Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 9  |  Issue : 2  |  Page : 194-200

Effect of recombinant growth hormone on immune response in pediatric burn patients


Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission29-Aug-2015
Date of Acceptance18-Nov-2015
Date of Web Publication11-May-2016

Correspondence Address:
Yasser A Salem
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain Shams University, 7, Bashar Ebn Bord st., Sixth District, Nasr city, 11371 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.182225

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  Abstract 

Background
Management of severely burnt children is one of the most challenging situations in the ICU. Control of the hypercatabolic state is the most limiting step that determines patient survival. Immunocompromisation and delayed wound healing usually result in severe sepsis, which is the most common direct cause of death in these patients. There is debate about the efficacy and safety of recombinant human growth hormone (rGH), although it has been used to improve healing of burnt patients. Role of growth hormone in immunomodulation has been proposed theoretically and serologically, but it has not been tested clinically. We reported in this study how far the use of rGH in the management of burnt patients can improve their immune status and increase survival.
Patients and methods
Forty pediatric patients were enrolled in this study, randomly assigned into two groups. Group A received rGH and was compared with group B, which did not receive rGH. Those two groups were compared with respect to overall mortality rate, hospital and ICU stay, serum transferrin, C-reactive protein, and positivity of blood culture.
Results
The overall mortality rate was slightly lower in group A (20%) compared with B group (25%). No significant decrease in hospital stay was noticed between the two groups. There was significant improvement in serum transferrin especially by day 14 in addition to a significant drop in C-reactive protein in group A. Group A was found to be more protected from bacteremia.
Conclusion
The use of rGH in pediatric burnt patients improves overall mortality and optimizes immune status, in addition to improvement of wound healing and donor site healing. This eventually reduces the length of hospital stay.

Keywords: burn, growth hormone, immunity, pediatric


How to cite this article:
Salem YA, Hassan R, Elfawy DM, Girgis N. Effect of recombinant growth hormone on immune response in pediatric burn patients . Ain-Shams J Anaesthesiol 2016;9:194-200

How to cite this URL:
Salem YA, Hassan R, Elfawy DM, Girgis N. Effect of recombinant growth hormone on immune response in pediatric burn patients . Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Apr 18];9:194-200. Available from: http://www.asja.eg.net/text.asp?2016/9/2/194/182225


  Introduction Top


Globally, burns are a serious public health problem. An estimated 265 000 deaths occur each year from fires alone, with more deaths from scalds, electrical burns, and other forms of burns, for which global data are not available. Fire-related deaths alone rank among the 15 leading causes of death among children and young adults between 5 and 29 years (http://www.who.int).

Growth hormone (GH) is produced by the pituitary gland. For decades, it could only be obtained by extraction from pituitary glands, but later it was produced through genetic engineering and made available for therapy as recombinant human growth hormone (rGH) [1]. One of the earliest reviews about the use of rGH in the management of burnt patients was that introduced by Rose and Herndon in 1997. In that study they stated that hyperaminoacidemia does not prevent protein catabolism from proceeding at a higher rate than protein anabolism [2]. In burns this is partly due to decreased GH and insulin-like growth factor-1 (IGF-1) levels following burn injury [3].

In 1998 Ramirez et al. [4] published an article that concluded the safety and efficacy of the use of rGH in pediatric burns. It is well known that most of the GH actions are mediated by IGF-1. Cioffi et al. [5] stated that IGF-1 therapy has a beneficial effect in preserving lean body mass during severe stress conditions by minimizing the flux of amino acids toward oxidation. In 2006 Przkora and colleagues studied the effect of extended use of rGH after hospital discharge of pediatric burn patients. They detected improvement in body composition and wound reconstruction among rGH users [6]. Lately, IGF-1 was proved to be protective against apoptosis of T lymphocytes.

Recently it was discovered that insulin-like growth factor-binding proteins (IGFBP-1) that bind IGF-1 are excreted in response to inflammatory reaction. Elevated levels of IGFBP-1 after burn injury have been observed. Moreover, this elevation has been correlated with severity of burn injury and sepsis coupled with poor outcome [7]. Serine phosphorylation of IGFBP-1 was proved to increase the affinity of IGFBP-1 to bind IGF-1 and eventually decrease bioavailability of IGF-1 [8].

Therefore, there is an evidence-based agreement that rGH has an anabolic effect and accelerates burn wound healing on long-term use [9]. Nevertheless, the short-term anabolic effect together with anti-inflammatory and immunological effects has not been well studied on clinical bases, although there are multiple experimental and serological studies that support this theory.

