Do critically ill surgical neonates have increased energy expenditure?

Do Critically I11 Surgical Neonates Have Increased Energy Expenditure? By Tom Jaksic, Stephen B. Shew, Tamir H. Keshen, Alexander Dzakovie, and Farook Jahoor Boston, Massachusetts; Houston, Texas; and Iowa City, Iowa

B a c k g r o u n d / P u r p o s e : Adult metabolic studies suggest that critically ill patients have increased energy expenditures and thus require higher caloric allotments. To assess whether this is true in surgical neonates the authors utilized a validated, gas leak-independent, nonradioactive, isotopic technique to measure the energy expenditures of a stable postoperative group and a severely stressed cohort. M e t h o d s : Eight (3.46 _+ 1.0 kg), hemodynamically stable, total parenteral nutrition (TPN)-fed, nonventilated, surgical neonates (5 with gastroschisis, 2 with intestinal atresia, and 1 with intestinal volvulus) were studied on postoperative day 15.5 + 11.9. These were compared with 10 (BW = 3.20 _+ 0.2 kg), TPN-fed, extracorporeal life support (ECLS)-dependent neonates, studied on day of life 7.0 _+ 2.8. Energy expenditure was obtained using a primed, 3-hour infusion of NaH13CO3, breath 13CO2 enrichment determination by isotope ratio mass spectroscopy, and the application of a standard regression equation. Interleukin (IL)-6 levels and C-reactive protein (CRP) concentrations were measured to assess metabolic stress. Comparisons between groups were made using 2 sample Student's t tests. Results:The mean energy expenditure was 53 -+ 5.1 kcal/kg/d

(range, 45.6 to 59.8 kcal/kg/d) for the stable cohort and 55 + 20 kcal/kg/d (range, 32 to 79 kcal/kg/d) for the ECLS group (not significant, P = .83). The IL-6 and CRP levels were significantly higher in the ECLS group (29 _+ 11.5 v0.7 _+ 0.6 pg/mL [ P < .001], and 31 _+ 22 v 0 . 6 _+ 1.3 mg/L [ P < .001], respectively). Mortality rate was 0% for the stable postoperative patients and 30% for the ECLS group. Conclusions: Severely stressed surgical neonates, compared with controls, generally do not show increased energy expenditures as assessed by isotopic dilution methods. These data suggest that the routine administration of excess calories may not be warranted in critically ill surgical neonates and support the hypothesis that neonates obligately redirect energy, normally used for growth, to fuel the stress response. This is a US g o v e r n m e n t work, There are no restrictions o n its use.

INDEX WORDS: Energy expenditure, neonates, critical illness, extracorporeal membrane oxygenation, extracorporeal life support.

(ECLS), in which there is an extremely high rate of protein catabolism and a markedly elevated plasma concentration of the acute-phase proteins such as C-reactive

DULT METABOLIC STUDIES suggest that critically ill surgical patients have elevated resting energy expenditures that are proportional to the severity of the underlying disease process. 1 This has led to the practice of multiplying an estimate of basal or resting energy expenditure by a stress factor, reflecting disease severity, to approximate caloric need. 1 Actual measurements of resting energy expenditures in long-term surgical intensive care unit patients, however, indicate that such an approach may lead to overfeeding. 2 The provision of surfeit calories is deleterious because it results in a higher CO 2 production rate leading to ventilatory compromise, the synthesis of excess fat with the evolution of a fatty liver, and even a paradoxical increase in net protein catabolism) -5 Newborns undergoing major surgery manifest only a transient 20% elevation in resting energy expenditure that returns to normal within 12 hours. 6 There is a paucity of data regarding the resting energy expenditure of neonates who remain critically ill for extended periods of time and require protracted total parenteral nutrition (TPN). A paradigm of continued metabolic stress in newborns is afforded by extracorporeal life support

