PEDIATRICS Vol. 121 No. 3 March 2008, pp. 497-507 (doi:10.1542/peds.2007-1363)
ARTICLE |
Age Differences in Inflammatory and Hypermetabolic Postburn Responses
a Shriners Hospitals for Children, Galveston, Texas
b Department of Surgery, University of Texas Medical Branch, Galveston, Texas
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The aim of this study was to identify contributors to morbidity and death in severely burned patients <4 years of age.
METHODS. A total of 188 severely burned pediatric patients were divided into 3 age groups (0–3.9 years, 4–9.9 years, and 10–18 years of age). Resting energy expenditure was measured through oxygen consumption, body composition through dual-energy x-ray absorptiometry, liver size and cardiac function through ultrasonography, and levels of inflammatory markers, hormones, and acute-phase proteins through laboratory chemistry assays.
RESULTS. Resting energy expenditure was highest in the 10- to 18-year-old group, followed by the 4- to 9.9-year-old group, and was lowest in the 0- to 3.9-year-old group. Children 0 to 3.9 years of age maintained lean body mass and body weight during acute hospitalization, whereas children >4 years of age lost body weight and lean body mass. The inflammatory cytokine profile showed no differences between the 3 age groups, whereas liver size increased significantly in the 10- to 18-year-old group and was lowest in the 0- to 3.9-year-old group. Acute-phase protein and cortisol levels were significantly decreased in the toddler group, compared with the older children. Cardiac data indicated increased cardiac work and impaired function in the toddler group, compared with the other 2 age groups.
CONCLUSIONS. Increased mortality rates for young children are associated with increased cardiac work and impaired cardiac function but not with the inflammatory and hypermetabolic responses.
Key Words: burn • intensive care • pediatric • outcome
Abbreviations: REE—resting energy expenditure • CO—cardiac output • SV—stroke volume • HR—heart rate • TBSA—total body surface area • IL—interleukin
Severe burns during childhood represent disastrous injuries, affecting nearly every organ system and leading to significant morbidity or death.1,2 Burns cause increased inflammation, hormone disturbances, and hypermetabolism, leading to physiologic changes that persist for 
12 months after the burn.1,3–8 Recent advances in burn care, such as metabolic support, control of infections, resuscitation, early excision and grafting of the burn wounds, and treatment of inhalation injury have improved outcomes for severely burned children and adults.1 Children <4 years of age, however, still have high mortality rates. According to the World Health Organization, the highest mortality rates for severe burns are observed in children <4 years and elderly adults >70 years of age.9 A recent study of 1647 children admitted to our hospital between 1985 and 2005 with burns involving >40% of total body surface area (TBSA) confirmed the World Health Organization data, demonstrating that toddlers had a significantly higher mortality rate, compared with older children and adolescents.10 Contributors to morbidity and death in burn patients are inflammatory and hypermetabolic responses, infections and sepsis, changes in body composition, organ failure, and cardiac dysfunction.1,11,12
The aim of this study was to compare the postburn responses in severely burned pediatric patients 0 to 3.9 years of age (toddlers), 4 to 9.9 years of age (prepubertal children), and 10 to 18 years of age (teenagers). We wanted to identify differences in the postburn responses between these 3 age groups, to establish new treatment options to improve morbidity and mortality rates for pediatric burn patients <4 years of age. We hypothesized that toddlers would have increased hypermetabolic and inflammatory postburn responses, leading to increased incidence of infections and sepsis, multiorgan failure, and death.
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METHODS |
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Study Design
This study was approved by the institutional review board of the University of Texas Medical Branch. Written informed consent was obtained from each patient's guardian before enrollment in the study. Inclusion criteria were as follows: children <18 years of age and burns involving >40% of TBSA. Between 1996 and 2006, severely burned patients who did not receive any anabolic agent or study drug treatment were included in the study and divided into 3 age groups, that is, 0 to 3.9 years of age (toddlers), 4 to 9.9 years of age (prepubertal children), and 10 to 18 years of age (teenager).
