Assessment of resting energy expenditure in mechanically ventilated patients

¹ From the Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Paris (CF, EG, J-LD, JL, and J-YF), and the Service de Pneumologie et Réanimation, Hôtel-Dieu de Paris, Paris (CF).

² Supported by Service de Réanimation Médicale, Hôpital Européen Georges Pompidou and Service de Pneumologie et Réanimation, Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris. This study was not sponsored by gifts or fellowships.

³ Address reprint requests to C Faisy, Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75908 Cedex 15 Paris, France. E-mail: christophe.faisy{at}wanadoo.fr.

ABSTRACT  
Background: Usual equations for predicting resting energy expenditure (REE) are not appropriate for critically ill patients, and indirect calorimetry criteria render its routine use difficult.

Objective: Variables that might influence the REE of mechanically ventilated patients were evaluated to establish a predictive relation between these variables and REE.

Design: The REE of 70 metabolically stable, mechanically ventilated patients was prospectively measured by indirect calorimetry and calculated with the use of standard predictive models (Harris and Benedict’s equations corrected for hypermetabolism factors). Patient data that might influence REE were assessed, and multivariate analysis was conducted to determine the relations between measured REE and these data. Measured and calculated REE were compared by using the Bland-Altman method.

Results: Multivariate analysis retained 4 independent variables defining REE: body weight (r² = 0.14, P < 0.0001), height (r² = 0.11, P = 0.0002), minute ventilation (r² = 0.04, P = 0.01), and body temperature (r² = 0.07, P = 0.002): REE (kcal/d) = 8 x body weight + 14 x height + 32 x minute ventilation + 94 x body temperature - 4834. REE calculated with this equation was well correlated with measured REE (r² = 0.61, P < 0.0001). Bland-Altman plots showed a mean bias approaching zero, and the limits of agreement between measured and predicted REE were clinically acceptable.

Conclusion: Our results suggest that REE estimated on the basis of body weight, height, minute ventilation, and body temperature is clinically more relevant than are the usual predictive equations for metabolically stable, mechanically ventilated patients.

Key Words: Resting energy expenditure • mechanical ventilation • indirect calorimetry • nutrition • metabolism • intensive care

INTRODUCTION  
Metabolism is acutely modified by any form of severe disease. Resting energy expenditure (REE) is also influenced by malnutrition (1, 2). Results of one study showed that malnutrition affected 40–50% of the patients in the intensive care unit (ICU) (3). Malnutrition may be linked to higher morbidity and mortality rates and increased length of stay (3). Thus, caloric requirements and specific metabolism are essential components of the care of these patients.

Long et al (4) emphasized that variables such as fever or type of the injury or illness influence the REE of patients who have undergone surgery without respiratory assistance. Other variables affecting the REE of ICU patients include the following: medications used, treatment procedures (5–7), modalities of mechanical ventilation (8, 9), weaning of respiratory support (10, 11), type of nutrition (12, 13), and body composition (1, 14). Few studies have compared REE measured by indirect calorimetry or REE calculated by using Harris-Benedict predictive equations (15) for adult patients requiring respiratory assistance. Moreover, these studies mainly included patients who had undergone minor surgery (5–7, 16–21) and showed that the difference between measured and calculated REE is substantial (from -30% to 49%). However, most of these investigations did not consider situations that modify REE or the limits of accuracy of indirect calorimetry in the ICU. Therefore, we prospectively studied the REE of mechanically ventilated patients in the ICU with the objective of identifying factors that might influence REE to propose an accurate method for calculating REE in patients receiving respiratory support.

SUBJECTS AND METHODS  
Subjects
This prospective, observational study was conducted over a 1-y period in a university teaching hospital. We evaluated adult patients who were intubated and mechanically ventilated for > 24 h. The local institutional review board approved the study design, and the procedures followed were in accordance with the Helsinki Declaration of 1975 as revised in 1983. Indirect calorimetry is a noninvasive technique that assesses the heat liberated during metabolic oxidative processes by measuring oxygen consumption ( ^·VO₂) and carbon dioxide production ( ^·VCO₂). However, many clinical conditions common to ICU patients are responsible for erroneous values measured by indirect calorimetry (6, 13, 22,23).

Thus, to obtain accurate REE measurements, patients were excluded for the following reasons.