From the Department of Surgery, Children's Hospital, Harvard Medical School, Boston, MA; USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine Departments of Surgery and Pediatrics, Texas Children's Hospital, Houston, TX; and the Department of Surgery, University af lowa, Iowa City, IA. Presented at the 31st Annual Meeting of the American Pediatric Surgical Association, Orlando, Florida, May 25-29, 2000. Funding has been provided from the USDA/ARS under Cooperative Agreement #6250-5100-6001. This work is a publication of the US Department of Agriculture (USDA )/Agricultural Research Service (ARS) Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Address reprint requests to Tom Jaksic, MD, PhD, Children's Hospital, Division of Pediatric Surgery, 300 Longwood Ave, Boston, MA 02115. This is a US government work. There are no restrictions on its use. 0022-3468/01/3601-0010500.00/0 doi: l O.l O53/jpsu.2001.20007

Journal of Pediatric Surgery, Vol 36, No 1 (January), 2001: pp 63-67

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JAKSIC ET AL

protein (CRP). 5,7 CRP concentration appears to reflect the degree of illness in pediatric surgical patients. 8 Precise measurement of resting energy expenditure in critically ill neonates using the standard methods of indirect calorimetry and the application of the Weir equation is difficult because of the requirement for a leak-free system. 9 Both neonates who are ventilated with uncuffed endotracheal tubes and those who are on ECLS do not have a closed respiratory circuit. Other sources of error for indirect calorimetric determinations of energy expenditures include the higher fractions of inspired oxygen (FiO2) used in critically ill patients and the low volumes of gas exchange in small neonates, l°,H A relatively new technique using the intravenous infusion of a very small quantity of a nonradioactive, stable isotope tracer, [13C]bicarbonate (NaH13CO3), allows the determination of CO 2 production and ultimately energy expenditure without the need for a closed respiratory circuit. Only the infusion rate of (NaHa3CO3) and the ratio of 13C labeled to unlabeled CO 2 are required to calculate CO 2 production. This technique is highly correlated (r = .98) with the estimates of energy expenditure obtained by indirect calorimetry and the Weir equation in surgical neonates. ~2 Thus, using the NaHa3CO3 isotopic dilution method this study sought to determine if severely stressed surgical neonates on ECLS showed increased resting energy expenditures as compared with similarly nourished, clinically stable, postoperative surgical newborns. We hypothesized that neonates obligately redirect energy, normally used for growth, to fuel the stress response, hence, resting energy expenditures would not be elevated in the ECLS group. Such data are useful in evaluating if the routine administration of excess calories is warranted in critically ill surgical neonates. MATERIALS AND METHODS

Subjects After obtaining approval from the Baylor College of Medicine Institutional Review Board and parental informed consent, 2 groups of surgical neonates were studied. The first consisted of 8, hemodynamicaily stable, spontaneously breathing babies (3.46 + 1.0 kg) who were studied on postoperative day 15.5 -+ 11.9. Gastroschisis was diagnosed in 5 of the neonates, intestinal atresia in 2, and intestinal volvulus in 1. At the time of the study, each patient's source of nutrition was TPN (containing lipid) supplying 3.1 -+ 0.7 g/kg/d protein (Trophamine; McGaw, Irvine, CA), and a total energy intake of 98 -+ 21 kcal/kg/d. The second cohort consisted of 10 (BW = 3.20 _+ 0.2 kg), TPN-fed, extracorporeal life support (ECLS)-dependent neonates, studied on day of life 7.0 + 2.8. Primary pulmonary hypertension was diagnosed in 4 of the patients, meconium aspiration in 3, congenital diaphragmatic hernia in 2, and sepsis in 1. Five of the patients were on venovenous ECLS, and 5 of the patients were on venoarterial ECLS. All calculations for the ECLS group are based on birth weight in an effort to obviate errors secondary to changes in hydration status. At the time of the study, each ECLS patient' s source of nutrition was TPN (containing

NaH13CO3 Infusion CO2 Samples Time

P

-I~

•

• • • • ]

[

[

[

0

lh

2h

3h

Fig 1. The study protocol depicts the primed (P), continuous intravenous infusion (arrow) of NaH13C03 and its relationship to CO 2 breath sampling (11). The time line is in hours.

