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1 From the Department of Internal Medicine IV, University of Vienna.
See corresponding editorial on page153.
ABSTRACT
Background: Nutritional support is an important link between the response to injury and recovery in critical illness.
Objective: Our goal was to evaluate energy and substrate metabolism in septic and nonseptic critically ill patients in the resting state and during the administration of standardized total parenteral nutrition.
Design: This was a prospective, clinical cohort study of 25 consecutively admitted critically ill patients either with (n = 14) or without (n = 11) sepsis who received total parenteral nutrition. Resting energy expenditure was measured on days 0, 2, and 7 by indirect calorimetry. Energy and substrate balances were calculated on days 2 and 7.
Results: Resting energy expenditure was not significantly different between septic and nonseptic patients on day 0 (2.65 ± 0.49 and 2.36 ± 0.56 kJ•min-1•m-2, respectively). Energy balances were positive for both groups on days 2 (0.68 ± 0.4 and 0.74 ± 0.6 kJ•min-1•m-2, respectively; NS) and 7 (0.65 ± 0.3 and 0.78 ± 0.5 kJ•min-1•m-2, respectively; NS). Substrate balances were not significantly different between groups on days 0, 2, and 7. Resting energy expenditure on day 0 was negatively correlated with the severity of illness in septic patients only (r = -0.58, P < 0.05).
Conclusions: Metabolic changes were not significantly different between septic and nonseptic critically ill patients during the administration of standardized total parenteral nutrition. A disease-specific macronutrient composition of total parenteral nutrition formulas does not seem to be necessary in either septic or nonseptic critically ill patients.
Key Words: Body temperature • intensive care • energy expenditure • sepsis • critically ill patients • severity of illness • substrate balances • substrate metabolism • total parenteral nutrition • nutritional support
INTRODUCTION
Nutritional support in critically ill patients is aimed at preventing the negative effects of starvation during the course of the disease and at minimizing the negative effects of protein catabolism (1, 2). Healthy and malnourished nonseptic patients utilize mainly carbohydrates for energy production and convert excess glucose into fat (3). In contrast, patients with sepsis show an increase in oxygen consumption and utilize mainly stored fat to meet their energy requirements (4–6). The same metabolic changes are found in nonseptic critically ill patients (7). Consequently, it was recommended that the portion of fat in artificial nutrition be increased for patients with either sepsis or nonseptic critical illness (5–7).
Although it seems likely that energy and substrate metabolism are not significantly different between septic and nonseptic critically ill patients, the 2 groups have not been compared directly. In addition, the responses of these 2 groups of patients to standardized nutritional support have not yet been investigated. Thus, we undertook the present study to evaluate energy and substrate metabolism in septic and nonseptic critically ill patients and the metabolic response to standardized total parenteral nutrition (TPN).
SUBJECTS AND METHODS
Subjects
This prospective, clinical cohort study included 25 patients (10 women, 15 men;
Metabolic studies
Before TPN was administered, the patients' resting energy expenditure (REE) and substrate oxidation rates were measured by indirect calorimetry after they had fasted overnight (day 0). Measurements were made by a technician who was not involved in the treatment and who was not informed of the diagnoses. The patients' daily energy supply was 25% above their measured REE (11) (Table 1). A TPN solution containing 45% glucose, 41% lipids, and 14% amino acids was infused continuously (Kabi Mix; Fresenius Kabi GmbH, Graz, Austria). TPN was started immediately after the first measurement at the calculated infusion rate and the infusion rate remained unchanged during the whole study period. REE and substrate oxidation rates were reevaluated on days 2 and 7.
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TABLE 1.. Substrates and volumes of total parenteral nutrition administered in each patient group1
Indirect calorimetry
Respiratory gas exchange was measured by computerized open-circuit indirect calorimetry (MMC 2900; SensorMedics, Anaheim, CA) as previously described (5, 12). Oxygen consumption and carbon dioxide production were measured in 1-min intervals and the average of a 30-min period was calculated. The system was calibrated at the beginning of each measurement.
