What Is Known
- Indirect calorimetry is the criterion standard in measuring energy needs in a clinical setting.
- Nutritional requirements in critically ill children are dynamic and malnutrition adversely affects outcomes.
What Is New
- Persistent negative energy and nitrogen balance exist during first week of treatment of critically ill children with severe sepsis.
- Predictive equations are inaccurate for estimating energy needs in children with severe sepsis.
- Underweight children have higher baseline resting energy expenditure during critical illness.
Nutritional support is a basic component of clinical management of critically ill children in the pediatric intensive care unit (PICU). Malnutrition in PICU is common, more so in developing countries (1). Common reasons for underfeeding are improper nutritional assessment, delayed initiation, and frequent interruption of feeds. This can lead to calorie and protein deficit which in turn may result in protein catabolism, decreased respiratory muscle strength, prolonged mechanical ventilation, and PICU stay (2). Improper nutritional assessment can also lead to overfeeding, which can cause hepatic steatosis, hyperglycemia, increased risk of infection, and prolonged mechanical ventilation (3). Nutritional status of these children further worsens due to increased metabolic demand during the course of critical illness and may have a negative impact on clinical outcome. Therefore, to fulfill the energy demands of these children, an accurate estimation of energy needs is essential.
Resting energy expenditure (REE) is the amount of energy expended at rest in 24 hours. Commonly, various predictive equations (Schofield equation, Harris-Benedict equation, and FAO/WHO/UNU equations) have been used to estimate the REE. The criterion standard to measure REE is using indirect calorimetry (IC). IC measures the respiratory gas exchange and gives a reliable estimate of REE independent of severity of illness or baseline nutritional status (4). But not many centers follow nutritional guidelines and very few use routine IC. In a worldwide survey of 156 PICU's in 52 countries, only 52% of centers had a nutritional protocol and only 14% use IC (5).
REE depends on the ongoing metabolic demand which in turn depends on the nature of disease. Children with traumatic brain injury and severe burns were found to be hypermetabolic, whereas children admitted in medical PICU were hypometabolic when measured REE (mREE) was measured using IC (3,6,7). Few studies in children with burns, post-op congenital heart disease, and critically ill requiring ventilation have concluded that the predictive equations do not accurately estimate energy needs in PICU (6,8,9). They may either under or overestimate the energy needs. The American Society of Parenteral and Enteral Nutrition recommends the routine use of IC for estimation of REE (10).
There are no studies in ventilated children with “severe sepsis” measuring energy balance using IC and comparing it with predictive equations. Therefore, we planned to study the energy needs using IC in children with severe sepsis. We further planned to calculate the energy balance, nitrogen balance, and to compare the mREE with predicted REE (pREE).
This was a single-center prospective observational study. All consecutive children ages 5 to 12 years with severe sepsis (11) requiring mechanical ventilation in a tertiary care PICU of North India from May 2016 to June 2017 were enrolled. We excluded children having chest tube with an active air leak, bronchopleural fistula, ventilator circuit leak >10%, FiO2 ≥60% or those on high-frequency oscillatory ventilation. Ethical approval was obtained from the Institute Ethics Committee and the study protocol was registered with Clinical Trial Registry, India (CTRI/2017/12/010982). A written informed consent was obtained from the parents or legal guardians before enrollment.
The aim of the study was to study the daily energy balance (difference between mREE and total caloric intake) in children with severe sepsis.
- 1. To determine the nitrogen balance using 24-hour urinary nitrogen method
- 2. To determine the agreement of mREE with pREE using Schofield (12), Harris-Benedict (13), and FAO/WHO/UNU (14) equations
- 3. To determine the correlation of severity of illness (using PRISM III, Sequential Organ Function Assessment [SOFA] score, and Vasoactive Inotropic Score [VIS]) with mREE.
Baseline demographic, anthropometric, severity of illness (PRISM III (15), daily SOFA (16), and daily VIS (17)) and nutritional details were recorded in predesigned proforma. WHO z scores for weight-for-age, height-for-age, and basal metabolic index (BMI) were calculated in all children and then classified as normal (BMI z score ≥ −2 to <+1); underweight (BMI z score <−2 z); overweight (BMI z score ≥1–<2); or obese (if BMI z score ≥2 z) (18).