In this prospective study, all patients received the same standard acute burn care. Within 48 hours after admission, each patient underwent total burn wound excision and grafting with autograft skin and allograft. Patients returned to the operating room when autograft donor sites healed and became available for reharvest (usually 6–8 days after the last operation). Sequential staged surgical procedures for repeat excision and grafting were performed until the wounds healed. Each patient received enteral nutrition via a nasoduodenal tube (Vivonex total enteral nutrition; Sandoz Nutritional Corp, Minneapolis, MN). The composition of Vivonex is 82% carbohydrate, 15% protein, and 3% fat. Daily energy intake was calculated to deliver 6300 kJ/m2 of TBSA burned plus 6300 kJ/m2 of TBSA. This feeding regimen was started at admission and continued at a constant rate until the wounds healed. Energy intake remained constant throughout the study periods.
Burned patients were connected to an Emtek vitals signs tracking system (Eclipsys; Rockville, MD) with standard echocardiographic leads. Heart rate (HR) was measured hourly and verified by each patient's nurse. The average HR for each 24-hour period was determined throughout the hospital stay. Clinical data were collected prospectively.
Indirect Calorimetry
As part of our routine clinical practice, all patients underwent resting energy expenditure (REE) measurements within 1 week after hospital admission and weekly thereafter during their acute hospitalization. For the present study, we chose the first metabolic study and compared it with the metabolic study at discharge. The studies were performed between midnight and 5 AM, while the patients were asleep and receiving continuous feeding. REE was measured by using a Sensor-Medics Vmax 29 metabolic cart (Sensor-Medics, Yorba Linda, CA). Subjects were tested in a supine position while under a large, clear, ventilated hood. The REE was calculated from the oxygen consumption and carbon dioxide production by using equations. All REE measurements were made at ambient temperatures of 30°C, which is the standard environmental setting for all patient rooms in our acute burn ICU. The REE measurements were used to guide nutritional management and to assess the level of metabolism. The discharge REE measurements were used to determine the level of hypermetabolism when the burn wounds were 95% healed and were included as part of this study. Measured values were compared with predicted normative values on the basis of the Harris-Benedict equation.
Body Composition
Height and body weight were determined clinically 5 days after admission and at discharge. Total lean body mass, fat, bone mineral density, and bone mineral content were measured with dual-energy x-ray absorptiometry. An Hologic model QDR-4500W dual-energy x-ray absorptiometry system (Hologic, Waltham, MA) was used to measure body composition. To minimize systematic deviations, the Hologic system was calibrated daily with a spinal phantom, in the anteroposterior, lateral, and single-beam modes. Individual pixels were calibrated with a tissue bar phantom, to determine whether the pixel was reading bone, fat, lean tissue, or air. Plain anteroposterior and lateral tibia-fibula radiographs were taken from each subject in each follow-up period, to evaluate possible premature closure of epiphyseal plates induced by anabolic agents.
Serum Hormone, Protein, and Cytokine Levels
Blood was collected from the burn patients at the time of admission, preoperatively, and postoperatively for 4 weeks, for serum cytokine hormone and protein analysis. Blood was drawn in a serum-separator collection tube and centrifuged for 10 minutes at 1320 rpm; the serum was removed and stored at –70°C until assayed.
Serum hormone and acute-phase protein levels were determined by using high-performance liquid chromatography and enzyme-linked immunosorbent assay techniques. The Bio-Plex Human Cytokine 17-Plex panel was used with the Bio-Plex suspension array system (Bio-Rad, Hercules, CA) to profile expression of 17 inflammatory mediators (interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, interferon-
, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and tumor necrosis factor). The assay was performed according to the manufacturer's instructions. Briefly, serum samples were thawed and then centrifuged at 4500 rpm for 3 minutes at 4°C. Serum samples were then incubated for 30 minutes with microbeads labeled with specific antibodies to one of the aforementioned cytokines. After a wash step, the beads were incubated with the detection antibody cocktail, with each antibody specific to a single cytokine. After another wash step, the beads were incubated with streptavidin-phycoerythrin for 10 minutes and washed, and the concentrations of each cytokine were determined by using the array reader.
