effects of human recombinant growth hormone on donor-site healing in burned adults

World J. Surg. 26, 2–8, 2002DOI: 10.1007/s00268-001-0170-9 WORLD

Journal ofSURGERY© 2002 by the Societe

Internationale de Chirurgie

Original Scientific Reports

Effects of Human Recombinant Growth Hormone on Donor-site Healing inBurned Adults

Fernando Losada, M.D.,1 Pedro P. García-Luna, M.D., Ph.D.,2 Tomás Gómez-Cía, M.D., Ph.D.,3

Manuela Garrido, R.N.,2 Jose L. Pereira, M.D., Ph.D.,2 Fernando Marín, M.D., Ph.D.,4

Ricardo Astorga, M.D., Ph.D.1

1Department of Endocrinology, Hospital Virgen del Rocío, Avda. Manuel Siurot s/n, 41013-Sevilla, Spain2Department of Nutrition Unit, Hospital Virgen del Rocío, Avda. Manuel Siurot s/n, 41013-Sevilla, Spain3Department of Plastic Surgery, Hospital Virgen del Rocío, Avda. Manuel Siurot s/n, 41013-Sevilla, Spain4Medical Research Department, Lilly S.A., Avda. de la Industria 30, 28108-Alcobendas, Spain

Published Online: October 25, 2001

Abstract. Patients suffering severe burns have an accelerated catabolismwith a highly negative nitrogen balance that may worsen their prognosis.Somatropin treatment has been shown to improve this balance in differ-ent hypercatabolic situations. Moreover, in children with extensive burnsit also reduces the healing time of the skin graft donor site and shortensthe hospital stay. In the existing literature there are no controlled pro-spective clinical trials in adult patients that confirm these data. Our aimwas to demonstrate the efficacy of recombinant growth hormone (somat-ropin) in reducing the healing time of the skin graft donor sites and thelength of stay in the burn unit in adult patients with severe burns. Arandomized, double-blind, placebo-controlled clinical trial was carriedout in 24 adult patients with severe burns (more than 40% of the totalbody surface burned or more than 15% full-thickness burns). Patientsreceived placebo (n � 11) or somatropin (n � 13) at a dosage of 0.15mg/kg/day divided into two equal doses (every 12 hours) via intramuscu-lar injection. Treatment was initiated the day the first autograft wasperformed and terminated the day the patient was discharged from theburn unit. The mean number (� SD) of skin grafts per patient wassimilar between the two groups (4.2 � 1.8 vs 3.4 � 1.8 in the placebo andsomatropin groups, respectively). No reduction in the healing time of theskin graft donor site was observed in the somatropin group compared tothe placebo group. Likewise, the time admitted to the burn unit was notsignificantly different, either in the absolute number of days (36.2 � 19.7vs 30.1 � 16.8 days in the placebo and somatropin groups, respectively)or in relation to the percentage of the total body surface burned or thebody surface with full-thickness burns. Growth hormone and insulin-likegrowth factor I (IGF-I) levels were three and five times higher, respec-tively, in the somatropin group than in the placebo group. Ten of thepatients treated with somatropin experienced hyperglycemia, and seven ofthem required insulin treatment. No other adverse side effect was ob-served. One patient in the placebo group died as a result of sepsis andmultiple organ failure. Somatropin, with the treatment regimen anddosage used in these studies, did not reduce the healing time of the skingraft donor sites or the length of hospitalization in the burn unit in adultpatients with severe burns.

Severe thermal injury initiates a pronounced hypermetabolicstress response characterized by catabolism, protein wasting, andan increase in oxygen consumption [1]. Recombinant humangrowth hormone (somatropin) has been shown to act as an ana-bolic agent that attenuates injury-induced catabolism, stimulatesprotein synthesis, and increases muscle mass [2, 3]. In large ther-mal injuries, skin loss presents unique problems for the surgeonattempting wound closure. Through the use of somatropin, rapidwound healing may reduce the hypermetabolic period, and therisk of infection, and it may accelerate healing of skin graft donorsites used for grafting of burned areas [4, 5]. In previous studies,administration of somatropin significantly reduced donor sitehealing times in burned pediatric patients [6–8]. This therapy hasbeen shown to increase the rate of skin graft donor site healing by20% to 30%, resulting in a 30% reduction in the length of hospitalstay [6]. However, these results have not been confirmed in awell-controlled prospective study in adult burn patients. Our aimwas to test the hypothesis that administration of somatropin toseverely burned adults would attenuate the catabolic responsefollowing burn injury, increase the rate of wound healing, andreduce the length of hospital stay in a single-center, placebo-controlled study.