1. Hemodynamic instability: introduction, dose modification, and withdrawal of inotropic drugs (catecholamines, ß₂-mimetic, and theophylline) during the preceding 2 h.
   
2. Respiratory instability: pulse oxygen saturation <90%, modification of ventilator settings during the preceding 2 h, and signs of hyperventilation (respiratory rate > 35/min) or respiratory weakness during pressure-support ventilation.
   
3. Variations in the carbon dioxide pool: a constant carbon dioxide pool is a good indicator of respiratory stability and allows a close approximation of ^·VCO₂ and the respiratory quotient (RQ = ^·VO₂/( ^·VCO₂) (24). Also, bicarbonate infusion, digestive or renal losses of bicarbonate (diarrhea, ureterosigmoidostomy, use of acetazolamide) or the use of extracorporeal blood lines for dialysis were reasons for exclusion.
   
4. An intravenous carbohydrate load >15 kcal·kg^-1·d^-1 (ie, 5000 mL of 5% dextrose/d): a relation exists between carbon dioxide production and carbohydrate or caloric intake (12, 25), especially in hypermetabolic and mechanically ventilated patients (5, 24, 26). Moreover, continuous enteral feeding increases thermogenesis from nutrient intake and could affect REE (13). Thus, continuous enteral feeding was stopped 6 h before calorimetry.
   
5. Air leaks around the respiratory circuit (aerosolization, lines for nitric oxide or heliox, and tracheal gas insufflation) or visible air leaks in the chest-drainage system.
   
6. Accumulation of intermediate metabolites [indirect calorimetry fails to assess the energy produced by metabolic interconversion processes (13)], ketogenesis, or alcoholic intoxication.
   
7. High level of inspired oxygen (FiO₂ expressed as a percentage): errors in ^·VO₂ measurement increase exponentially with rising FiO₂ concentrations (27). As determined by Weissman et al (28), the limits of accuracy in measuring FiO₂ concentrations with our metabolic monitor ranged from 0.21 to 0.80. Patients who required an FiO₂ > 80% to obtain a pulse oxygen saturation > 90% were also excluded.
   

Measurements and instrumentation
After inclusion in the study, simple acute physiology scores 24 h after admission to the ICU and for the 24-h-period before indirect calorimetry were calculated (29). REEs were calculated with the use of Harris-Benedict equations (15) as follows:

RESULTS  
Of the 132 patients intubated and mechanically ventilated for >24 h over a 1-y period, only 70 patients were eligible for metabolic monitoring. Sixty-two patients were excluded from the study: 32 because of hemodynamic instability, 13 for respiratory instability or a high FiO₂ concentration, 7 for carbon dioxide pool variation, 4 because of inadequate nutrition, and 4 because of air leaks around the respiratory circuit or visible air leaks in the chest-drainage system. The demographic and descriptive data of the eligible patients are summarized in Tables 1 and 2. Data collected just before the calorimetric measurements are listed in Tables 3 and 4.

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TABLE 1 . Causes of acute respiratory failure in the patients whose resting energy expenditure was measured by indirect calorimetry¹  

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TABLE 2 . Demographic and descriptive characteristics of the patients eligible for metabolic monitoring¹  

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TABLE 3 . Medications used, organ dysfunction, nutrition, vital signs, and anthropometric and bioelectrical variables in patients eligible for metabolic monitoring¹  

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TABLE 4 . Modalities of respiratory support and respiratory variables for the patients eligible for metabolic monitoring¹  
We performed 1260 REE measurements over 5-min periods; 128 (10%) of these values were excluded from the statistical analysis because the quality criteria were not satisfied (RQ < 0.7 or tracheal aspiration was needed). The median of excluded 5-min periods was 1/patient (range: 0–12). Mean measured REE and calculated REE (Harris-Benedict equations) differed significantly (1890 ± 404 compared with 1399 ± 243 kcal/d, respectively; P < 0.001). Mean calculated REE corrected according to Long et al (4) was not significantly different from measured REE (1817 ± 528 compared with 1890 ± 404 kcal/d, respectively). The mean FeCO₂ was 36 ± 9 mm Hg, and the mean RQ was 0.76 ± 0.05.

