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. 2008 Jan 22;93(4):1270–1275. doi: 10.1210/jc.2006-2158

Urinary Cortisol and Catecholamine Excretion after Burn Injury in Children

William B Norbury 1, David N Herndon 1, Ludwik K Branski 1, David L Chinkes 1, Marc G Jeschke 1
PMCID: PMC2291486  PMID: 18211976

Abstract

Introduction: A severe burn causes increased levels of urine cortisol and catecholamines. However, little is known about the magnitude of this increase or how and when the levels return to normal. The purpose of this study was to determine in a large clinical prospective trial the acute and long-term pattern of urine cortisol and catecholamine expression in severely burned children.

Methods: Pediatric patients with burns greater than 40% total body surface area (TBSA), admitted to our unit over a 6-yr period, were included into the study. Clinical data including length of stay, number of operations, and duration and number of infections were determined. Patients had regular 24-h urine collections during their acute admission and reconstructive periods. Urine collections were analyzed for cortisol, epinephrine, and norepinephrine. Each urine cortisol was compared with age-adjusted reference ranges. Ninety-five percent confidence intervals and ANOVA analysis were used where appropriate.

Results: Two hundred twelve patients were included in the study (75 females and 137 males), with a mean ± sem TBSA of 58 ± 1% (third-degree 45 ± 2%) and mean age of 9 ± 0.4 yr. Urinary cortisol levels were significantly increased (3- to 5-fold) up to 100 d after the burn and then approached normal levels (P < 0.05). The rise in urine cortisol was significantly higher in male than female patients (P < 0.05). Early hypercortisolemia was associated with increased duration of severe infection (P < 0.05). Persistent hypercortisolemia was associated with increases in both infection rates and duration of severe infection (P < 0.05). Urinary catecholamines showed a significant increase at 11–20 d after the burn (P < 0.05). Urinary norepinephrine levels were significantly increased up to 20 d and then returned to normal (P < 0.05).

Conclusions: Urinary levels of cortisol, epinephrine, and norepinephrine are significantly increased after a major burn. Early hypercortisolemia is associated with increased duration of severe infection. Persistent hypercortisolemia is associated with increases in both infection rates and duration of severe infection.

In pediatric patients with severe burns greater than 40% of their total body surface, early and persistent hypercortisolemia is associated with increased infection rates and duration of severe infection, respectively.

The typical response to stress necessitates the actions of several different biological systems, namely autonomic, endocrine, and immune systems (1). The patient’s response immediately after major thermal injury includes both emotional and physical stress. This rapid response is brought about by sudden increases in sympathetic nervous system activity and endogenous stress hormone levels (2,3). The developmental reason for this response is to allow the body to overcome a transient stressful event or survivable trauma. However, after severe burns, this response continues for a protracted period of time after the initial injury because the stressor remains as a source of stimulation. The concept of acute and chronic stressful responses was described in a classical work by Hans Selye (4) in which he described a short alarm reaction followed by a prolonged resistance phase. It is this persistent stress response that results in the deleterious sequelae including longstanding hypermetabolism, substantial loss of lean body mass, and immune suppression. Severe burns covering more than 40% total body surface area (TBSA) are typically followed by a period of hypermetabolism and catabolism that can last for more than 24 months after injury (5,6,7). The reasons for the changes seen in metabolism are unclear, and the pathways are poorly defined. However, there is a marked and sustained increase in endogenous immunosuppressive stress hormones including glucocorticoids and catecholamines secondary to up-regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Stimulation of this axis may be due, in part, to internal cooling of the patient leading to catecholamine driven increases in resting energy expenditure (REE) to restore normal body temperature (8).

Increases in cortisol levels have been shown to reflect the severity of injury in traumatic insult (9). Significant increases in cortisol (10,11,12,13,14) and catecholamines (15,16) are seen after major burns and thought to initiate the cascade of events leading to the hypermetabolic response with its ensuing catabolic state. This large initial rise in cortisol has been shown to lead to increased REE (17) and short-term bone loss (14) and reduce T helper lymphocyte proliferation with a subsequent reduction in the patient’s ability to fight infection (18). Large increases in cortisol levels have also been shown to increase net protein breakdown of skeletal muscle (19) and increase efflux of intracellular amino acids (17). Little is know about the magnitude of the change in hormone production or how and when the levels return to normal. One study involving 14 pediatric patients showed an 8-fold increase in cortisol levels after severe thermal injury and linked this to a marked decrease in type I collagen and bone formation, together with a lack of detectable surface osteoblasts and a reduction in biochemical markers of osteoblast differentiation (14). The purpose of this study was to determine, in a large clinical prospective trial, the acute and long-term pattern of urine cortisol and catecholamine expression in severely burned children.