Urine Cortisol Levels
Urine cortisol levels were determined with standard laboratory techniques, accounting for urine amount, creatinine levels, and creatinine clearance.
Cardiac Function
M-mode echocardiograms were completed as follows. At the time of the study, none of the patients presented with or had suffered previously from concomitant diseases affecting cardiac function, such as diabetes mellitus, coronary artery disease, long-standing hypertension, or hyperthyroidism. Study variables included resting cardiac output (CO), cardiac index, stroke volume (SV), and resting HR. SV and CO were adjusted for TBSA and expressed as indexes. All ultrasound measurements were made with a Sonosite Titan echocardiography system, with a 3.5-MHz transducer. Recordings were performed with the subjects supine and breathing freely. M-mode tracings were obtained at the level of the tips of the mitral leaflets in the parasternal long-axis position, and measurements were performed according to the American Society of Echocardiography recommendations. Left ventricular volumes determined at end-diastole and end-systole were used to calculate ejection fraction, SV, CO, and cardiac index. Three measurements were performed and averaged for data analysis.
Liver Size
Ultrasound measurements in this study were made with a HP Sonos 100 CF echocardiography system (Hewlett Packard Imaging Systems, Andover, MA). The liver was scanned by using an Eskoline B scanner, a modified HP 7214 A diagnostic sounder, and a modified 3.5-MHz transducer probe. To obtain the ultrasound liver weight, a 3.5-MHz transducer was placed directly below the midline of the rib cage in the right upper quadrant, on a vertical line running through the right nipple, with the patient in the supine position. Once the liver was observed, measurements were made by scanning in a plane perpendicular to the base of the liver. The base of the liver and the free edge of the hepatic dome were marked on the display screen, and the distance between those 2 points was measured automatically.
The formula used for estimating liver weight from the single longitudinal scan along the right nipple line was weight = (1.15l)3d, where l3 represents the volume of a cube cut in half diagonally, to approximate the shape of a normal liver in situ. A factor of 1.15 was used to correct for the portion of the liver (15%) lateral to the left nipple line, representing the most inferior point of the liver. This correction was estimated from the liver at autopsy. The density (d) of the liver was measured on several sections through water displacement. Determining the right nipple line was not difficult unless the nipple was obliterated by a severe burn to the thorax. In such cases, an approximation was made and recorded as such. Actual size was then compared with predicted size. Measurements were made at week 1 post-admit (acute 1), 2 weeks post-admit (acute 2), and 3 weeks post-admit (acute 3), as well as at discharge (D/C).
Statistical Analyses
One-way analysis of variance, with Bonferroni's posthoc correction, was used to compare the 3 groups. Data are expressed as proportions or means ± SEMs, where appropriate. Significance was accepted at P < .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Demographic Features
A total of 188 severely burned pediatric patients were included in the present study; 55 were 0 to 3.9 years of age, 70 were 4 to 9.9 years of age, and 63 were 10 to 18 years of age. The only difference between groups in terms of demographic data was in age (Table 1). There was no significant difference in gender distribution, time from burn to admission, burn size, length of ICU stay, length of ICU stay per percentage of burn, or incidence of inhalation injury, infection, multiorgan failure, or death between the groups (Table 1). Significant differences (P < .05) between groups in body height and weight at admission were found (Table 1).
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Indirect Calorimetry
The measured REE and the predicted REE calculated with the Harris-Benedict formula were increased significantly (P < .05) in older children (10–18 years of age), compared with children 4 to 9.9 years of age and children 0 to 3.9 years of age (Fig 1). The middle age group had significantly increased (P < .05) REE and predicted REE, compared with the youngest children (Fig 1). The youngest age group demonstrated only a slightly increased REE or predicted REE during the acute hospital stay.
