What Is Known
- Energy overfeeding, associated with worse outcome, is prevalent in critically ill children.
- The definition of overfeeding is mostly based on the ratio of caloric intake to measured resting energy expenditure.
- An alternative method to detect overfeeding is the comparison of measured respiratory quotient to the predicted respiratory quotient based on macronutrient intake.
What Is New
- The proportion of mechanically ventilated children identified as overfed varies depending on the definition.
- No clinical endpoint or (surrogate) marker has been studied to determine maximum caloric intake.
- A definition of overfeeding ideally should take into account age, nutritional status, and the phase of critical illness.
Nutritional support affects outcome in critically ill children (1–3). Undernutrition has long been the primary focus for nutritional research, but overfeeding is also prevalent in pediatric intensive care units (PICUs) (1,4–6). Caloric overfeeding is associated with increased mortality in critical ill adults (7). It may lead to liver dysfunction by increasing the risk for hepatobiliary complications, such as steatosis and cholestasis, and might increase the risk of infection secondary to hyperglycemia (8). Overfeeding of glucose leads to lipogenesis with an increase in carbon dioxide (9), resulting in a difficulty to wean from the ventilator (10,11). Furthermore, overfeeding during critical illness might evoke a phenotype of autophagy deficiency as a potentially important contributor to mitochondrial, organ, and skeletal muscle damage, particularly when amino acid enriched parenteral nutrition (PN) is provided (12,13). Also in critically ill children, unintended consequences of overfeeding are likely to occur (14).
To prevent these detrimental effects, nutritional therapies are ideally guided by resting energy expenditure (REE) throughout the course of illness (15). REE can be measured (mREE) by indirect calorimetry or predicted by use of equations, and might be affected by the type, severity and stage of disease (16–18). Because there is a lack of studies using clinical endpoints to determine the optimal caloric intake in critically ill children, recommendations on minimum caloric intake are often based on equilibrating energy or protein balances (19,20). So far, however, no clinical endpoint or (surrogate) marker has been studied to determine the optimal maximum caloric intake in this population. Overfeeding is arbitrarily defined as a ratio caloric intake/REE >110% (7,21–23) or >120% (14,24–28) (see related studies in Table 1). As an alternative method the comparison of measured respiratory quotient (RQ) to the predicted RQ based on the macronutrient intake (RQmacr) is suggested (29,30). The measured RQ is derived from the ratio of CO2 production over O2 consumption and reflects the use of different substrates. An RQ value >1.0 indicates lipogenesis and is frequently used to identify carbohydrate overfeeding (29). RQmacr is the weighted average of the RQs of the different macronutrients administered, which can be obtained from the modified Lusk table. A difference >0.05 between RQ and RQmacr has been proposed to define overfeeding (29,30).
The aim of the present study was to compare different definitions of overfeeding in critically ill mechanically ventilated children based on measurements of mREE, RQ, and caloric intake and to find an appropriate definition to study the effect of overfeeding on clinical endpoints in future trials.
Neonates and children up to the age of 18 years admitted to our level III multidisciplinary PICU were consecutively included in the study when they met the criteria for indirect calorimetric measurements: mechanical ventilation with a Servo ventilator (Siemens-Elema, Solna, Sweden), FiO2 < 60%, tube leakage <10%, and hemodynamic stable condition (blood pressure and heart rate within 2 standard deviation [SD] of age-related values).
The institutional review board of the Erasmus MC approved the study protocol, and written parental informed consent was obtained before children entered the study. Data, including age, sex, weight, primary diagnosis, surgical status, days on mechanical ventilation, length of stay on the pediatric intensive care unit, route of nutritional support, and energy and macronutrient intake were recorded. The severity of illness on admission was assessed by the Pediatric Risk of Mortality score (31). Nutritional status on admission was defined by weight for age (WFA) SD-scores using Dutch Growth Standards (32); children were categorized as underweight if their WFA SD-score was <−2.
Indirect calorimetry measurements were performed as soon as possible after admission. Oxygen consumption and carbon dioxide production, standardized for temperature, barometric pressure, and humidity were measured for at least 2 hours using the Deltatrac (Datex Division Instrumentarium, Helsinki, Finland) metabolic monitor. Measured REE (mREE) was calculated with the modified Weir formula (33). The properties of the Deltatrac metabolic monitor have been described previously (34). The RQ was calculated from the measured oxygen consumption and carbon dioxide levels (24).
Children were fed enterally and/or parenterally according to the local feeding protocol (25) and the judgment of the attending physician. A glucose infusion was provided during the first 12 to 24 hours after admission aimed at a carbohydrate intake of 4 to 6 mg/kg/min (children <30 kg) or 2 to 4 mg/kg/min (>30 kg) (35,36). Enteral nutrition (EN), consisting of human milk or standard formula, was started as soon as possible in all patients, either continuously or intermittently through a postpyloric or nasogastric tube. PN was started within 48 hours after admission in case of insufficient EN, either by peripheral infusion or by central venous access. Fluid and electrolyte intakes were adjusted to individual requirements.