Patients and Methods

Two hundred twelve patients admitted to our hospital with burns over 40% TBSA were entered into the study after informed consent was obtained. This study was approved by the Institutional Review Board for Human Studies at the University of Texas Medical Branch, Galveston. Twenty-four-hour urine collections were taken regularly throughout acute hospital stay and during admissions for reconstructive operations. These samples were collected and chilled by the bedside before transport to our clinical lab for processing using a Dynex Technologies (Chantilly, VA) DSX processing system and an ELISA kit from Diagnostic Systems Laboratories (Webster, TX).

Urinary catechloamine levels were measured by HPLC, using commercially available kits from Bio-Rad (Hercules, CA) with manufacturer’s instructions.

Free cortisol levels were measured using an ELISA kit from Diagnostic System Laboratories/Beckman Coulter (Webster, TX) on automatic Dyonex DSX instrument. Total cortisol levels are measured in our lab by liquid-liquid extraction followed by HPLC method. It is important to note that free cortisol levels are affected by the amount of binding protein available, whereas total cortisol levels are an indicator of cortisol secretion. Cortisol binding protein levels are very low during the acute phase post burn and they increase over time during recovery; therefore free cortisol levels decrease faster than total cortisol levels. In this study we chose to measure free cortisol because it was the established clinical laboratory method at the time.

Admission data

On admission, the extent and degree of burn was assessed and recorded on a standard Lund and Browder chart by the attending burns surgeon present. Information also recorded at the time of admission included burn-related (date and mechanism) as well as demographic data (age, gender, and ethnicity). All thermally injured children with burns over 30–40% of their TBSA who consented to an Institutional Review Board-approved experimental protocol between 1998 and 2007 and who were admitted to our burn unit and required at least one surgical intervention were included in this study. Patients were resuscitated according to the Galveston formula with 5000 ml/m2 TBSA burned + 2000 ml/m2 TBSA lactated Ringer’s solution given in increments over the first 24 h. Within 48 h of admission, all patients underwent total burn wound excision, and the wounds were covered with available autograft skin, and any remaining open areas were covered with homograft. After the first operative procedure, it took 5–10 d until the donor site was healed, and patients were then taken back to the operation theater. This procedure was repeated until all open wound areas were covered with autologous skin material.

All patients underwent the same nutritional treatment according to a standardized protocol. The intake is calculated as 1500 kcal/m2 body surface + 1500 kcal/m2 area burn, or we assessed the need by measuring the REE, multiplying by 1.4 with weekly adjustments as previously published (5,6,20). The nutritional route of choice in our patient population was enteral nutrition. Therefore, almost all patients received nutrition via a duodenal (Dobhof) or nasogastric tube. Parenteral nutrition was given only in rare instances if the patient did not tolerate any tube feeds.

Statistical analysis

Elevation of cortisol was evaluated by examining the 95% confidence interval of the mean. Differences between male and female groups were evaluated with two-way ANOVA with factors sex and time followed by Tukey’s test. Expression of epinephrine and norepinephrine were evaluated over time relative to more than 500 d using one-way ANOVA of ranks followed by Dunn’s method.

Results

Two hundred twelve patients, 137 male and 75 female, with burns in excess of 40% TBSA were enrolled into the study. Each patient had regular 24-h urine collections taken both during the acute hospital admission and subsequent stays for reconstructive purposes. Patient characteristics are depicted in Table 1 as means ± sd.

Table 1.

Demographics of patient population

Males Females
n 137 (65%) 75 (35%)
Age (yr)a 9.5 ± 5.1 6.7 ± 4.8
TBSA (%)a 58.7 ± 16.9 56.8 ± 14.9
TBSA (% third-degree)a 45.6 ± 24.1 44.4 ± 21.6
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a

Mean ± sd. 

We divided the results into seven different time points: 0–10 (admission), 11–20 (acute reconstruction), 21–40 (preparation for discharge), 41–100 (discharge), 101–200 (first reconstruction operation appointment), 201–500 (subsequent reconstruction admissions), and more than 500 d (long-term outpatient appointments). The time points chosen reflect the typical time course for pediatric patients through our burn unit.