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Body Composition
As expected, the 4- to 9.9-year-old children were significantly longer and heavier (P < .05) than the 0- to 3.9-year-old children, and the 10- to 18-year-old children were significantly longer and heavier (P < .05) than the 4- to 9.9-year-old children. The youngest children did not lose any body weight from 5 days after admission to hospital discharge; during that period, they gained 4%, whereas the 4- to 9.9-year-old children lost 2% of their body weight and the oldest children lost 5% (P < .05) (Fig 2). The youngest children also grew during the acute hospital stay, whereas the middle and oldest groups did not grow (P < .05) (Fig 2). Attenuated body weight loss in the youngest children was associated with preserved lean body mass. Whereas the youngest children gained lean body mass (change: 2%), the middle and oldest children lost lean body mass (change: middle: –7%; oldest: –5%; P < .05) (Fig 2). There were no differences in the changes in total fat and proportion of fat, bone mineral content, and bone density from admission to discharge for the 3 age groups (Fig 2).
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Serum Hormone, Protein, and Cytokine Levels
There were no differences between the 3 age groups in levels of acute-phase proteins such as C3 complement,
2-macroglobulin, haptoglobin, and 1-acid glycoprotein (Fig 3). Serum C-reactive proteins levels were significantly decreased (P < .05) in children 0 to 3.9 years of age, compared with the other 2 age groups (Fig 3).
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Serum levels of the constitutive hepatic proteins prealbumin, apolipoprotein A1, and apolipoprotein B were not different between the groups. We found that transferrin levels were increased significantly (P < .05) in the 4- to 9.9-year-old group, compared with the 10- to 18-year-old group (Fig 4).
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Serum insulin-like growth factor-I and insulin-like growth factor-binding protein-3 levels were higher in the 10- to 18-year-old group at 2 time points, compared with the 0- to 3.9-year-old and 4- to 9.9-year-old groups (P < .05) (Fig 5). Serum growth hormone levels were increased 2 to 7 days after burn in the 0- to 3.9-year-old group, compared with the other 2 age groups (P < .05) (Fig 5). There were no differences between groups in serum insulin levels. Serum estrogen levels were highest in the 10- to 18-year-old group, with no differences between the other 2 groups (P < .05) (Fig 5). Serum testosterone levels were not different between groups at all time points. In terms of inflammatory markers, we found that there were no differences between the 3 age groups in IL-6, IL-8, IL-10, granulocyte/macrophage colony-stimulating factor, macrophage inflammatory protein-1β, monocyte chemoattractant protein-1, granulocyte colony-stimulating factor, IL-17, IL-13, tumor necrosis factor, IL-1β, IL-5, IL-7, IL-12p70, interferon-
, IL-2, and IL-4 levels during the entire study period (data not shown).
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Urine Cortisol Levels
Cortisol concentrations in 24-hour urine samples were increased in all age groups immediately after burn, compared with normal values. However, urine cortisol levels were highest in the 10- to 18-year-old group, compared with the other age groups (P < .05) (Fig 6). Urine cortisol levels remained significantly increased (P < .05) in the 10- to 18-year-old group, compared with the other 2 groups, during the entire study period. There was no difference between the 0- to 3.9-year-old and 4- to 9.9-year-old groups at any time.
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Cardiac Function
Within 24 hours after admission, cardiac function was determined. To rule out right heart failure and to ensure equal filling pressure, central venous pressure was also measured. There was no difference in central venous pressure between the 3 groups (0–3.9 years: 6 ± 0.6 mm Hg; 4–9.9 years: 5.8 ± 0.8 mm Hg; 10–18 years: 5.7 ± 0.7 mm Hg). Predicted CO was increased significantly (P < .05) in all 3 groups, with the greatest increase in the 0- to 3.9-year-old group, followed by the 4- to 9.9-year-old group (Fig 7). Predicted SV was highest in the 0- to 3.9-year-old patient group, followed by the 4- to 9.9-year-old group (P < .05) (Fig 7). Predicted HR was lowest in the youngest children, followed by the middle age group (P < .05) (Fig 7). At acute hospital discharge, predicted CO and SV remained highest and predicted HR lowest for the youngest children (P < .05) (Fig 7).