lipid) supplying 2.6 + 0.6 g/kg/d protein (Trophamine; McGaw), and a total energy intake of 89 _+ 18 kcal/kg/d. During ECLS support, ventilator settings were set at minimal levels to prevent atelectasis, and the ECLS circuit and a servocontrolled radiant warmer maintained core body temperature. There were no transfusions of blood products during the investigation. All neonates on ECLS were studied in the neonatal intensive care unit and were not operated on for at least 72 hours before the study. Inclusion criteria for ECLS were based on 2 of the following 3 criteria: an oxygen index greater than 40, Pao 2 less than 40 mm Hg for 2 hours, and a lactate level of 3 mmol/L and rising.

Study Protocol In the control group baseline expired breath samples were obtained using a 3-way Rudolph valve and a face mask connected to a modified Douglas bag. A primed (9 /xmol/kg), 3-h continuous intravenous infusion (6/xmol/kg/h) of sterile, pyrogen-free NaH13CO3 (13C isotopic enrichment 99%; Cambridge Isotope Laboratory, Andover, MA) was administered using a calibrated Medfusion syringe pump (model 2010; Medex, Inc, Duluth, GA) and Medex infusion tubing with an in-line 0.22/xm filter (model FS-116; Medex, Inc). The length of the infusion was based on previous work that confirmed the presence of an isotopic steady state within 90 to 120 minutes. 12-14 Four sets of duplicate CO 2 breath samples were collected at 15-minute intervals over the last hour of the infusion using the same method as the baseline samples. Infusates were prepared aseptically, tested for sterility and pyrogenicity on a routine basis, and stored at 6°C until used. An identical protocol was utilized for the ECLS patients except that the CO 2 samples were collected from the outlet valve of the Kolobow membrane lung connected to the ECLS circuit. Thirty minutes before the initiation of the infusion protocol, the carbogen (carbon dioxide and air mixture) was temporarily discontinued for the duration of the infusion protocol. This was done to eliminate the exogenous source of carbon dioxide and hence avoid a false overestimation of the carbon dioxide production rate. The isotopic study design is summarized in Fig 1. CRP levels were determined from plasma samples of the above ECLS patients using radioimmunodiffusion assay (The Binding Site, Birmingham, UK) and expressed as milligrams per liter. IL-6 levels were obtained using ELISA assay (R&D Systems, Minneapolis, MN) and expressed as picograms per milliliter. These data were compared to a TPN-fed, clinically stable, neonatal control group from whom plasma samples were similarly obtained and analyzed for CRP and IL-6 levels.

Analytical Methods The individually prepared, syringed infusates were weighed before and after each experiment to confirm the accuracy of the administration rate. Immediately after the end of the infusion, each subject's syringed infusate was capped air free, and the NaH13CO3 concentration was measured by acid/base titration using 6 mmol/L HC1. Isotopic enrichment of expired CO 2 was assessed by monitoring ions at m/e (mass to charge ratio) of 44 and 45 with a continuous flow isotope ratio mass

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spectrometer (Europa Scientific, Crewe, UK) and expressed as atom % excess above baseline. Steady-state values were obtained by determining the average CO 2 isotopic enrichment after reaching plateau, as previously described) 5 The CO 2 production rate (RaCO2) was calculated using the standard steady-state equationt6: RaCO2 ( m m o l / k g / h ) - I n f (mmol/kg/h) •[(E~ (99% e n r i c h e d ) / E C Q (atom % e x c e s s ) ) - 1 ] where E 1 is the isotopic enrichment of the NaH13CO3 infusate, Inf is the infusion rate of NaH13CO3, and EGO 2 is the mean isotopic enrichment of 13CO2 at plateau during the NaH13CO3 infusion. The uncorrected energy expenditure (kcal/kg/d) was calculated from RaCO z and individual energy equivalents of CO 2 (EequivCO2) as follows: EE (kcal/kg/d) =RaCO 2 (mol/kg/h)'22.4 (L-CO2/mol) •EequivCO2 (kcal/L-CO2)-24 (h/d) where, based on the known substrates of the TPN administered during the study to each patient, the energy equivalent of CO 2 was ascertained