Calculations
REE is expressed in kJ•min-1•m-2. REE and oxidation rates for glucose, fat, and protein were calculated according to Ferrannini (13). The nonprotein respiratory quotient was calculated by subtracting the exchange attributable to protein oxidation from the total gaseous exchange. It was assumed that for each 1 g nitrogen produced, 5.923 L oxygen was consumed and 4.754 L carbon dioxide was produced (respiratory quotient for protein: 0.803) (14). For calculation of urea nitrogen appearance rates, changes in plasma urea concentration were taken into account (15). Urinary urea nitrogen was measured colorimetrically (16). The proportion of nonprotein energy derived from carbohydrate and fat was calculated from the nonprotein respiratory quotient. The protein oxidation rate (g/d) was calculated as 6.25 x 24-h urea nitrogen production (g/d) (17). Twenty-four–hour carbohydrate, fat, and protein balances were calculated as 24-h intake minus 24-h oxidation. Protein balance was corrected for miscellaneous nitrogen losses of 4 g/d (18), which is equivalent to a protein intake of 418.4 kJ/d (100 kcal/d). Changes in the free glucose pool were calculated as follows: change in glucose pool = change in blood glucose concentration x 0.25 L/kg body wt (19).
Statistical analysis
This study was exploratory in nature. Data from the 2 groups of patients were compared by using the Mann-Whitney U test. To show differences in values of both groups of patients across time, a repeated-measures analysis of variance (Greenhouse-Geisser test) was used. If the results of the repeated-measures analysis of variance were significant, linear contrasts were used for post hoc testing. Furthermore, differences in the metabolic variables between day 2 and day 0, day 7 and day 0, and day 7 and day 2 were calculated. The chi-square test was applied to compare mortality and the sex distribution between the 2 groups. Correlations were assessed by using Spearman's rank correlation coefficient (r). STATISTICA for WINDOWS (release 5.01; StatSoft, Inc, Tulsa, OK) and SAS (release 6.12; SAS Institute Inc, Cary, NC) were used for the statistical analysis. Results are presented as means ± SDs. P values <0.05 were considered to be statistically significant.
RESULTS
Of the 25 patients studied, 14 were septic and 11 were not. The 2 groups were not significantly different with respect to sex, age, height, and weight (Table 2). The underlying diseases, the infectious agents, and the site of infection for the septic patients are presented in Table 3. The underlying diseases of the nonseptic patients are presented in Table 4. No positive cultures and no evidence of an infection site were detectable in nonseptic patients. On day 0, the respiratory rate was higher in septic patients, whereas there were no significant differences between the groups in temperature, heart rate, arterial partial pressure of carbon dioxide, and white blood cell count (Table 5). Laboratory variables measured on days 0, 2, and 7 are summarized in Table 6.
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TABLE 2.. Characteristics of the patients in each group1
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TABLE 3.. Underlying diseases, infection sites, and infectious agents of the septic patients1
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TABLE 4.. Underlying diseases of the nonseptic patients1
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TABLE 5.. Sepsis criteria of both patient groups on day 01
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TABLE 6.. Laboratory variables assessed during the study period1
The severity of illness as assessed by the APACHE III score was not significantly different between the groups (septic patients: 70.2 ± 11.1; nonseptic patients: 78.9 ± 24.9; Tables 3 and 4). The APACHE III score correlated negatively with measured REE in septic patients (r = -0.58, P < 0.05). No such association was found in nonseptic patients. REE was positively correlated with body temperature in septic patients only (12.2% rise in REE/°C rise in body temperature; Figure 1). No association between body temperature and APACHE III score was found in either group.
FIGURE 1. . Relation between body temperature and resting energy expenditure (REE) in septic (, solid line; r = 0.63, P < 0.05) and nonseptic (X, dotted line; r = 0.46, NS) patients. For septic patients, y = 0.3273x - 9.4325; for nonseptic patients, y = 0.4275x - 13.462.
REE was not significantly different between groups on day 0, and no significant differences in REE were detected between groups during the study period. Furthermore, REE did not change within groups during the study period (Tables 7 and 8). The respiratory quotient increased significantly in both groups on day 2 compared with day 0 and remained high on day 7. No significant differences in respiratory quotient between groups were observed on days 0, 2, and 7.
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TABLE 7.. Metabolic variables assessed during the study period1
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TABLE 8.. Differences in metabolic variables over time in both groups1
Substrate balances were not significantly different between groups during the study period (Table 7). Energy balances became positive in both groups on day 2 (septic patients: 0.68 ± 0.4 kJ•min-1•m-2; nonseptic patients: 0.74 ± 0.6 kJ•min-1•m-2; NS) and day 7 (septic patients: 0.65 ± 0.3 kJ•min-1•m-2; nonseptic patients: 0.78 ± 0.5 kJ•min-1•m-2; NS). There was no significant difference within the groups between days 2 and 7.