This study was designed to clinically test the short-term anabolic and immunological effect of rGH in pediatric burn patients.


  Patients and methods Top


After obtaining approval from medical committee and after approval from departmental ethical committee, between August 2012 and April 2014 we collected data from 48 burnt children who were admitted to Aldemerdash burn intensive care unit (ICU). Their ages ranged between 1 and 6 years. The total burn surface area (TBSA) was between 20 and 50%. Burn surface area was estimated according to the Lund and Browder chart. Type of burn was determined according to history. Patients with blast injuries or suspected accompanying polytrauma were excluded. Informed consent was taken from guardians with respect to enrollment in the study and the use of rGH after a thorough discussion clarifying that patients' data would be collected from their regular charts and laboratory findings.

These patients were randomly assigned into two groups using a computer-generated sequence. Group A received rGH at a dose of 0.06 U/kg/day subcutaneously [4] starting from the third day after injury, in addition to regular management according to the protocol of the burn ICU, which included fluid therapy, antibiotic policy, nutritional support, and organ support. Group B received only the regular management according to protocol. Duration of the study was 14 days after admission. Six patients from group B were excluded as rGH was prescribed earlier than 14 days because of their condition. Two patients from group A were excluded as they were discharged against medical advice. Finally both groups included 20 patients each who were included in the clinical trial. Proc power of SAS (SAS 9.4 version released 2013) program was used to calculate the sample size with estimated power more than 0.8 after considering C-reactive protein (CRP) level and serum transferrin level as two separate primary outcomes.

Daily vital data were collected in the form of heart rate, mean blood pressure, and core rectal temperature. Temperature reading in the study was recorded twice per day and the mean was calculated. The reading was taken at inert intervals away from dressing times and physiotherapy or activity (8:00 a.m. and 8:00 p.m. were found to be suitable timings). In addition, peak temperature over 24 h had to be recorded for each patient. Readings of CRP and serum transferrin were taken on day 1 as baseline reading and on days 7 and 14. Complete blood profiles were collected every 2 days. Blood cultures were drawn on the seventh day after admission or when indicated according to protocol. Positive blood culture at any time within the study time frame was included and analyzed. Surgical interventions carried out for patients in both groups were recorded, which was either excision only or excision-grafting, in addition to overall mortality.

Data were collected, coded, tabulated, and analyzed using SPSS v12.0. Numerical variables were presented as mean and SD, whereas categorical variables were presented as number of cases and percentage. Between groups comparison of numerical variables were performed with two sample student t-test, whereas those of categorical variables were performed by means of the c2 -test. P-values less than 0.05 were considered statistically significant.


  Results Top


Study population

Both groups A and B were found to be comparable with respect to age, weight, and TBSA%, according to [Table 1]. The age range in both groups was 1-6 years. TBSA was between 20 and 50%. There was no difference in statistical significance regarding length of hospital stay between the two groups (28.54 ± 7.54 days for case group compared with 30.45 ± 9.58 days for the control group).
Table 1 Demographic data and length of hospital stay with no statistically significant difference

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Type of burn injury was mostly scald burn (85%) because of the age group selected for our study. Only 15% were flame burns. No other type of burn injury was recorded in this study. Both groups were almost comparable with regard to the type of burn injury, as illustrated in [Table 2].
Table 2 Type of burn in both groups with no statistically significant difference

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Surgical intervention in the form of excision or excision and grafting was 20% in group A compared with 35% in group B. This reflects decreased demands for surgical intervention and increased power of healing and dependency on conservative wound management in group A, reflecting better healing power [Table 3]. This decrease was not statistically significant, but it has clinical significance especially if we correlate with the record of two patients in group A who were grafted twice from the same donor site within 10 days, which did not happen in group B.
Table 3 The need for surgical intervention with no statistically significant difference

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CRP and serum transferrin were selected to assess inflammatory response in both groups. Their measurements were taken on day 1 as a baseline parameter and on days 7 and 14 as follow-up. Baseline readings were comparable in both groups. Regarding CRP there was significant drop in group A readings on day 14, as illustrated in [Table 4]. Readings on day 7 were still comparable between the two groups. This indicated a significant drop in the inflammatory response in patients using rGH in comparison with those who did not use rGH, as illustrated in [Table 4] and [Figure 1].
Figure 1: Results of C-reactive protein measurement

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Table 4 Results of C-reactive protein measurement, which is highly significant by day 14

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Measurement of serum transferrin was taken on days 1, 7, and 14. There was significant elevation of serum transferrin level in group A patients by day 14, indicating early reversibility of the hypercatabolic state, as illustrated in [Table 5] and [Figure 2].
Figure 2: Serum transferrin level with improvement by day 14 in group A, which is highly significant.