Univariate analysis
No significant relation was found between measured REE and the cause of acute respiratory failure or presence of organ dysfunction, documented infection, or immune deficiency (Table 5). Women had a significantly lower REE than did men (Table 5) and women were significantly shorter. Type of respiratory or nutritional support or the use of sedatives or vasoconstrictors, inotropic agents, morphine or its derivatives, or curare did not significantly change the measured REE in our patients (Table 6). These observations did not change when REE was adjusted for weight or height (data not shown). Measured REE did not differ between patients who died and those who survived (1883 ± 389 compared with 1898 ± 422 kcal/d, respectively; P = 0.99). A statistically significant relation was noted between measured REE and 7 variables: body weight, height, body mass index, height²/Z₂ estimated by bioelectrical impedance, body temperature, arterial blood oxygen saturation, and minute ventilation (Table 7).

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TABLE 5 . Univariate analysis: association between resting energy expenditure (REE) measured by indirect calorimetry and various clinical characteristics of the patients eligible for metabolic monitoring¹  

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TABLE 6 . Univariate analysis: association between resting energy expenditure (REE) measured by indirect calorimetry and type of respiratory or nutritional support or medications used in patients eligible for metabolic monitoring¹  

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TABLE 7 . Univariate analysis: relation between resting energy expenditure measured by indirect calorimetry and quantitative variables in the patients eligible for metabolic monitoring¹  
Multivariate analysis
Multivariate linear regression analysis, performed with the abovementioned 7 variables and sex, identified 4 independent predictors of REE (body weight, height, minute ventilation, and body temperature) and yielded the following equation to predict REE from these independent variables for men and women (Table 8):

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TABLE 8 . Multivariate analysis: independent variables determining resting energy expenditure in the patients eligible for metabolic monitoring¹  

DISCUSSION  
The results of this study show that the REE of 70 mechanically ventilated patients was affected by only a few determinant variables (weight, height, body temperature, and minute ventilation) and that usual predictive equations failed to accurately estimate REE in these patients. However, because calculations that use predictive equations appear easier to apply than does indirect calorimetric REE in routine practice in the ICU, we wanted to identify those variables that are most closely linked to REE to attempt to establish a relation between these variables and REE.

To the best of our knowledge, this is the first study that assessed indirect calorimetric measurements to develop a simple predictive formula for evaluating REE in clinical practice in the ICU. To remain within the scope of this pilot study, we were particularly cautious in selecting the patients by using multiple exclusion criteria to avoid the unsteady state; in addition, we used a rigorous protocol of indirect calorimetric measurements by using 4 different quality criteria. Indirect calorimetry does not seem applicable immediately after ICU admission, particularly in critically ill patients but could be after a delay that allows stabilization. This delay is probably not crucial, considering the possible usefulness of REE evaluation to routinely manage the nutrition of critically ill patients. As a consequence, the sickest patients could not be evaluated in our study because they had multiple criteria of exclusion; nonetheless, studied patients were indeed severely ill considering their simple acute physiology scores and ICU outcomes.

Measured REE was 25% higher than the calculated REE obtained with the Harris-Benedict equations. This finding agrees with previously reported values (5–7, 16–21). In our study, the difference between measured REE and calculated REE was statistically significant but not when the latter equations were corrected for the hypermetabolism factors proposed by Long et al (4). Although a good correlation was obtained between calculated REE (Harris-Benedict equations) and measured REE, the Bland-Altman analysis showed a statistically significant and clinically relevant mean bias between the 2 methods. This bias could reflect the underfeeding of our patients. Indeed, we limited enteral intakes before the metabolic measurements were made because continuous enteral feeding increases the thermogenesis from nutrient intake and could affect REE (13). Limiting caloric intake for a long time will reduce REE in malnourished patients and result in false predictions calculated with the Harris-Benedict equations (1). By contrast, Zauner et al (37) showed in healthy subjects that, after short-term fasting (3 d), REE rises as a result of an increase in serum norepinephrine. We considered that a brief suspension of caloric intake did not affect the calculated REE of our patients because we stopped enteral feeding just 6 h before the metabolic measurements began. Moreover, the correction factors proposed by Long et al did not improve the accuracy of the Harris-Benedict equations in our critically ill patients. The use of constant hypermetabolism factors, which are mediated by time (4), could explain the poorer REE prediction. However, time from hospital or ICU admission was not a determinant factor of REE in our patients. Also, our results confirmed that REE estimated with the use of the Harris-Benedict equations and Long et al’s correction factors were not reliable for mechanically ventilated patients.