If any patient had more than one urine collection taken during each time point, the results were averaged to give a single mean result for each patient at each time point. We then compared the results found against standard age-adjusted reference ranges (0–10 yr, 2–27 μg/24 h; 10–20 yr, 5–55 μg/24 h).

The mean urine cortisol increased initially to 284 ± 26 μg/24 h and then fell steadily over the next 3 months to settle close to the normal range at about 100 d after the burn. This is a 5- to 6-fold increase from normal resting urine cortisol levels (Fig. 1). In addition, we normalized urine cortisol to body surface area, giving us the urine cortisol index for each patient; the resulting data mirror the raw cortisol data shown in Fig. 1.

Figure 1.

Figure 1

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Twenty-four-hour urine cortisol (UC) increases by an average of 5- to 6-fold initially followed by a decrease over time to around the normal range at 100 d after the burn (mean ± sem). *, P < 0.05 vs. normal range depicted at base of graph (shaded area).

We have previously reported a difference in hypermetabolic response between the groups with higher REE in males than females (6). In light of this, we looked at the differences between males and females as an internal standard control. We found marked differences between the initial urine cortisol values (Fig. 2) (P < 0.05). The male patients had a significantly greater increase in urine cortisol that was sustained to around 40 d after the burn compared with females (P < 0.05). Thereafter, the levels between the groups were very similar, arriving close to the normal range at approximately 3 months after the burn (Fig. 2).

Figure 2.

Figure 2

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Difference in male and female urine cortisol expression initially (P < 0.05), although the reduction to normal range is the same for both groups at about 3 months after initial injury (mean ± sem).

When we correlated the intensity of endocrine activation with outcome, we compared those patients with raised urine cortisol against those within the normal range over the first 100 d after injury. We showed that there were no significant differences in length of stay between the two groups at any time in the first 100 d (Fig. 3A). Hypercortisolemia in patients during the first 10 d after the burn was associated with a significant increase in duration of severe infection (Fig. 3B), whereas persistent hypercortisolemia was associated with a significant increase in both duration and number of separate severe infections (P < 0.05; Fig. 3, B and C). No correlation was found between hypercortisolemia or normocortisolemia and mortality or burn size at any time point.

Figure 3.

Figure 3

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A, Normal vs. raised urine cortisol (UC) vs. length of stay (LOS) (normalized for TBSA). No significant differences are seen at any time point (mean ± sem). B, Urine cortisol vs. duration of severe infection. Acute and persistent hypercortisolemia are significantly associated with increased duration of severe infection (mean ± sem) *, P < 0.05. C, Urine cortisol vs. duration of severe infection. Persistent hypercortisolemia is significantly associated with increased number of severe infections (mean ± sem). *, P < 0.05.

No significant association was found between increased stress hormone release and mortality. Neither was there any association between raised endogenous stress hormones and the number of operations needed during the acute admission.

We saw similar patterns of expression in both epinephrine (Fig. 4A) and norepinephrine (Fig. 4B) with a rise initially followed by a fall to around 100 d. Due to the wide disparity in both mean and confidence intervals for reference ranges of epinephrine and norepinephrine, we cannot show that these values are outside the normal range. However, due to the size of the group evaluated, we can state with some confidence that in this case, there was a significant rise followed by decrease in both catecholamines (P < 0.001). The maximal rise on catecholamines was prolonged (11–20 d). This was an unexpected finding because it did not mirror the changes seen in cortisol production.

Figure 4.

Figure 4

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A, Urinary epinephrine increases initially after burn injury and then decreases over time to around 100 d (mean ± sem). *, P < 0.001 vs. more than 500 d. B, Urinary norepinephrine increases initially after burn injury and then decreases over time to around 100 d (mean ± sem). *, P < 0.001 vs. more than 500 d.