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Liver Size
Liver seize increased in all 3 age groups after burn and remained elevated until discharge. Children 0 to 3.9 years of age demonstrated a significantly attenuated liver size increase (P < .05), compared with children 4 to 9.9 years of age and children 10 to 18 years of age (Fig 8).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The highest morbidity and mortality rates for severe burns are observed in children <4 years of age and elderly adults >70 years of age.9,10 A recent study of 1647 children admitted to our hospital between 1985 and 2005 with burns involving >40% of TBSA confirmed the World Health Organization data demonstrating that infants and toddlers have significantly higher mortality rates, compared with older children and adolescents.9,10 The aim of the present study was to identify possible contributing factors to increased postburn morbidity and mortality rates. Contributors to morbidity and death in burn patients are the inflammatory and hypermetabolic responses, infections and sepsis, changes in body composition, organ failure, and cardiac dysfunction. We divided 188 severely burned children with burns involving >40% of TBSA into 3 groups, that is, toddlers (0–3.9 years of age), prepubertal children (4–9.9 years of age), and pubertal/teen-aged youths (10–18 years of age). Demographic data for the patient population were similar in terms of burn size, gender distribution, time from burn to admission, length of ICU stay, inhalation injury, incidence of infection and sepsis, multiorgan failure, and operations.
The metabolic rate is extremely high in burns; energy requirements are immense and met by the mobilization of proteins and amino acids.13 Increased protein turnover and degradation and negative nitrogen balance are characteristics of this severe critical illness.14 As a consequence, the structure and function of essential organs, such as skeletal muscle, skin, liver, immune system, and cellular membrane transport functions, are compromised.13,15,16 This compromise can lead to multiorgan dysfunction or even death.13 Catecholamines involved in the hypermetabolic response to burn injury are released from sympathetic nerve endings and the adrenal medulla.17–20 Norepinephrine levels are increase 2- to 10-fold, in proportion to burn size. Close correlations exist between the increases in plasma catecholamine levels, cytokine levels, and metabolic rate.11,20,21 Our data showed that young children had a significantly attenuated hypermetabolic response, which was associated with preserved body mass. REE and predicted REE were significantly decreased in children 0 to 3.9 years of age, compared with the other age groups. Decreased hypermetabolism was associated with significantly lower stress hormone levels. Urine cortisol levels were significantly decreased in toddlers. The attenuated stress response in toddlers was associated with attenuated muscle and lean body mass loss. Although teenagers and children 4 to 9.9 years of age lost significant amounts of body weight, toddlers maintained body weight and even grew during the acute hospital stay. In terms of body composition and bone mineral density, toddlers were not different from older children, because they underwent the changes in body composition and loss of bone mineralization described previously.1,21
The reason for the decreased hypermetabolic response is not clear. We and others1 hypothesized that the inflammatory response contributes to hypermetabolism but, despite differences in the hypermetabolic response between ages, we found no differences between the 3 age groups in cytokine expression profiles. It seems that toddlers experience less inflammation, because levels of the acute-phase protein C-reactive protein were significantly decreased in toddlers, compared with the other 2 age groups. Attenuated inflammation and hypermetabolism led to increased growth hormone levels in toddlers. Insulin-like growth factor-I and insulin-like growth factor-binding protein-3 levels in normal children are age-dependent and are increased in older children, which we observed also in our burn population. In agreement with previous observations, however, endogenous anabolic hormone levels were significantly decreased in all age groups, compared with normal, age-matched children.
Glucose kinetics in severely burned patients are almost always abnormal.22,23 Glucose is used almost entirely through inefficient anaerobic mechanisms, as characterized by increased lactate production, which accounts for increased glucose consumption.22–24 Glucose production, particularly from alanine, is elevated in almost all patients with severe burns.14 The increased gluconeogenesis renders these amino acids unavailable for reincorporation into body protein. Nitrogen is excreted primarily in urea, contributing to the progressive depletion of body protein stores. Increased anaerobic metabolism, lactate production, and insulin resistance are associated with increased mortality rates; therefore, we determined insulin levels in our patient population. We found no differences in metabolic markers or insulin levels, which indicated no differences in glucose metabolism between the 3 groups.