DISCUSSION
Our results suggest that no significant differences in measured REE and substrate oxidation rates after an overnight fast existed between septic and nonseptic critically ill patients. Infusion of a standardized TPN formula resulted in no significant changes in REE between or within groups during the study period. Thus, the metabolic response to TPN might not differ between septic and nonseptic critically ill patients. In septic patients, REE was negatively correlated with the severity of illness. Although it has been shown that enteral nutrition is preferable in critically ill patients, we chose to use the parenteral route in this study to avoid enteral substrate losses that might be difficult to assess and because it remains unclear whether macronutrients provided enterally are satisfactorily absorbed because of a possible exocrine pancreatic insufficiency in critically ill patients (20).
Nutritional support is indicated to prevent or correct protein-energy malnutrition when adequate food intake is not possible for long periods of time (1). For providing energy, many different TPN solutions with different macronutrient compositions are available. Metabolic changes in critically ill patients are the result of systemic actions of mediators released in response to trauma, injury, or infection (2). The concentration of these mediators is associated with the severity of illness (21) and it was shown that REE correlates positively with different severity scoring systems (22, 23). Although it was not the aim of this study to compare the REE of critically ill patients and healthy control subjects, our measurements of REE were in the range of values published by other authors for critically ill septic and nonseptic patients (4, 5, 24). Surprisingly, we found a negative association between the APACHE III score and REE in the septic patients but not in the nonseptic patients. This negative association between the severity of illness and REE agrees with results reported by Kreymann et al (24), who also found that REE decreased with the severity of sepsis. Kreymann et al argued that this negative association is a mediator-related effect. Experimental data support these clinical findings; it was shown that combined infusion of interleukin 1 and tumor necrosis factor decrease mitochondrial oxygen consumption in vitro (25).
In our study body temperature was positively correlated with REE in the septic patients. This agrees with the findings of Frankenfeld et al (26), who showed that febrile patients with systemic inflammatory response syndrome were significantly more hypermetabolic than were afebrile patients with systemic inflammatory response syndrome. The amount of the increase in our patients (12%/°C) corresponds to that found by DuBois (27) and Wallace et al (28). No such association was found in our nonseptic patients. This may have been due to the smaller sample size of the nonseptic patient group, or the association itself may not exist. Energy balances were positive in both groups during the administration of TPN in an amount 25% above the REE measured on day 0.
In accordance with the findings of earlier studies (5–7), fat was the main substrate for oxidation, and glucose oxidation was depressed in all our patients after an overnight fast. The respiratory quotient rose in both groups after the initiation of TPN. Substrate balances for carbohydrate and fat became positive in both septic and nonseptic patients. This might reflect that the same metabolic derangement is manifest in both groups of critically ill patients and that metabolic adaptation to substrate administration does not seem to differ. Thus, our data suggest that no specific adaptation of macronutrient composition in feeding of septic and nonseptic critically ill patients is necessary. An alternative explanation for our data is that the methods used were not sufficiently sensitive or the statistical power to find differences between the 2 groups of patients was too low (ie, type I error).
In contrast with the case in healthy subjects and nutritionally depleted patients (3), the respiratory quotient in the subjects in our study never exceeded 1.0, indicating that no net de novo lipogenesis was present (ie, total lipid oxidation was higher than total lipid synthesis) in our critically ill patients despite positive energy and substrate balances. Protein oxidation rates remained unchanged during the administration of TPN in all patients and protein balances were not significantly different from zero after the administration of TPN. However, because protein oxidation rates were calculated from the urea nitrogen appearance rate only, we cannot make conclusions concerning protein metabolism in critically ill patients (18).
In conclusion, septic and nonseptic critically ill patients seem to show the same alterations in energy and substrate metabolism. The metabolic responses during the administration of standardized TPN are comparable in these patients. Therefore, a disease-specific macronutrient composition of a TPN formula does not seem to be necessary for septic or nonseptic critically ill patients.
ACKNOWLEDGMENTS
We thank Barbara Schneider for her statistical assistance and Katrin Kornfell for her thoughtful revision of the manuscript.
REFERENCES