Discussion

Severe burns result in major metabolic, physiological, and psychological changes in a child’s life. The typical changes in metabolism seen are the development of a hyperdynamic circulation (21), increased body temperature (22), increased protein catabolism with peripheral protein wasting (23), increased lipolysis leading to fatty infiltration of the liver (24), and increased glycolysis and futile substrate cycling (25). These changes are responsible for much of the morbidity and mortality seen with such an injury and as such are important targets for available treatments, including early excision and grafting, aggressive treatment of sepsis, early commencement of high-protein high-carbohydrate enteral feeding, elevation of the immediate environmental temperature to 31.5 C (±0.7 C), and early institution of an aerobic resistive exercise program (26). Over the last 20 yr, great strides have been made in these areas during the initial treatment of massive thermal injuries (26), resulting in decreased morbidity and mortality. The exact cause of the hypermetabolic response is still inadequately understood and the biochemical pathways poorly defined. We know that there is a marked increase in stress hormones including glucocorticoids and catecholamines (14,27). This initial increase is due to stimulation of the HPA axis which should, under normal conditions, be controlled via negative feedback by the products of adrenal stimulation. During the prolonged phase of recovery from severe burns, which typically can be weeks to months, there is a dissociation between high-plasma cortisol and low ACTH levels, which implies non-ACTH-mediated mechanisms for regulation of the adrenal cortex (28,29). Additional circulating factors such as cytokines might suppress ACTH synthesis and secretion. Factors such as endothelin-1 (30) and atrial natriuretic peptides (30,31) are elevated at stages when ACTH is suppressed.

The normal circadian rhythm for serum cortisol is lost after a severe burn (32,33); therefore, for this study, urinary cortisol was taken as a more accurate measure of the total daily production of cortisol by the patient. A limitation of this study is that we were unable to elucidate the time course for the resumption of normal circadian changes in serum cortisol level. This is the focus of ongoing research. A further limitation of this study was that unfortunately, most of the patients were admitted to our unit from abroad, mainly from Mexico and South America. Therefore, we were unable to analyze data from the first few hours after injury.

After a severe injury, cortisol levels increase in proportion to the severity of traumatic insult (9). This increase in cortisol, as well as the increase in circulating catecholamines after a massive burn, initiates a cascade of events leading to the hypermetabolic response with its ensuing catabolic state. This large initial rise in cortisol has been shown to lead to increased REE (17), short-term bone loss (14), and reduced T helper lymphocyte proliferation with a subsequent reduction in the patient’s ability to fight infection (18). Large increases in cortisol levels have also been shown to increase net protein breakdown of skeletal muscle (19) and increase efflux of intracellular amino acids (17). Increases in catecholamines lead to a hyperdynamic circulation (34), loss of lean body mass (35), and increased lipolysis (25), principally in the periphery leading to increases in fatty deposition of the liver (36). However, little is known about the magnitude of increase in either catecholamines or cortisol or indeed when they return to more normal levels. We have shown that urinary catecholamines increase initially and then reduce with time up to around 100 d. However, the significance of these changes is unclear due to the lack of tight reference ranges for pediatric patients of different ages. We have also shown in this study that urine cortisol increases in the initial postburn phase by between 4- and 6-fold. The levels then decrease over time, returning to normal range at around 3 months after injury. Furthermore, we have also shown that there is a marked difference between male and female pediatric patients in response to burn injury. Here, we have shown that although both male and female pediatric patients have raised urine cortisol after burn injury, the increase is significantly greater in male patients. If we can reduce the impact of this initial rise in cortisol, perhaps we can reduce the deleterious effects on the body and therefore improve overall outcome for the patient, restoring them to a normal, functional existence. We are currently undertaking a trial using ketoconazole, an antifungal agent that suppresses the production of cortisol as a side effect. We have had very favorable results so far with reduced infection rates (nonfungal) in those patients with attenuated cortisol production. Side effects have been minimal in our pediatric patients.

Large doses of opiates and opioids are used to reduce nociceptive perception in patients with severe thermal injury. However, the impact of opioids and opiate use in the presence of persistent stressful stimuli has yet to be fully elucidated. Opiate-mediated effects have been hypothesized to result from either direct interaction with opioid receptors on cells of the immune system (37,38) or indirectly through the activation of opioid receptors within the central nervous system and the resulting modulation of HPA axis and the sympathetic nervous system (39,40).

This study provides evidence that severe burn injury in children results in sustained changes in HPA axis dynamics, and we outline the time course for hypercortisolemia in children with severe burns. We also show that measurement of high urine cortisol may indicate an increased susceptibility to infection. Additional studies are needed to determine whether the increases seen are due to a reduced cortisol-binding globulin or increased endogenous production.

Acknowledgments

We gratefully acknowledge the assistance of Gabriella Kulp, M.S., for her invaluable assistance with sample processing.

Footnotes

This project was supported by National Institutes of Health Grants NIH P50 GM 60338, NIH T32 GM 008256, and Shriners Hospital Grants 8480 and 8660.

Disclosure Statement: We have no relationships or conflicts to disclose for any author.

First Published Online January 22, 2008

Abbreviations: HPA, Hypothalamic-pituitary-adrenal; REE, resting energy expenditure; TBSA, total body surface area.

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