Energy goals for EN were based on the body weight–based Schofield equation (37) on the first day of admission and on the Recommended Dietary Allowances for the subsequent length of stay (Dietary Reference Intake: energy, protein, and digestible carbohydrates, 2001, Health Council of the Netherlands: The Hague). Parenteral energy goals were based on the weight-based guidelines of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition throughout PICU stay (38). Actual total daily intake of energy, carbohydrate, protein, and fat was derived from patient records on the day of calorimetry.
An RQ of administered macronutrients (RQmacr) was calculated based on the modified Lusk table after determination of the ratio of carbohydrate to fat for the total nonprotein calories of the intake provided on the day of the measurement (29). The measured RQ was compared to the RQmacr. The RQ was assumed to approximate the RQmacr, if RQ = RQmacr ± 0.05 (29,30). No corrections were made for losses of macronutrients in stools, when EN was given (39).
The following definitions of energy overfeeding were used and compared:
- Caloric intake/mREE > 110%
- Caloric intake/mREE > 120%
- RQ > RQmacr + 0.05
Statistical analyses were performed using SPSS 21 for Windows, SPSS software (IBM Corp., Armonk, NY). Results are expressed as proportion, mean and standard deviation, or median and interquartile range. Differences between groups were analyzed by use of the Mann-Whitney and Kruskal-Wallis test. Pearson correlation coefficient (r) was used to evaluate the strength of the relation between RQ and carbohydrate intake, and between the continuous variables on which the definitions are based: RQ–RQmacr and the ratio caloric intake/mREE. Linear regression analysis was used to further define the relation between RQ–RQmacr and the ratio caloric intake/mREE. Two-tailed P values <0.05 were considered significant.
Measurements were performed in 78 children (51 boys). Clinical and nutritional characteristics are shown in Table 2. Median age was 6.3 (interquartile range 1.5–29.3) months. An SD-score for WFA < −2 was found in 23 children (30%). The reason for admission was medical in 77% of the children, with 32% respiratory insufficiency. The median length of stay at the time of measurement was 1 day (interquartile range 1–3) after PICU admission. All children were mechanically ventilated and sedated with midazolam and/or morphine. Seventy-four percent of the children received EN; 57% were fed by EN exclusively; and 18% received a mixture of EN and PN. Total PN was provided in 15% of the children; 10% of the children received only glucose infusion at time of measurement.
Table 3 shows patient demographics and nutritional characteristics in relation to the different definitions of energy overfeeding studied.
For the total population, mean mREE was 48 (±9.6) kcal/kg compared to a mean caloric intake of 52 (±29) kcal/kg/day. The mean RQ was 0.88 (± 0.08). Fifty percent of the children (n = 39) were provided with >110% of mREE and 40% (n = 31) with >120%. These children had a significant lower SD-score WFA (−1.8 vs −0.5, P = 0.004) and, as expected, had a significant higher intake of calories (P < 0.001), protein (P < 0.001), fat (P < 0.001), and carbohydrates (P < 0.001) per kilogram compared to the children without overfeeding. Children with an SD-score WFA < −2 had a significant higher intake of calories per kilogram than children with an SD-score WFA ≥ −2 (61 vs 48 kcal/kg/day, P = 0.031). The ratio caloric intake/mREE was 119% in children with an SD-score WFA <−2 and 100% in the children with an SD-score ≥ −2 (P = 0.091).
In 22% of the children (n = 17) RQ was higher than RQmacr + 0.05. Fourteen of these children (82%) were also identified as overfed according to the ratio caloric intake/mREE of >120% definition. Children identified as overfed by RQ had a significant higher intake of calories (71 vs 44 kcal/kg/day, P = 0.001), protein (2.2 vs 0.9 g/kg/day, P < 0.001), and fat (2.9 vs 0.9 g/kg/day, P < 0.001) per kilogram and a higher ratio caloric intake/mREE (71 vs 44 kcal/kg/day, P < 0.001) compared with the children with an RQ < RQmacr ± 0.05.
There was a significant positive correlation between RQ-RQmacr and the ratio caloric intake/mREE (r = 0.627, P < 0.001) (Fig. 1). Caloric overfeeding as defined by RQ (RQ exceeding RQmacr + 0.05) occurred if the ratio caloric intake/mREE exceeded 165%, reflecting a mean caloric intake of 79 kcal/kg/day in our population.
The present study showed that when different definitions indicating overfeeding were applied to a group of critically ill mechanically ventilated children, a wide variation in the proportion of children identified as overfed was found, ranging from 23% to 50%. RQ exceeded RQmacr + 0.05 from a ratio caloric intake/mREE of 165%.