Nutritional data including time of commencement of feeds, route of nutritional support, daily calorie, and protein intakes were measured. As per our unit policy, type of feed, timing of initiation, and hiking of feeds were done uniformly. Volume of feed was based on Holliday-Segar equation (19). Targeted calories were 50 to 60 kcal · kg−1 · day−1 and proteins 1.5 to 2 g · kg−1 · day−1(20).
pREE was calculated using Schofield's (12), Harris-Benedict (13), and FAO/WHO/UNU (14) equations. IC measurements were taken between day 1 and 7 or till extubation, whichever was earlier. First measurement was taken preferably within 24 hours but definitely within 48 hours. Measurements were done by the primary investigator (J.I.) after undergoing required training from the technical experts. Recommended prerequisites and procedure of IC were followed (eTable 1). Calorimetric measurements were made using a portable metabolic cart (Quark RMR, COSMED). It measures resting oxygen consumption (Vo2), carbon dioxide production (Vco2), and respiratory quotient. REE was autocalculated from these parameters using Weir equation.
Difference between daily total nitrogen intake and loss was calculated as per the equation below.
Nitrogen balance (g/day) = (protein intake (g/day)/6.25) – (UUN g/day × 1.25) (21).
To measure urinary urea nitrogen (UUN), 24-hour urine was collected daily for 7 days or till Foley catheter was in situ. From this, 3 mL of urine was collected daily and frozen at −80oC. UUN was estimated on clinical chemistry analyzer (Advia 1800). Total urinary nitrogen excretion was estimated using a factor of 1.25 to account for nonurea nitrogen (21).
Energy balance—difference between mREE and total caloric intake.
Ventilation-free days—1 point for each day during the measurement period that patient is both alive and free of mechanical ventilation.
3 to 10 years
Boys: (19.6 × weight kg) + (1.033 × height cm) + 414.9 Girls: (16.97 × weight kg) + (1.618 × height cm) + 371.2
10 to 18 years
Boys: (16.25 × weight kg) + (1.372 × height cm) + 515.5 Girls: (8.365 × weight kg) + (4.65 × height cm) + 200
Boys: 66.47 + 13.75 × weight in kg + 5.0 × Height − 6.76 × age
Girls: REE = 655.10 + 9.56 × weight in kg + 1.85 × Height − 4.68 × age
3 to 10 years
Boys: 22.7 × weight in kg + 495
Girls: 22.5 × weight in kg + 499
10 to 18 years
Boys: 17.5 × weight + 651
Girls: 12.2 × weight + 746
Descriptive analysis of continuous outcomes was summarized as mean (standard deviation [SD]) or median (interquartile range [IQR]) as appropriate. Analysis of variance was used to compare nonparametric continuous data and Chi square test to compare categorical variables. Repeated measures analysis of variance was used to determine the significance between variables at different time points. Spearman correlation coefficient (rho) was used to determine the correlation between 2 variables. Bland-Altman plot was used to evaluate the agreement between pREE and mREE. Generalized estimate equation model was used to compare the 2 groups of repeated variables. P value <0.05 was considered significant. STATA 11.0 package was used for data analysis.
Total of 40 patients (24 boys) with a median (IQR) age 7 (5.2, 10) years were included in the study (Figure, Supplemental Digital Content 1, https://links.lww.com/MPG/B610). Seven children (17.5%) were underweight and 1 was obese. Acute CNS infections (n = 18; 45%) and severe pneumonia (n = 7; 17.5%) were the commonest admitting diagnosis. Mean (±SD) PRISM III score was 19 ± 7, with calculated risk of mortality being 30%. Thirty-five children were on vasoactive support. A total of 4 children died (10%). Median (IQR) ventilation-free days were 19 (11, 22) days (Table 1). Four children developed health care–associated infection.
All patients were started on enteral feeds by 12 (6, 19) hours of admission. Full feeds were achieved in all by median (IQR) time of 58 (44, 71) hours. Total of 176 IC measurements were obtained in 40 children with an average of 4 per patient. Mean ± SD mREE for all patients was 1123 ± 310 kcal or 51 ± 17 kcal/kg and the mean ± SD respiratory quotient was 0.77 ± 0.07.
Mean daily energy balance was negative on all the days of measurement. Mean ± SD cumulative energy balance per patient over 7 days was −1761 ± 2226 kcal. Nitrogen balance was negative for initial 5 days and then improved on day 6 and 7 (Table 2).
