. Nutritional support for critically ill children. Cochrane Database Syst Rev 2016;(5), CD005144. http://dx.doi.org/10.1002/14651858.CD005144.pub3. [78] Valentine SL, Nadkarni VM, Curley MA, Pediatric Acute Lung Injury Consensus Conference G. Nonpulmonary treatments for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015;16(5 Suppl. 1): S73e85. [79] Hadfield RJ, Sinclair DG, Houldsworth PE, Evans TW. Effects of enteral and parenteral nutrition on gut mucosal permeability in the critically ill. Am J Respir Crit Care Med 1995;152(5 Pt 1):1545e8. [80] Gianotti L, Alexander JW, Nelson JL, Fukushima R, Pyles T, Chalk CL. Role of early enteral feeding and acute starvation on postburn bacterial translocation and host defense: prospective, randomized trials. Crit Care Med 1994;22(2):265e72. [81] Minard G, Kudsk KA. Is early feeding beneficial? How early is early? New Horiz 1994;2(2):156e63. [82] Bortenschlager L, Roberts PR, Black KW, Zaloga GP. Enteral feeding minimizes liver injury during hemorrhagic shock. Shock 1994;2(5):351e4. [83] Kudsk KA. Current aspects of mucosal immunology and its influence by nutrition. Am J Surg 2002;183(4):390e8. [84] Jabbar A, Chang WK, Dryden GW, McClave SA. Gut immunology and the differential response to feeding and starvation. Nutr Clin Pract 2003;18(6): 461e82. [85] Rice TW, Swope T, Bozeman S, Wheeler AP. Variation in enteral nutrition delivery in mechanically ventilated patients. Nutrition 2005;21(7e8): 786e92. [86] McClave SA, Chang WK. Feeding the hypotensive patient: does enteral feeding precipitate or protect against ischemic bowel? Nutr Clin Pract 2003;18(4):279e84. [87] Artinian V, Krayem H, DiGiovine B. Effects of early enteral feeding on the outcome of critically ill mechanically ventilated medical patients. Chest 2006;129(4):960e7. [88] Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: a systematic review. Crit Care Med 2001;29(12):2264e70. [89] Ibrahim EH, Mehringer L, Prentice D, Sherman G, Schaiff R, Fraser V, et al. Early versus late enteral feeding of mechanically ventilated patients: results of a clinical trial. JPEN J Parenter Enteral Nutr 2002;26(3):174e81. [90] Braunschweig CA, Sheean PM, Peterson SJ, Gomez Perez S, Freels S, Lateef O, et al. Intensive nutrition in acute lung injury: a clinical trial (INTACT). JPEN J Parenter Enteral Nutr 2015;39(1):13e20. [91] Simpson F, Doig GS. Parenteral vs. enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention to treat principle. Intensive Care Med 2005;31(1):12e23. [92] Doig GS, Simpson F, Sweetman EA, Finfer SR, Cooper DJ, Heighes PT, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013;309(20):2130e8.

Please cite this article in press as: Loi M, et al., Nutritional support of critically ill adults and children with acute respiratory distress syndrome: A clinical review, Clinical Nutrition ESPEN (2017), http://dx.doi.org/10.1016/j.clnesp.2017.02.005

e8

M. Loi et al. / Clinical Nutrition ESPEN xxx (2017) e1ee8

[93] Harvey SE, Parrott F, Harrison DA, Bear DE, Segaran E, Beale R, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med 2014;371(18):1673e84. [94] Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA 1998;280(23):2013e9. [95] Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001;74(4):534e42. [96] Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr 2009;28(4):387e400. [97] Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P, Canadian Critical Care Clinical Practice Guidelines C. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27(5):355e73. [98] Martindale RG, McClave SA, Vanek VW, McCarthy M, Roberts P, Taylor B, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: executive summary. Crit Care Med 2009;37(5):1757e61.

[99] Sanchez C, Lopez-Herce J, Carrillo A, Mencia S, Vigil D. Early transpyloric enteral nutrition in critically ill children. Nutrition 2007;23(1):16e22. [100] King W, Petrillo T, Pettignano R. Enteral nutrition and cardiovascular medications in the pediatric intensive care unit. JPEN J Parenter Enteral Nutr 2004;28(5):334e8. [101] Mikhailov TA, Kuhn EM, Manzi J, Christensen M, Collins M, Brown AM, et al. Early enteral nutrition is associated with lower mortality in critically ill children. JPEN J Parenter Enteral Nutr 2014;38(4):459e66. [102] Goday PS, Mehta NM. Pediatric critical care nutrition. McGraw-Hill's Access Pediatrics. 1st ed. New York, N.Y.: McGraw Hill Medical; 2015. http:// accesspediatrics.mhmedical.com/book.aspx?bookid¼1198. [103] Mehta NM. Parenteral nutrition in critically ill children. N Engl J Med 2016;374(12):1190e2. [104] Valentine SL, Sapru A, Higgerson RA, Spinella PC, Flori HR, Graham DA, et al. Fluid balance in critically ill children with acute lung injury. Crit Care Med 2012;40(10):2883e9. [105] Kreymann KG, Berger MM, Deutz NEP, Hiesmayr M, Jolliet P, Kazandjiev G, et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr 2006;25(2):210e23.

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