Early hypophosphatemia in critically ill children and the effect of parenteral nutrition: A secondary analysis of the PEPaNIC RCT.

BACKGROUND & AIMS: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. METHODS: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. RESULTS: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). CONCLUSIONS: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH.

Nutritional intake and gastro-intestinal symptoms in critically ill COVID-19 patients.

BACKGROUND & AIMS: Critically ill COVID-19 patients seem hypermetabolic and difficult to feed enterally, due to gastro-intestinal (GI) symptoms such as high gastric residual volumes (GRV) and diarrhea. Our aim was to describe the association of nutritional intake and GI symptoms during first 14 days of ICU admission. METHODS: Observational study including critically ill adult COVID-19 patients. Data on nutritional intake [enteral nutrition (EN) or parenteral nutrition] and GI symptoms were collected during 14 days after ICU admission. Target energy and protein feeding goals were calculated conform ESPEN guidelines. GI symptoms included GRV (ml/d), vomiting, abdominal distension, and faeces (ml/d). High GRV's were classified as ≥2 times ≥150 ml/d and diarrhea as Bristol stool chart ≥6. GI symptoms were defined as mild if at least one symptom occurred and as moderate when ≥2 symptoms occurred. Acute gastrointestinal injury (AGI) grades of III were classified as GI dysfunction and grades of IV were considered as GI failure with severe impact on distant organs. Linear mixed model analysis was performed to explore the development of nutritional intake and GI symptoms over time at day (D) 0, 4, 10, and 14. RESULTS: One hundred and fifty patients were included [75% male; median age 64 years (IQR 54-70)]. BMI upon admission was 28 kg/m2 (IQR 25-33), of which 43% obese (BMI > 30 kg/m2). Most patients received EN during admission (98% D4; 96% D10-14). Mean energy goals increased from 87% at D4 to 93% D10-14 and protein goals (g/kg) were increasingly achieved during admission (84% D4; 93% D10-14). Presence of moderate GI symptoms decreased (10% D0; 6% D4-10; 5% D14), reversely mild GI symptoms increased. Occurrence of GI dysfunction fluctuated (1% D0; 18% D4; 12% D10; 8% D14) and none of patients developed grade IV GI failure. Development of high GRV fluctuated (5% D0; 23% D4; 14% D10; 8% D14) and occurrence of diarrhea slightly increased during admission (5% D0; 22% D4; 25% D10; 27% D14). Linear mixed models showed only an association between AGI grades III and lower protein intake at day 10 (p = 0.020). CONCLUSION: Occurrence of GI symptoms was limited and seems no major barrier for EN in our group of critically COVID-19 patients. Nutritional intake was just below requirements during the first 14 days of ICU admission. The effect on nutritional status remains to be studied.

Energy expenditure and feeding practices and tolerance during the acute and late phase of critically ill COVID-19 patients.

BACKGROUND & AIMS: Different metabolic phases can be distinguished in critical illness, which influences nutritional treatment. Achieving optimal nutritional treatment during these phases in critically ill patients is challenging. COVID-19 patients seem particularly difficult to feed due to gastrointestinal problems. Our aim was to describe measured resting energy expenditure (mREE) and feeding practices and tolerance during the acute and late phases of critical illness in COVID-19 patients. METHODS: Observational study including critically ill mechanically ventilated adult COVID-19 patients. Indirect calorimetry (Q-NRG+, Cosmed) was used to determine mREE during the acute (day 0-7) and late phase (>day 7) of critical illness. Data on nutritional intake, feeding tolerance and urinary nitrogen loss were collected simultaneously. A paired sample t-test was performed for mREE in both phases. RESULTS: We enrolled 21 patients with a median age of 59 years [44-66], 67% male and median BMI of 31.5 kg/m2 [25.7-37.8]. Patients were predominantly fed with EN in both phases. No significant difference in mREE was observed between phases (p = 0.529). Sixty-five percent of the patients were hypermetabolic in both phases. Median delivery of energy as percentage of mREE was higher in the late phase (94%) compared to the acute phase (70%) (p = 0.001). Urinary nitrogen losses were significant higher in the late phase (p = 0.003). CONCLUSION: In both the acute and late phase, the majority of the patients were hypermetabolic and fed enterally. In the acute phase patients were fed hypocaloric whereas in the late phase this was almost normocaloric, conform ESPEN guidelines. No significant difference in mREE was observed between phases. Hypermetabolism in both phases in conjunction with an increasing loss of urinary nitrogen may indicate that COVID-19 patients remain in a prolonged acute, catabolic phase.

Achieving enteral nutrition during the acute phase in critically ill children: Associations with patient characteristics and clinical outcome.