Materials and Methods

Patients and Study Design

Patients selected for this study were between 18 and 65 years ofage, of either sex, and with more than 40% of their total bodysurface burned (TBSB) and/or 15% of the total body surface withfull-thickness burns that required skin grafting (TBSB 3rd degree).All burns were due to flame injuries, with electrical or chemicalburns being excluded. No patient had clinical evidence or historyof malignancy, acquired immunodeficiency syndrome, previous orcurrent treatment with corticosteroids, or any chronic condition,

Correspondence to: P.P. Garcia Luna, M.D., Ph.D., e-mail: [email protected]

including diabetes mellitus, arterial hypertension, liver or heartdisease, renal insufficiency, collagenosis, or serious obesity (bodymass index [BMI] � 35 kg/m2). Patients with multiple traumaswere also excluded. All procedures were carried out in accordwith the ethical standards of the Helsinki Declaration of 1975, andthe study protocol was reviewed and approved by the EthicalReview Board of our hospital. All patients, or relatives whenappropriate, read and signed an informed consent form. Twenty-four patients (19 males and 5 females) entered into a double-blindprospective randomized study to test the efficacy of somatropin(recombinant human growth hormone, Humatrope, Eli Lilly andCompany, Indianapolis, USA) on skin graft donor site healingtime. Patients, physicians, and nursing staff members were blindedto the content of the study drug vials.

Subjects received either 0.15 mg/kg/day of somatropin or pla-

cebo divided into two identical doses administered at 8:00 and20:00 hours via intramuscular injection. The maximum dailysomatropin dose was 11.84 mg (32 IU). Experimental drug ad-ministration began the day that the first autograft was performedand continued until the patient was discharged from the burn unit.Discharge from the burn unit was considered when the patientwas not septic and did not require any special support or moni-toring measures; the wound had almost epithelized, leaving lessthan 10% of the initial total burn surface unclosed; and there wasno evidence of medical or surgical complications related to thewounds that required the patient to remain in the burn unit. Allsubjects received resuscitation fluids to meet their calculated re-quirements. Enteral nutrition (Traumacal, Mead Johnson, Evans-ville, IN, USA) via nasogastric tube with a continuous perfusionpump [9] was provided early after admission to meet caloricrequirements, which were calculated weekly by indirect calorim-etry (Deltratac, Datex Instrumentarium, Helsinki, Finland) per-formed over 20 to 30 minutes on supine patients who continuedreceiving enteral nutrition. The value obtained was then correctedby multiplying by a factor of 1.3 to account for the hypermetabolicstate. Oral food intake was allowed as desired and tolerated, andparenteral supplements, when needed, were included in the finalcaloric intake determinations. Patients were treated by escharec-tomy of the burn areas and autografts from healthy areas. Graftswere obtained by using a Padget electric dermatome with a thick-ness between 0.15 and 0.20 millimeters. Grafts were applied eitherin layers or as a mesh over the burn areas that had previously beencleaned. The donor graft areas were covered with an opaquematerial of hydrocolloid cellulose (Varihesive Westons Chemist,Brighton, England). Starting the fifth day after autograft, thedonor site area was evaluated daily by the same person (T.G .-C.)throughout the entire study. The donor site was classified ashealed when it was adequate for being reharvested as a newautograft donor site.

Routine safety clinical evaluation included pulse rate, temper-ature, and systolic and diastolic blood pressure. The possibility ofdeveloping benign intracranial hypertension was evaluated by aneurologist at the beginning of the study, after one week, andupon completion of treatment by both clinical evaluation andfunduscopy.

Laboratory Studies

Baseline and twice-weekly routine laboratory studies includedcomplete blood counts and a serum chemistry panel. HbA1c,fructosamine, serum growth hormone (GH; RIA, Sanofi Diagnos-tics Pasteur Inc, Chaska, MN, USA), insulin-like growth factor I(IGF-I; IRMA after acid-ethanol extraction, Nichols, San Juan

Table 1. Characteristics of the study population.

Characteristic

Placebogroup(n � 11)

Somatropingroup(n � 13)

Mean (SD) Mean (SD)

Age (years) 35.7 (11.5) 37.6 (14.0)Sex (male/female) 9/2 10/3Height (cm) 170.4 (9.3) 168.5 (6.1)Weight (kg) 72.8 (10.5) 77.7 (10.5)TBSB (%) 44.4 (14.7) 41.5 (11.3)TBSB full-thickness (%) 35.1 (17.9) 29.8 (12.9)Interval burn injury—first

autograft (days)19.6 (13.6) 13.3 (4.1)

Number of grafts/patient 4.2 (1.8) 3.4 (1.8)Somatropin dose (mg/day) 9.92 (0.8) 10.6 (0.9)

TBSB: total body surface burned.Differences between groups were not statistically significant.