Agreement of Predicted Energy Expenditure and Measured Resting Energy Expenditure
Average predicted energy expenditure by Schofield was 984 ± 176; Harris-Benedict was 1000 ± 132 and FAO/WHO/UNU was 1011 ± 166 kcal. None of these equations were in agreement with mREE on Bland-Altman plots. The mean (2SD) energy difference with mREE for Schofield was 139 (537) kcal (P = 0.002); for Harris-Benedict was 123 (536) kcal (P = 0.006) and for FAO/WHO/UNU was 113 (542) kcal (P = 0.012) (Fig. 2, Supplemental Digital Content 2, https://links.lww.com/MPG/B610). The predictive equations were accurate in estimating REE within ±10% of mREE in 29.5% of measurements using Schofield; 25% using Harris-Benedict and 29.5% using FAO/WHO/UNU equations. In rest, these equations either underestimate (Schofield 44.3%; Harris-Benedict 46%; FAO/WHO/UNU 41%) or overestimate REE (Schofield 26.2%; Harris-Benedict 29%; FAO/WHO/UNU 29.5%) (Table 3).
Correlation of Measured Resting Energy Expenditure With Disease Severity and Baseline Nutrition Status
None of the severity indices such as PRISM III, daily SOFA score, and daily VIS showed any correlation with mREE (Table 4). Cumulative energy balance over 7 days correlated positively with the ventilation-free days (P = 0.048). On regression analysis no parameter was, however, predictive of either mortality or ventilation-free days (Table 4). Mean mREE was significantly higher in underweight group (68 ± 24 kcal/kg) compared to nonunderweight group (48 ± 12 kcal/kg); P = 0.025 (eTable 2).
Optimization of nutrition is critical in the management of septic children. Both undernutrition and overnutrition can lead to delayed recovery and metabolic complications. REE is highly variable in critically ill children as it is influenced by anthropometry (lean body mass) (22,23), disease state, and PICU interventions (sedation, neuromuscular blockade (24,25), ventilation, temperature control (26), and vasoactive medications (27)). Stress response to severe infection may result in variable immunological, metabolic, or endocrine alterations each of which has an influence on REE (28). This makes REE unpredictable, signifying the need for its actual measurement. We measured REE using IC, calculated actual caloric intake, and the difference was computed to derive energy balance daily. In our study, we demonstrated that critically ill septic children have a persistent negative energy and nitrogen balance during initial week of illness.
Metabolic rate increases significantly during stress states like burns, trauma, or head injury. In a cohort of children with head injury, the energy expenditure was found to vary from hyper- to hypometabolic state and was largely influenced by the interventions such as sedation, neuromuscular blockage, and barbiturates (7). In patients with burns, mREE was about 1.5 times higher than that of pREE (6). In a study on 57 children by Taylor et al (29), mainly postsurgery or liver failure, they, however, reported median REE of 37.2 kcal · kg−1 · day−1. Evidence on REE in pediatric severe sepsis is scant. Oosterveld et al (30) in a subgroup analysis of 13 children with sepsis demonstrated a higher mREE (51.4 ± 16 kcal · kg−1 · day−1) compared to subgroup of post-surgery (42.3 ± 14 kcal · kg−1 · day−1) or trauma (35.5 ± 8 kcal · kg−1 · day−1) patients. The mREE in our cohort (51 ± 17 kcal · kg−1 · day−1) was similar to that of Oosterveld et al (30). Higher mREE in sepsis than surgical cases could be due to presumed increase in metabolic needs. An adult study on critically ill septic patients reported poor outcomes with high metabolic rate (31). We also observed high mREE in underweight children. This explains the fact that underweight children have high energy deficit; further precipitated by critical illness and sepsis (32). These children therefore have higher energy requirement.
We could not achieve target energy intake of 50 to 60 kcal · kg−1 · day−1 in 12 of 17 children at day 5 despite starting enteral feeds early (median 12 hours). This implies that majority of our patients were underfed. In contrast, Jotterand Chaparro et al (33) could achieve 58 kcal · kg−1 · day−1 in critically ill to achieve neutral energy and nitrogen balance. The reason for not achieving the target could be due to increased severity of illness, feeding interruptions due to various reasons and majority of patients on vasoactives. Thus, underfeeding predominated in our cohort. This is in contrast to western PICUs where there is a prevalent risk of overfeeding (3). The positive correlation between cumulative energy balance and ventilation-free days in our study implies that underfed are at risk of decreased respiratory muscle strength thereby leading to prolonged ventilation. This is in accordance with Briassoulis et al (34), who reported that, underfeeding negatively influenced the outcomes in these children. We did not find any association between mREE and outcomes like mortality or ventilator-free days.