BACKGROUND & AIMS: In the absence of methodologically sound randomized controlled trials (RCTs), current recommendations for timing and amount of enteral nutrition (EN) in critically ill children are based on observational studies. These studies have associated achievement of a higher EN intake in critically ill children with improved outcome. Inherent to the observational design of these underlying studies, thorough insight in possible confounding factors to correct for is essential. We evaluated the associations between EN intake and 1) patient and daily clinical characteristics and 2) clinical outcomes adjusted for these patient and clinical characteristics during the first week of critical illness with a multivariable mixed model. METHODS: This secondary analysis of the multicentre PEPaNIC RCT investigated a subgroup of critically ill children with daily prospectively recorded gastrointestinal symptoms and EN intake during the first week with multivariable analyses using two-part mixed effect models, including multiple testing corrections using Holm's method. These models combined a mixed-effects logistic regression for the dichotomous outcome EN versus no EN, and a linear mixed-effects model for the patients who received any EN intake. EN intake per patient was expressed as mean daily EN as % of predicted resting energy expenditure (% of EN/REE). Model 1 included 40 fixed effect baseline patient characteristics, and daily parameters of illness severity, feeding, medication and gastrointestinal symptoms. Model 2 included these patient and daily variables as well as clinical outcomes. RESULTS: Complete data were available for 690 children. EN was provided in 503 (73%) patients with a start after a median of 2 (IQR 2-3) days and a median % of EN/REE of 38.8 (IQR 14.1-79.5) over the first week. Multivariable mixed model analyses including all patients showed that admission after gastrointestinal surgery (-49%EN/REE; p = 0.002), gastric feeding (-31% EN/REE; p < 0.001), treatment with inotropic agents (-22%EN/REE; p = 0.026) and large gastric residual volume (-64%EN/REE; p < 0.001) were independently associated with a low mean EN intake. In univariable analysis, low mean EN intake was associated with new acquired infections, hypoglycaemia, duration of PICU and hospital stay and duration of mechanical ventilation. However, after adjustment for confounders, these associations were no longer present, except for low EN and hypoglycaemia (-39%EN/REE; p = 0.018). CONCLUSIONS: Several patient and clinical characteristics during the first week of critical illness were associated with EN intake. No independent associations were found between EN intake and clinical outcomes such as mortality, new acquired infection and duration of stay. These data emphasize the necessity of adequate multivariable adjustment in nutritional support research and the need for future RCTs investigating optimal EN intake.

Definitions, predictors and outcomes of feeding intolerance in critically ill children: A systematic review.

BACKGROUND & AIMS: Clinicians and researchers often use feeding intolerance (FI) as main cause for insufficient enteral nutrition (EN). However, there is no uniform definition for FI. A uniform definition is essential for future studies focusing on predictors and outcomes of FI and enteral nutrition. A systematic review was performed to investigate the definitions, prevalence, predictors and outcomes of FI in critically ill children. METHODS: The databases Medline, Embase, Cochrane CENTRAL, Web of Science were searched. Inclusion criteria were interventional, observational or case-control studies (>10 patients) in which a definition of FI was reported in critically ill children (0-21 years). RESULTS: FI was defined in 31 unique studies performed in 2973 critically ill children. FI was most commonly defined as presence of gastrointestinal (GI) symptoms and/or large gastric residual volume (GRV) (n = 21), followed by discontinuation of EN due to GI symptoms (n = 7) and inadequate delivery of EN (n = 3). Median prevalence of FI was 20.0% [IQR 7.4%-33.0%]. Large GRV, abdominal distention, diarrhoea and vomiting/emesis, were the predominantly reported GI symptoms to define FI. FI was associated with severity of illness, mortality and nosocomial infections. CONCLUSIONS: Feeding intolerance is inconsistently defined in the current literature, but appears to be a prevalent concern in critically ill children. FI is most frequently defined by the presence of GI symptoms. A standardized definition is needed for both clinical and research purpose to determine the consequences of FI in relation to short-term and long-term outcomes. The new proposed definition for FI entails the inability to achieve enteral nutrition target intakes in combination with the presence of GI symptoms indicating GI dysfunction. PROTOCOL REGISTRATION: PROSPERO registration number: CRD42018092967. Registered on 07 June 2018.

Peptide nutrient-energy dense enteral feeding in critically ill infants: an observational study.