Sex hormones such as estrogens and testosterone are also the focus of current investigations. Chaudry and colleagues25–29 showed that estrogen administration improved survival rates and mitochondrial function after hemorrhagic shock. Ferrando and colleagues30–32 showed that testosterone administration attenuated protein loss and catabolism after burn. The exact mechanisms through which sex hormones exert their effects have not been determined but currently are being studied. In the present study, we found that children 10 to 18 years of age had significantly higher estrogen levels during the early phase after burn injury, compared with the other 2 age groups, but then levels decreased and no difference could be detected. Serum testosterone levels were never significantly different between the 3 age groups. These data indicated that sex hormones are not contributing to increased mortality rates in toddlers, which was not what we expected or hypothesized.
The only significant difference that we were able to detect in this study that indicated a worse outcome in toddlers was cardiac function. Toddlers demonstrated significantly increased CO and SV trying to maintain organ perfusion. This increased cardiac work persisted over the entire acute study period. Whereas older children recovered in terms of cardiac function and work, toddlers remained at high levels of CO and SV for the duration of the study. Furthermore, whereas HR decreased in older children, HR remained nearly unchanged, at increased beats per minute, in toddlers. Because preload was not significantly different between groups, we suggest that cardiac work was significantly increased in toddlers and this increased cardiac work led to cardiac failure and myocardial dysfunction and thus increased mortality rates. Myocardial depression associated with severe burn injury was shown in several studies.33–35 Our group conducted a study to determine systolic and diastolic function in 40 severely burned pediatric patients. We found that 40% of the patients had a decreased ejection fraction of <50% and 25% of the patients had impaired diastolic function, which was independent of systolic function (Kinsky M, unpublished data, 2006). Those data demonstrated that myocardial depression plays an important role during the postburn response, and modulation of myocardial depression may improve clinical outcomes. The hypothesis that myocardial dysfunction may be one of the main contributors to death in young children was confirmed in a recent retrospective autopsy study.10 In that study, it was shown that postmortem heart weights were significantly increased in young children, compared with older patients, indicating myocardial dysfunction. Microscopic findings in the heart revealed congestion and ischemic changes. The importance of cardiac dysfunction is even more pronounced because we showed that the kidney, lung, and liver worked equally well in all 3 age groups and did not contribute to increased mortality rates in toddlers.
In the present study, we wanted to determine factors contributing to morbidity and death in severely burned pediatric patients. One major criticism of this study is that there was no significant difference in mortality rates in our study groups. Therefore, it is difficult to identify specific contributors to death. However, given the homogeneity of our patient groups except for age, we suggest that, by identifying cardiac dysfunction as the only difference in the postburn responses between age groups, we might have determined a major contributor to postburn morbidity.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In the present study, we identified differences in the postburn responses in severely burned toddlers, compared with older children. We showed that toddlers demonstrated increased cardiac work and function after the burn. In contrast to our hypothesis, hypermetabolism, catabolism, organ function, and inflammatory response were not significantly different between age groups. Therefore, we suggest that increased morbidity rates in young children may be associated with increased and subsequently impaired cardiac function but not with the inflammatory and hypermetabolic responses. Improving cardiac function and cardiac work in children <4 years of age may improve morbidity and mortality rates for this patient population.
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ACKNOWLEDGMENTS |
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This study was supported by grants from Shriners Hospitals for Children (grants 8660, 8760, and 9145), the National Institutes of Health (grants R01-GM56687, T32-GM008256, and P50-GM60338), the National Institute on Disability and Rehabilitation Research (grant H133A020102), and the American Surgical Association Foundation.
We thank Eileen Figueroa and Steve Schuenke for their help in the preparation of this manuscript.
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FOOTNOTES |
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Accepted Aug 10, 2007.
Address correspondence to Marc G. Jeschke, MD, PhD, Galveston Burns Unit, Shriners Hospitals for Children, 815 Market St, Galveston, TX 77550. E-mail: majeschk{at}utmb.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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