Previous studies in critically ill postcardiac surgery and head injury children have demonstrated positive nitrogen balance by day 5 with a protein intake of at least 1.5 g · kg−1 · day−1(35–37). We too observed a similar pattern. Negative nitrogen balance during initial 5 days can be explained by sepsis-induced catabolism or protein intake less than target, resulting in increased muscle protein breakdown, halting of anabolic protein synthesis and shunting of metabolites to synthesis of acute phase reactants. This results in fall of circulating serum protein levels as evident with low serum albumin levels (2.6 ± 0.6 g/dL) in our cohort. If prolonged, this may lead to loss of lean body mass. Different methods have been used in calculating total nitrogen loss among various studies (20). Total urinary nitrogen measured directly is more accurate but less feasible compared to others which estimate nitrogen loss from UUN with or without a correction factor. In this study, we estimated UUN and used a correction factor to account for nonurea nitrogen losses. Although this method is less accurate in critically ill children with rapidly changing physiology, this was the only feasible method in our setting. Same method has been used in many other studies as well (35,36,38).
Various studies have tried multiple predictive equations to predict energy needs in different settings. None of these equations have been able to predict REE within ±10% of mREE in >50% of patients (39). Harris-Benedict equation was least accurate of all with adequate prediction in only one fourth of the cases. The reason for this could be that Harris-Benedict was derived from >16-year-old volunteers and extrapolated to infants and children. The other reason for these equations to be inefficient is that all 3 are derived from healthy volunteers and may not be accurate in dynamically evolving critically ill children. Our study showed that the 3 commonly used predictive equations (Schofield, Harris-Benedict, FAO/WHO/UNU) underestimated mREE in severe sepsis children thereby implying that predicted values are lower than the actual energy needs. The recent study by Jotterand Chaparro et al (40) in predominantly postsurgical patients, evaluated the accuracy of 15 equations using differential and proportional bias method and Bland-Altman plots. Most of these equations underestimated or overestimated REE. In contrast to our data, in adults with sepsis, mREE values correlated well with Harris-Benedict and Schofield equation–derived pREE (41). A stress multiplication factor ranging from 1.1 and 1.6 was, however, used to derive pREE, which is not the current practice in children (42).
The metabolic response to critical illness such as trauma, surgery, burns, or sepsis is variable from hypermetabolic to a hypometabolic state in children (6,43,44). Also, the duration of this response is unpredictable with sustained response seen for weeks after severe burns to a short-lived response after surgeries (6,43). Physician's assessment of this metabolic response may not be accurate in approximately 60% of patients (3). This reiterates the fact that these predictive equations are not useful in such metabolically unstable children and may require regular IC measurements as recommended by American Society of Parenteral and Enteral Nutrition guidelines (10). IC is, however, not available in most of the centers. Main reasons are cost, time-consuming measurements, and difficult to perform in spontaneously breathing or in noninvasive ventilation. Given the inaccuracies of the predictive equations and the wide variability of the REE in critically ill children, IC, however, appears to be the way forward.
In a study by Briassoulis et al (45), nitrogen balance was negatively correlated with PRISM, mortality, and multiorgan dysfunction. Other studies examining correlation of PRISM with mREE, however, found no correlation (46,47). We found that severity of illness has no association with energy needs. Although we hypothesized that use of catecholamines may be associated with a higher metabolic rate, we could not find any significant association of daily VIS score with mREE.
We could demonstrate a significant positive correlation between cumulative energy balance and ventilation-free days rho = 0.31 (P = 0.048). Similar association has been reported in literature with decrease in mortality with increasing enteral feeds (48). Another study showed that increase in caloric intake by 1000 kcal/day significantly decreased mortality in adults (49).
Strengths and Limitations
This is the first study in critically ill children with severe sepsis on ventilator evaluating the energy balance using IC. We followed standard protocols including the prerequisites for calorimetry, appropriate calibration, achieving steady state, and performed calorimetry for a recommended duration of 30 minutes daily. We also calculated daily nitrogen balance. Our study had few limitations. Firstly, it was a single-center study with small sample size. Secondly, the included patients may have been at various stages of their illness which could not be accounted. Thirdly, we did not assess the body composition of our patients and reasons for interruption to feeding. Finally, we did not include children younger than 5 years of age, as our metabolic cart has a minimal bias flow, which could not be attained in them. Data from larger multicentric trials involving different categories of baseline nutritional status and sepsis etiologies will help in developing accurate predictive equations and nutrition guidelines.
Predictive equations are inaccurate in estimating the REE in critically ill children with severe sepsis. IC remains the criterion standard for accurate assessment of energy intake and it should be considered in all patients with metabolic disturbances in addition to anthropometry-based nutritional assessment. Underweight children have higher baseline REE. Titration of caloric and protein intake based on individual needs may improve the outcomes.
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