Overfeeding in critically ill children has been predominantly reported with the definition based on the ratio caloric intake/REE (Table 1) (14,21–25,27,28). The proposed and frequently used upper limits of 110% or 120% are, however, consensus based and not derived from sound studies with clinical endpoints. A recent systematic review in which 9 studies were summarized and a recent single-center study by Jotterand Chaparro et al investigated the influence of energy and protein intake on protein balance in critically ill children. It was found that a minimum intake of respectively 57 and 58 kcal/kg/day and of 1.5 g protein/kg/day were required to achieve a positive protein balance (19,20). Taking into account a ratio caloric intake/mREE > 110% and >120%, a subgroup analysis of our study showed that 36% and 23% of the children, respectively, did not achieve this minimal energy intake of 57 kcal/kg/day but would be identified as being overfed. This identification of a patient as being overfed while they can be presumed to have a negative protein balance would be a contradiction, regardless of the fact that a positive protein balance should be interpreted as an intermediate and not a clinical outcome measure (40). Based on our data the upper limit of caloric intake was found to be 165% of the ratio caloric intake/mREE based on RQ-RQmacr, reflecting a caloric intake of 79 kcal/kg/day. This upper limit is more in line with the identified minimum intakes than the most frequently used limits of 110% and 120%.
An age-dependent definition of overfeeding, however, might be necessary. In the single-center study by Jotterand Chaparro et al, it was shown that nitrogen balance was equilibrated with a caloric intake close to mREE in children younger than 3 years, and 122% of mREE in children older than 3 years (19).
Another reason to question the use of the ratio caloric intake/mREE to identify overfeeding throughout the course of PICU stay is the effect of the phase of critical illness. Several studies have shown that REE remains stable during the first week after admission (16,21,41). This implies that, when using this ratio to guide nutritional therapy, the upper limit of caloric intake remains stable in this period as well, even if the patient is recovering, and extra energy is presumed necessary for tissue repair and growth. Furthermore, REE is measured in rest, whereas the patient in the recovery phase will be mobilizing. These patients have a higher energy need than patients who are not able to mobilize, but this increase in caloric requirements cannot be identified with current methods.
So far, only one study, with a limited number of surgical infants, investigated the relation between caloric intake and the phases of the metabolic stress response using an RQ > 1.0, reflecting lipogenesis, to define overfeeding (11); it was found that the rate of overfeeding was lower in the resolving stress group, defined by a C-reactive protein (CRP) level of 2 mg/dL or less, compared to the acute stress group (CRP > 2 mg/dL) (33.4% vs 69.2%, P < 0.001). Although inflammatory parameters such as a CRP level might be used to guide caloric intake, it is not clear how soon energy intake can be increased without the risk of overfeeding, because no single metabolic or hormonal markers or parameters have consistently shown to indicate the start of the anabolic phase. When the child is in the recovery phase and is able to mobilize, optimal caloric intake might be as high as the recommended intake for healthy children (24) or even higher to compensate for catch-up growth.
The risk of overfeeding might also be affected by the nutritional status of the child. More attention is paid to nutritional support of malnourished children or children at nutritional risk (42) and absolute weight-based intake goals are lower for malnourished patients than nonmalnourished peers (25). Also in our study, caloric intake was higher in children with an SD-score WFA < −2. Therefore nutritional goals are more easily reached in this population, but with a concomitant increased risk of overfeeding. Besides the increased caloric intake, malnourishment is likely to affect energy expenditure by an altered body composition. In a recent study, mREE in malnourished critically ill children was found to be 80% of predicted (43), highlighting the need for measurement of energy requirements to identify overfeeding in this specific group of children. This hypometabolic state was reflected in an increased ratio caloric intake/mREE of 145% (43). We also found that children identified as being overfed by the ratio caloric intake/mREE, had a significantly lower SD-score, compared to children without overfeeding. This contrasting combination of lowered mREE and caloric overfeeding described in malnourished children, might be linked to an amplification of mitochondrial dysfunction associated with the stress response (43,44). Therefore the effect of nutritional status on the risk of overfeeding may be intertwined with the phases of critical illness.
Because the difference of RQ-RQmacr reflects the use of different macronutrients within a patient, it acts as a more functional parameter to describe overfeeding throughout the course of illness and for different age groups. The use of this parameter might be, however, limited when caloric intake is less than mREE (45) and during the acute phase of critical illness when endogenous energy production is present, even with adequate energy provision (46). RQ is also affected by factors unrelated to feeding (29).
Our study is further limited by the small number of patients, the lack of clinical endpoints, and the fact that we only performed single measurements. Therefore, it should be followed by larger prospective studies on the effect of intake on clinical outcomes, preferably with a longitudinal design.
To conclude, the proportion of mechanically ventilated patients identified as overfed ranged widely from 23% to 50% depending on the criteria applied. The currently used definitions to describe overfeeding fail to take into account several relevant factors associated with critical ill children and are therefore not generally applicable to the PICU population. We advocate the development of a definition for overfeeding dependent on age, nutritional status, and phase of illness, preferably based on clinical outcome measures.
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