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Table 5 Serum transferrin level with improvement by day 14 in group A, which is highly significant

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Analysis of body temperature readings showed reduction of mean body temperature especially by the beginning of the second week in group A [Table 6]. Although the result was statistically nonsignificant, it had clinical significance. In contrast, in group B elevation of body temperature was sustained. Also the daily peak temperature reduced in group A.
Table 6 Comparison of mean body temperature in both groups by day 7 with no statistically significant difference

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Regarding the total leukocytic count (TLC) it was found that there was no statistically significant difference between the two groups, although group A showed mild decrease in TLC. Nevertheless, recording of TLC below 2000 was absent in group A, whereas four cases were recorded in group B. Moreover, when absolute lymphocyte count was analyzed independently it was found to be higher in group A than in group B with statistical significance. This might be explained by inhibition of apoptosis of T lymphocytes.

Positivity of blood culture was taken as the immunity parameter that reflects the immunity status of patients. An overall 70% of group A had negative blood cultures during the length of their hospital stay, compared with only 55% of the control group. This difference was found to be statistically nonsignificant. As illustrated in the table most of this difference was in the gram-negative bacilli group [Table 7].
Table 7 Blood culture results that show less positivity in group A, which is statistically nonsignificant

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Finally overall mortality rate was slightly lower in group A (20%) compared with group B (25%), as illustrated in [Table 8]. Nevertheless, this reduction was not statistically significant.
Table 8 Overall mortality in both groups with no statistically significant difference

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  Discussion Top


rGH has been used for decades in the management of pediatric burn patients. Its introduction was to antagonize the hypercatabolic state that complicates burn injury [4]. It was found that mere increase in amino acids as protein precursor is not sufficient. Several studies have been performed to test and prove the efficacy of rGH in creating a positive difference in burn wound healing. To some extent this efficacy was guaranteed [3,4].

Mortality was studied in a controlled trial of 54 adwult burn patients who survived the first 7 postburn days. Those patients who experienced difficulty in wound healing were treated with rGH and compared with those healing at the expected rate with standard therapy. Mortality of rGH-treated patients was 11% compared with 37% not receiving rGH (P = 0.027) [10]. Singh et al. [11] studied two groups of patients (n = 22) with comparable third-degree burns; those who received rGH had improved wound healing and lower mortality (8 vs. 44%). The significant decrease in mortality in their study in comparison with ours is perhaps due to the higher TBSA% they selected and less efficient nutritional strategy as they were performed in the mid-90s. Demling [12] found significantly improved weight retention and wound healing time with GH or oxandrolone compared with standard treatment in 36 adults with severe burns, coinciding with our results.

However, an randomized controlled trial in 56 children with more than 40% TBSA found no benefit of rGH alone compared with or in combination with propranolol [13]. That might be due to the anabolic effect of insulin used to adjust hyperglycemia as a consequence of propranolol use. It was recorded in their study that 15 out of 21 patients who received propranolol required insulin infusion to control their blood sugar level below 200 mg/dl.

Another placebo-controlled trial found no benefit of GH with regard to length of hospitalization in 24 adult patients with severe burns [14]. Two phase III double-blind randomized controlled trials of GH treatment in adults following cardiac or abdominal surgery, multiple trauma, or acute respiratory failure found increased in-hospital mortality rates in patients who received GH [15]. The potential for increased mortality prompted additional studies in critically burnt pediatric patients. Ramirez et al. [4] retrospectively studied 263 pediatric burn patients; those treated with GH had no increase in mortality compared with matched patients who did not receive GH. However, all trials that concluded increased mortality with the use of GH stressed on the use of high doses in adult patients.

In the last decade several studies have been designed to identify the molecular mechanism of action of rGH. The role of IGF-1 was interesting. Its use in avoiding complications of rGH was considered. Study on IGF-1 intracellular mechanism reveals its importance in the inhibition of mitochondrial apoptosis especially in cells exposed to high glucose [16]. Later, another pathway was discovered, the phosphatidyl inositol 3 kinase/Akt pathway, which protects pituitary cells from apoptosis (i.e. Akt is an oncogene from the AKT-8 thymoma cell line that was derived from the AKR/J mouse back in the 70s of the last century) [17]. Hence, there is no clinical evidence that supports these experimental findings. In this trial we tried to provide a preliminary proof for that theory through the improvement in absolute lymphocyte count among rGH users.