We established that organ dysfunction, the drugs administered, and therapeutic procedures did not affect the REE in our mechanically ventilated patients. Indeed, there were no significant differences in the REE between patients who received pressuresupport, volume-assisted, or volume-controlled ventilation. This result differs from previously published data (8–11). The combination of factors affecting REE might explain this lack of difference because they cancel each other out. For example, 51% of our patients simultaneously received morphine or its derivatives (which decreased the REE) and inotropic agents (which increased the REE). Such combinations are commonly administered in the ICU. Bruder et al (38) measured REE by indirect calorimetry in 24 patients with head injuries and showed that sedation considerably influenced REE. These authors affirmed that sedation changed REE by changing body temperature, which remains the main determinant of REE. According to these same authors, infection also influences REE independently of body temperature. Moriyama et al (36) showed that the REE of patients with septic systemic inflammatory response syndrome increased in a heterogeneous population, including burn victims and postoperative (heart and digestive tract) patients not receiving respiratory support. In contrast, we did not identify infection as an independent factor associated with REE; however, we used different criteria to define infection, and most of our patients had medical problems. In addition, because the methods used to measure REE in our study and that of Moriyama et al were very different, the REE values are likely not comparable. Moreover, because our sample size was not sufficiently large to reach adequate statistical power in these situations, we were unable to discern significant REE difference between patients with and without curare use or liver failure.

Our multivariate analysis indicated that the independent factors defining REE were those closely linked to metabolism (weight, height, minute ventilation, and body temperature). Roza and Schizgal (1), using the regression equations developed by Moore (34), showed excellent correlation between REE and active cell mass in 337 healthy subjects. To the best of our knowledge, no studies have been conducted in an ICU to evaluate both the REE and the body composition of patients. Anthropometric and bioelectrical impedance measures, both of which can be conducted bedside in the ICU, require constant fat-free mass hydration (72%) to clinically asess body composition (32, 39). Unfortunately, edema and perturbed cellular hydration are common in critically ill patients and may affect the estimation of body composition with regression equations. Moreover, it is unknown how the regression equations used for estimating fat-free mass and active cell mass are affected by the acute inflammatory process frequently present in ICU patients (40). This is why we merely studied the relation between REE and height²/Z₁ and height²/Z₂. Unlike Roza and Schizgal, we found no relation between REE and height²/Z₁, probably because many of our mechanically ventilated patients had abnormalities in water volume.

Indirect calorimetry requires 3–4 h of metabolic and hemodynamic stability to obtain accurate REE measurements—a long time for critically ill patients. Moreover, estimating REE with the use of Fick’s method is not reliable in the ICU (41, 42). The predictive equation derived from our multivariate analysis was strongly correlated with measured REE, and the mean bias between the 2 methods was close to zero. The limits of agreement between the 2 methods were clinically acceptable. However, according to our selection criteria, metabolic stability is required to calculate REE with this predictive equation. In our clinical experience, most ventilated patients briefly satisfy these criteria, thereby allowing their REE to be estimated with the predictive equation but not with indirect calorimetry. Furthermore, overestimation of the quality of the prediction is possible for 2 reasons: 1) because the equation was developed in a specific population, which limits its generalization to other populations, and 2) because any equation developed with a given data set must be validated with another set. Finally, although our results suggest that, for stable mechanically ventilated patients, REE estimated with the use of weight, height, minute ventilation, and body temperature is clinically more reliable than is REE estimated with predictive models, further prospective validation is needed to confirm these results in a larger group of ICU patients.

ACKNOWLEDGMENTS  
We acknowledge Gilles Chatellier (Department of Medical Informatics and Biostatistics, Hôpital Européen Georges Pompidou) for statistical advice.

CF was responsible for conceiving and designing the study, collecting and analyzing the data, and drafting the report. EG and J-LD were responsible for interpreting the data and drafting the report. JL and J-YF were responsible for revising the report. No author had any financial or personal interest in any company or organization relevant to the field of research in connection with this work.

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