arterial ECLS patients (n = 5) had a mean resting energy expenditure of 54 -+ 19 kcal/kg/d (not significant, P = .87). The IL-6 levels were significantly higher in the E e L S group than in clinically stable TPN-fed neonates (29 + 11.5 v 0.7 -+ 0.6 pg/mL [P < .001]). Similarly, the CRP levels were significantly higher in the ECLS cohort than in the clinically stable TPN-fed neonates (31 _+ 22 v 0.6 -+ 1.3 mg/L [P < .001]). Within ECLS patients, plasma IL-6 and plasma CRP levels did not correlate significantly with resting energy expenditure (r = - 0 . 1 2 9 and r = - 0 . 4 9 7 , respectively). There also was no correlation between IL-6 and CRP plasma levels themselves within the ECLS group (r = -0.048). The hospital mortality rate was 30% for the E e L S group and 0% for the stable postoperative patients.

asl7~

DISCUSSION E~quivCO2 (kcal/L-CO2) = ( fat %kcal'6.599) + ( p r o t e i n %kcal.5.576) + ( glucose %kcal.5.047). The uncorrected energy expenditure of each patient, based on the NaH13CO3 infusion (EE (kcal/d)), was then converted to an accurate estimate of resting energy expenditure (IndirCal (kcal/d)) using the following linear regression with an expected r 2 of 96%12: IndirCal (kcal/d)= - 9 . 3 4 1 +(0.705.EE (kcal/d))

Statistical Analysis All values are expressed as mean + SD. Statistical analyses were performed using 2 sample Student's t tests, and Pearson correlation, with Minitab version 11.1 (Minitab Inc, State College, PA) statistical software on an IBM-compatible personal computer. Significance was determined as P less than .05.

RESULTS

The mean resting energy expenditure was 53 _+ 5.1 kcal/kg/d (range, 45.6 to 59.8 kcal/kg/d) for the 8 fully TPN-fed, postoperative, surgical patients and 55 _+ 20 kcal/kg/d (range, 32 to 79 kcal/kg/d) for the 10 fully TPN-fed patients in the ECLS group (not significant, P = .83; Fig 2). Subgroup analysis showed that the venovenous ECLS patients (n = 5) had a mean resting energy expenditure of 56 _+ 20 kcal/kg/d and the venoon

UJ

Control

EeLS

Fig 2. The mean resting energy expenditure -+ SD of 8 stable, TPN-fed, postoperative neonates (control) is compared with 10, TPNfed neonates on extracorporeal life support (ECLS), Two-sample t test shows the means to be not significantly different with a P = ,83,

A careful appraisal of energy requirements in critically ill surgical neonates is essential as both underestimates and overestimates of energy needs are associated with potentially harmful consequences. Protein accretion is augmented by an adequate energy allotment, and this is particularly evident when protein intake is marginal. 18 Overfeeding results in CO 2 retention, evolution of a fatty liver, and a paradoxical elevation in net protein catabolism. 34 In critically ill adult populations a positive correlation between the degree of illness and resting energy expenditure has resulted in a long-standing practice of providing higher caloric supplementation to those with severe disease. 1 Formally resting energy expenditure encompasses the basal metabolic rate plus diet-induced thermogenesis (the heat generated by the consumption of food); however, the latter is a relatively small component even in neonates. Resting energy expenditure is measured directly or indirectly. Direct methods are based on the principle that all energy eventually is converted to heat. In practice, a subject is placed in a thermally isolated chamber, and the heat dissipated is accurately determined over a prolonged period. 19 This technology is not easily applicable to ill patients. Indirect calorimetry relies on the measurement of Vo 2 (the volume of oxygen consumed), Vco 2 (the volume of carbon dioxide consumed), and in some instances a correction factor derived from urinary nitrogen excretion to calculate resting energy expenditure. 9,2° Intubated patients with uncuffed, hence, leaking, endotracheal tubes and those patients on an ECLS circuit pose problems for this technique, because a closed collection system is difficult to obtain. Nonradioactive stable isotopes may be used in neonates to measure energy expenditure by quantifying CO 2 production rate, and these techniques do not require a leak-free respiratory system. Doubly labeled water,