Elevation of IGFBP-1 in burn patients was documented by Mendoza et al. [18] in 2013. Moreover, burn injury claimed to increase phosphorylation of IGFBP to a more active phosphorylated form. This results in decrease in bioavailability of the active form of IGF-1 and diminishes its protective effect [8]. In an elegant article Law and colleagues expressed the effect of IGF-1 on maturation of T cells and prevention of its apoptosis. They stated that the maturation effect of IGF-1 is partially mediated by monocytes and the antiapoptotic effect in part by interleukin-6 (IL-6) [19]. That is why monocytosis has been noticed by the second week among rGH users but it has not been statistically analyzed.

From all of the above we can conclude that interruption of the distal effect of GH on end organs is the main pathology in cases of sepsis-mediated apoptosis rather than interruption of central release of GH. Hence, the use of rGH in the management of burn patients has a different rationale from, for instance, its use as replacement therapy in dwarfism.

Our work was designed to test the therapeutic effect of rGH on immunological and inflammatory response in burn patients in addition to the well-known anabolic effect. Immunological effect was reflected by fever incidence, leukocytic count, and blood culture positivity. Inflammatory response was assessed by CRP level and serum transferrin.

There are a wide variety of inflammatory indicators that might indicate acute inflammation severity. Collectively they are called acute-phase reactants. Those with elevated levels with inflammation are called positive acute-phase reactants, whereas others with reduced levels during inflammatory reaction are called negative acute-phase reactants. CRP was chosen to be our positive acute-phase reactant [20]. Serum transferrin was our negative acute-phase reactant. Serum transferrin is a plasma protein with a short half-life. Its elevation usually reflects the reversal of the hypercatabolic state in burn patients. It has been established that it is a more sensitive indicator of protein catabolism compared with albumin. Also it was used as an anti-inflammatory parameter; hence, this hypercatabolic state is usually secondary to the ongoing inflammatory process. Analysis of CRP levels indicates a significant drop in its level by the second week of administration of rGH. This drop coincides with improvement of healing power. That response could be explained by shift of hepatic protein synthesis strategy from inflammatory mediators to anabolic proteins.

Another indicator was elevation in serum transferrin level, which is considered a negative inflammatory acute-phase reactant. Its elevation was also by the second week. More frequent measurement of this mediator might be useful in the more precise identification of the mean time of onset of the anti-inflammatory effect of rGH. Serum transferrin is characterized by a short half-life and hence remission and relapse monitoring is easy. This anti-inflammatory response might be mediated also through reduction in IL-6. Future studies are required to correlate rGH treatment with IL-6 levels. Relative control of fever that accompanies the reduction of serum transferrin might be a part of the successful anti-inflammatory response or due to the improvement in the immune response that will be discussed later.

It is well known that infections are the primary cause of death in burn patients (http://www.who.int). Besides the strict infection control policies used to protect those patients, improvement in their immunocompromised system is mandatory. The immune response was indicated in this study by testing the ability of the body to defend the blood stream from bacteria. Low incidence of positivity of blood culture among patients receiving rGH indicates better immune system performance. This result was partially correlated with better fever control in group A. This group also reveals better control of TLC along their course of management. Moreover, higher level of absolute lymphocytic count might be explained by the inhibition of T-cell apoptosis. Although this result is not statistically significant it could be an indicator. Studies including a larger population may be of help. Absence of leukopenia in the case group strengthens the immunoprotective action of rGH. In a randomized, double-blind, placebo-controlled trial of 40 severely burnt children, the length of hospital stay was reduced from a mean of 0.8 days per TBSA% burned for the placebo group to 0.54 days per TBSA% burned for the treatment group (P < 0.05). But similar infection rates were recorded in both groups [21].

Nevertheless, we have recorded two cases from the case group with documented catheter-related intravascular thrombosis, which we did not encounter in group B. It might be because of better production of clotting factors by the liver or a side effect from the use of rGH. Therefore, we recommend extra caution to be taken because of catheter-related thrombosis. Ironically, we did not encounter the well-known side effect of tachycardia or hyperglycemia and none of them required b-blockers.