BACKGROUND: Enteral feeding is challenging in critically ill infants. Target intakes are often not achieved as a result of fluid restriction, procedural interruptions and perceived enteral feeding intolerance. In those infants perceived to have poor feeding tolerance, the use of a peptide nutrient-energy dense enteral feed (PEF) may improve nutritional intake and minimise feeding interruptions as a result of gastrointestinal symptoms. The aim of this observational study was to characterise the use of a PEF amongst critically ill infants in two paediatric intensive care units (PICUs). METHODS: Records from critically ill infants aged <12 months admitted to two PICUs were retrospectively reviewed with a PICU length of stay (LOS) ≥ 7 days. Achievement of nutritional targets for the duration of PEF was reviewed. Gastrointestinal symptoms, including gastric residual volume, constipation and vomiting, were evaluated as tolerance parameters. RESULTS: In total, 53 infants were included, with a median age on admission of 2.6 months. Median admission weight was 3.9 kg in PICU-1 and 4.7 kg in PICU-2. Median (interquatile range) energy intake in PICU-1 and PICU-2 was 68 (47-92) and 90 (63-124) kcal kg-1 , respectively, and median (interquatile range) protein intake 1.7 (1.1-2.4) g kg-1 and 2.5 (1.6-3.2) g kg-1 , respectively. Feeding was withheld because of feeding intolerance in one infant (4%) on two occasions in PICU-1 for 2.5 h and in two infants (7%) on two occasions in PICU-2 for 19.5 h. Gastric residual mean (SD) volumes were 3.5 (5.4) mL kg-1 in PICU-1 and 16.9 (15.6) mL kg-1 in PICU-2. CONCLUSIONS: Peptide nutrient-energy dense feeding in infants admitted to the PICU is feasible, well tolerated and nutritional targets are met. However, with this study design, it is not possible to draw any conclusions regarding the benefit of PEF over standard PE feed in critically ill children and future work is required to clarify this further.

Weight improvement with the use of protein and energy enriched nutritional formula in infants with a prolonged PICU stay.

BACKGROUND: Reaching an optimal nutritional intake is challenging in critically ill infants. One possible way to minimise nutritional deficits is the use of protein and energy-enriched (PE)-formulas. We aimed to describe weight achievement and gastrointestinal symptoms in infants admitted to the paediatric intensive care unit (PICU) while receiving PE-formula for a prolonged period. METHODS: Records from infants admitted to a multidisciplinary PICU and using PE-formula were analysed retrospectively. Infants were eligible if they received PE-formula daily for at least 2 weeks. Weight achievement was determined as the difference between weight-for-age (WFA) Z-scores at the start and end of PE-formula use. Gastrointestinal symptoms, including gastric residual volume, constipation and vomiting, were evaluated as tolerance parameters. RESULTS: Seventy infants with a median [interquartile range (IQR)] age of 76 (30-182) days were eligible. The PICU duration was 50 (35-83) days during which they received PE-formula for 30 (21-54) days. Predominant admission diagnoses were post-cardiac surgery, respiratory and cardiac diagnosis. A significant mean (SD) WFA Z-score increase of 0.48 (1.10) (P < 0.001) and a median (IQR) weight gain of 5.80 (3.28-9.04) g kg-1 day-1 was observed. Multivariate regression showed that a lower WFA Z-score at start was associated with a higher WFA Z-score increase during PE-formula use (ß -0.35 (95% confidence interval =  -0.50 to -0.19); P < 0.001). The maximum 24-h gastric residual volume was 8.1 mL (IQR = 2.2-14.3) for each 1 kg in bodyweight. Three (4%) infants were treated for diarrhoea and three infants were treated for vomiting. CONCLUSIONS: The majority of infants with a prolonged PICU stay showed weight improvement when using PE-formula. PE-formula was well tolerated because gastrointestinal symptoms only occurred in few infants.

Current clinical trials in paediatrics: Report of the ESPEN special interest group in paediatrics.

BACKGROUND & AIMS: At the 38th annual ESPEN congress in The Hague, the Netherlands, the Special Interest Group (SIG) in Paediatrics presented data about current research activities in the field of paediatric nutrition which are performed worldwide and translated this to future research perspectives. METHODS: Extensive search of all registered observational and interventional clinical trials in the database ClinicalTrials.gov using the search terms: children nutrition, paediatrics nutrition and children feeding. RESULTS: A total of 717 studies were found; 173 were duplicates and 114 included adult participants and were therefore excluded. Hence, 430 remained for analysis, of which 69% were randomized controlled trials. The most investigated research topic was nutrition in specific diseases (n = 98), followed by obesity (n = 92), and studies including premature infants (n = 48). The overall median estimated enrolment of children in the trials was 150 children [IQR 50-365]. There were 44 studies in which >1000 participants will be enrolled and six studies with >10,000 participants. Studies including >1000 participants were primarily performed in North America (39%), Africa (27%), and Europe (16%). CONCLUSIONS: This SIG report showed that 430 clinical nutrition trials in paediatrics are registered and current research focusses primarily on specific diseases and obesity. The SIG paediatrics encourages future research to invest in well-controlled interventional trials.