66

2H21802, has been used for this purpose in stable infants, 21 but possesses some drawbacks. This technique involves approximately 5 days of urine collections and relies on constant water balance to ensure a meaningful integrated estimate of energy expenditure over this interval. Further, 2H2~sOz is very expensive. The labeled [13C]bicarbonate method for quantifying CO 2 production rate, outlined in this report, relies on an inexpensive (NaH13CO3) isotope tracer that yields a precise estimate of energy expenditure over 3 hours and requires only breath samples (Fig 1). Validation studies of the NaH13CO3 technique in surgical neonates showed that it has a correlation coefficient of 0.98 with respect to resting energy estimates garnered by indirect calorimetry and the Weir equation. 12 Applying the NaH13CO3 isotopic dilution method this study sought to determine if severely stressed surgical neonates showed increased resting energy expenditures as compared with stable postoperative surgical newborns. Both groups were TPN fed and received similar caloric and protein allotments. ECLS neonates were chosen as a model of prolonged severe metabolic stress because these patients are known to have the highest rates of net protein catabolism of any critically ill group. 7 Plasma IL-6 and CRP levels also were used to assess if the ECLS neonates were truly under metabolic stress during the time of the study. IL-6 is a cytokine, released by activated T cells and macrophages, that is elevated in children after surgery, correlates with increased protein turnover, predicts mortality risk, and is associated with the acute phase protein response. 22-24 The hepatically derived acute phase protein, C-reactive protein (CRP), also has been positively correlated with the degree of neonatal illness. 25 As expected, both plasma IL-6 and CRP levels were markedly elevated in the ECLS group as compared with stable TPN-fed neonates (P < .001). Further, the ECLS patients had a 30% mortality rate prior to discharge, whereas the stable postoperative patients all survived to discharge. The mean resting energy expenditure for the 8 postsurgical patients who acted as controls for this study was 53 _+ 5.1 kcal/kg/d and for the 10 patients in the ECLS group it was 55 -+ 20 kcal/kg/d (not significant, P = .83; Fig 2). The control resting energy expenditure was comparable with published estimates in other stable TPN-fed neonatal cohorts. 26 Subgroup analysis showed that the venovenous ECLS patients had a mean resting energy expenditure of 56 _+ 20 kcal/kg/d, and the venoarterial ECLS patients had a mean resting energy expenditure of 54 ± 19 kcal/kg/d (not significant, P = .87). Hence, there was, on average, no increase in resting energy expenditure in the ill ECLS group compared with the