  Conclusion Top


The use of rGH in pediatric burnt patients provides control of systemic inflammatory response syndrome (SIRS) and improves overall mortality and immune status, in addition to improvement of wound healing and donor site healing. This eventually reduces the hospital stay. More comprehensive studies to correlate rGH with performance of the immune system and inflammatory cytokine levels are needed. Special attention should be directed to catheter-related thrombosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Breederveld RS, Tuinebreijer WE. Recombinant human growth hormone for treating burns and donor sites (Review). Cochrane Library 2012; Cochrane Handbook for systematic reviews of Interventions, Cochran collaboration published by Wiley & sons Ltd., 1-48.  Back to cited text no. 1
    
2.
Rose JK, Herndon DN. Advances in the treatment of burn patients. Burns. 1997; 23: Suppl 1:S19-S19S26.  Back to cited text no. 2
    
3.
Gore DC, Honeycutt D, Jahoor F, Wolfe RR, Herndon DN. Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg 1991; 126:38-43.  Back to cited text no. 3
    
4.
Ramirez RJ, Wolf SE, Barrow RE, Herndon DN. Growth hormone treatment in pediatric burns: a safe therapeutic approach. Ann Surg 1998;228:439-448.  Back to cited text no. 4
    
5.
Cioffi WG, Gore DC, Rue LW III, Carrougher G, Guler HP, McManus WF, Pruitt BA Jr. Insulin-like growth factor-1 lowers protein oxidation in patients with thermal injury. Ann Surg 1994; 220:310-316;discussion 316-319.  Back to cited text no. 5
    
6.
Przkora R, Herndon DN, Suman OE, Jeschke MG, Meyer WJ, Chinkes DL, et al. Beneficial effects of extended growth hormone treatment after hospital discharge in pediatric burn patients. Ann Surg 2006; 243: 796-801; discussion 801-803.  Back to cited text no. 6
    
7.
Hunninghake GW, Doerschug KC, Nymon AB, Schmidt GA, Meyerholz DK, Ashare A. Insulin-like growth factor-1 levels contribute to the development of bacterial translocation in sepsis. Am J Respir Crit Care Med 2010; 182:517-525.  Back to cited text no. 7
    
8.
Coverley JA, Baxter RC. Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol 1997; 128:1-5.  Back to cited text no. 8
    
9.
Branski LK, Herndon DN, Barrow RE, Kulp GA, Klein GL, Suman OE, et al. Randomized controlled trial to determine the efficacy of long-term growth hormone treatment in severely burned children. Ann Surg 2009; 250:514-523.  Back to cited text no. 9
    
10.
Knox J, Demling R, Wilmore D, Sarraf P, Santos A Increased survival after major thermal injury: the effect of growth hormone therapy in adults. J Trauma 1995; 39:526-530.  Back to cited text no. 10
    
11.
Singh KP, Prasad R, Chari PS, Dash RJ Effect of growth hormone therapy in burn patients on conservative treatment. Burns 1998; 24:733-738.  Back to cited text no. 11
    
12.
Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury. Burns 1999; 25:215-221.  Back to cited text no. 12
    
13.
Hart DW, Wolf SE, Chinkes DL, Lal SO, Ramzy PI, Herndon DN Beta-blockade and growth hormone after burn. Ann Surg 2002; 236:450-456.  Back to cited text no. 13
    
14.
Losada F, García-Luna PP, Gómez-Cía T, Garrido M, Pereira JL, Marín F, Astorga R Effects of human recombinant growth hormone on donor-site healing in burned adults. World J Surg 2002; 26:2-8.  Back to cited text no. 14
    
15.
Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341: 785-792.  Back to cited text no. 15
    
16.
Hao CN, Geng YJ, Li F, Yang T, Su DF, Duan JL, Li Y. Insulin-like growth factor-1 receptor activation prevents hydrogen peroxide-induced oxidative stress, mitochondrial dysfunction and apoptosis. Apoptosis 2011; 16:1118-1127.  Back to cited text no. 16
    
17.
Kang BP, Urbonas A, Baddoo A, Baskin S, Malhotra A, Meggs LG. IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose. Am J Physiol Renal Physiol 2003: 285:1013-1024.  Back to cited text no. 17
    
18.
Mendoza AE, Maile LA, Cairns BA, Maile R. Burn injury induces high levels of phosphorylated insulin-like growth factor binding protein-1. Int J Burns Trauma 2013; 3:180-189.  Back to cited text no. 18
    
19.
Law HK, Tu W, Liu E, Lau YL. Insulin-like growth factor I promotes cord blood T cell maturation through monocytes and inhibits their apoptosis in part through interleukin-6. BMC Immunol 2008; 9:74.  Back to cited text no. 19
    
20.
Carlson DE, Cioffi WG Jr, Mason AD Jr, McManus WF, Pruitt BA Jr. Evaluation of serum visceral protein levels as indicators of nitrogen balance in thermally injured patients. J Parenter Enteral Nutr 1991; 15:440-444.  Back to cited text no. 20
    
21.
Herndon DN, Barrow RE, Kunkel KR, et al. Effect of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990; 212:424-429.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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