JAKSIC ET AL

stable, similarly nourished, postoperative control patients. Interestingly, the one available study that examined patients on ECLS using the principles of indirect calorimetry and a closed respiratory circuit also arrived at a similar mean resting energy expenditure of 57 kcal/kg/ d. 27 One of our earlier studies that assessed protein and energy needs in neonates on and post ECLS was justly criticized for the use of uncorrected isotopic data to estimate energy expenditure. 7 Applying the calculations of the current report to those data it is apparent that this previously reported venoarterial cohort of patients also had a mean resting energy expenditure close to the current findings (53 kcal/kg/d). Although the stable postoperative controls and ECLS patients had a similar mean resting energy expenditure, the coefficient of variation was 9.6% for the controls and 36% for the ECLS group. Unfortunately, within the ECLS cohort, neither plasma IL-6 or plasma CRP levels were predictive of resting energy expenditure. This high variability in the resting energy expenditures of critically ill neonates is similar to findings noted in adult critically ill patients. 2 It underscores that group estimates of energy expenditure in critically ill neonates may be substantially inaccurate for any given individual and emphasizes the importance of developing actual measurement techniques to optimally tailor nutritional support strategies. An interesting question that arises is how critically ill neonates fuel the metabolic stress response without generally increasing resting energy expenditure. A plausible explanation is afforded by the fact that neonates, unlike adults, are actively growing. Only approximately 65% of neonatal energy requirements are necessary to meet resting energy expenditure. 2s The remainder is utilized primarily for maintaining growth, and less so for temperature regulation and to meet the demands of activity. Hence, based on the data of this study, the total energy needs of intravenously fed, full-term, surgical neonates would be about 85 kcallkg/d. Ill neonates stop growing, become lethargic, and require a thermally supported ambient. Thus, this energy is available to supply the metabolic response to injury without any consistent alteration in resting energy expenditure. Other factors, such as the use of sedation also may further lower resting energy expenditure. From a therapeutic standpoint it would be best to support the metabolic reaction to illness and, at the same time, augment growth; however, substrate manipulation alone seems limited in its ability to facilitate this process. Another study has shown that the provision of calories, in excess of 80 to 90 kcal/kg/d, to neonates on ECLS does not improve protein balance and only raises the CO2 production rate. 5 It may be concluded that critically ill surgical neonates, when compared with stable postoperative new-

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borns, do not manifest an increase in mean resting energy expenditure and would thus seem not to require the routine administration of excess calories. Critically ill neonates do, however, demonstrate a high degree of variability in resting energy expenditure and may benefit

from actual measurements to optimize their nutritional therapy. ACKNOWLEDGMENTS The authors thank J.P. Wen, Margaret Frazer, and Melanie Del Rosario for technical assistance.

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15. Jahoor F, Burrin DG, Reeds PJ, et al: Measurement of plasma protein synthesis rate in infant pig: An investigation of alternative tracer approaches. Am J Physiol 267:R221-R227, 1994 16. Kien CL: Isotopic dilution of CO z as an estimate of CO2 production during substrate oxidation studies. Am J Physiol 257:E296E298, 1989 17. Elia M: Energy equivalents of CO 2 and their importance in assessing energy expenditure when using tracer techniques. Am J Physiol 260:E75-E88, 1991 18. Calloway DH, Sector H: Nitrogen balance as related to caloric and protein intake in active young men. A m J Clin Nutr 2:405-412, 1954 19. Scale JL, Rumpler WV: Synchronous direct gradient layer and indirect room calorimetry. J Appl Physiol 83:1775-17781, 1997 20. Ferrannini E: The theoretic basis of indirect calorimetry: A review. Metabolism 37:287-301, 1988 21. Jones PJ, Winthrop AL, Schoeller DA, et al: Validation of doubly labeled water for assessing energy expenditure in infants. Pediatr Res 21:242-246, 1987 22. Sweed Y, Puri P, Reen DJ, et al: Early induction of IL-6 in infants undergoing major abdominal surgery. J Pediatr Surg 27:10331036, 1992 23. De Bandt JP, Chollet-Martin S, Hernvann A, et al: Cytokine response to burn injury: Relationship with protein metabolism. J Trauma 36:624-628, 1994 24. Sullivan JS, Kilpatrick L, Costarino AT, et al: Correlation of plasma cytokine elevations with mortality rate in children with sepsis. J Pediatr 120:510-515, 1992 25. Pourcyrous M, Bada HS, Korones SB, et al: Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatric 92:431-435, 1993 26. Pencharz P, Beesley J, Saner P, et al: Total-body protein turnover in parenterally fed neonates: Effects of energy source studied by using [15N]glycine and [1-13C]leucine. A m J Clin Nutr 50:1395-1400, 1989 27. Cilley RE, Wesley JR, Zwischenberger JB, et al: Metabolic rates of newborn infants with severe respiratory failure treated with extracorporeal membrane oxygenation. J Pediatr Surg 23:306-311, 1988 28. Shew SB, Jaksic T: The metabolic needs of critically ill children and neonates. Semin Pediatr Surg 8:131-139, 1999