Table 2. Donor site healing times (days).

Autograftno.

Placebo group Somatropin group

Mean (SD) Mean (SD)

1 6.90 (0.74) (n � 10) 6.62 (0.87) (n � 13)2 6.40 (0.84) (n � 10) 6.17 (0.72) (n � 12)3 6.63 (1.19) (n � 8) 6.57 (1.13) (n � 7)4 7.17 (1.33) (n � 6) 6.50 (0.84) (n � 6)

Differences between groups were not statistically significant.

Table 3. Interval between first autograft and withdrawal from the burnunit.



Mean (SD) Mean (SD)

Interval between first autograft andwithdrawal from burn unit(days) (LOSBU)

36.2 (19.7) 30.1 (16.8)

LOSBU/% TBSB 0.94 (0.57) 0.72 (0.44)LOSBU/% TBSB full-thickness 1.26 (0.64) 1.07 (0.63)

LOSBU: length of stay in the burn unit (this interval is equivalent tothe total number of days on study medication).

Differences between groups were not statistically significant.

Table 4. Caloric intake.



Mean (SD) Mean (SD)

Basal daily Kcal required* 2192 (552) 2649 (458)Total daily Kcal required 2827 (746) 3270 (609)Total daily Kcal administered 2776 (442) 2900 (451)

*p � 0.032.

Losada et al.: Effects of Somatropin in Burned Adults 3

Capistrano, CA, USA), insulin-like growth factor binding pro-tein-3 (IGFBP-3; RIA, Nichols, San Juan Capistrano, CA, USA),insulin (RIA, DPC, Los Angeles, CA, USA), C-peptide (RIA,Byk-Sangtec Diagnostica GmbH, Dietzenbach, Germany), andthyroid-stimulating hormone (TSH; immunoradiometric assay,Immunotech, Marseille, France) were measured weekly by anindependent laboratory (Reference Labs, Barcelona, Spain) inorder to maintain the blinded conditions of the study. All bloodsamples were drawn before the morning somatropin dose. Toevaluate serum GH concentration profiles, serial blood sampleswere obtained immediately before and 2, 4, 8, 12, 16, and 24 hoursafter administration of the 8:00 dose of somatropin on the secondand eighth days after drug administration was started.

Statistical Analysis

Based on previous publications [6, 10], six completer patients wereneeded in each treatment arm, with a two-tailed alpha error of0.05 and 90% power, to detect what we considered a clinicallyrelevant reduction of two days in graft donor site healing time.However, we doubled this sample size, taking into account thehigh probability of mortality in this high-risk population. Inferen-tial analysis of the qualitative variables was carried out usingChi-squared analysis. The quantitative variables that met condi-tions of normality were evaluated with parametric tests (t-test andanalysis of variance). Qualitative variables that did not meet thetest of normality and ordinal variables with more than two datapoints were analyzed by using the test of Friedman. The Mann-Whitney U test was used for comparisons between groups.

Analysis of donor site healing time and length of stay in theburn unit was performed by comparing the functions of survivalper treatment group with the log-rank statistics. Statistical testswere performed when the patient number in each group was equalto or greater than five. Normality of the variables was determinedusing the tests of Kolmogorov-Smirnov or Shapiro-Wilk. Thealpha-error was set at 5%. If not stated otherwise, results arepresented as mean � standard deviation. The statistical programSPSS for Windows (version 7.5) was used for these analyses.

Results

There were no significant differences between the two groups insex, age, height, weight, TBSB (total and full-thickness), intervalbetween the burn injury and first autograft, study medicationdose, or number of grafts received (Table 1). The mean healingtime of the donor sites of the first four autografts was not differentbetween the two treatment groups (Table 2). All grafts healed in5 to 9 days in both groups.

Although a reduction in the number of days spent in the burnunit, both absolute and relative to the percentage of TBSB (totaland full-thickness), was observed in the group receiving somat-ropin, this difference was not statistically significant (Table 3).

We found a significant increase in mean basal metabolic rate inpatients receiving somatropin compared to the placebo group;however there was no difference between the groups in mean totalmetabolic expenditure or total calories received (Table 4).

In regard to the analytical variables, at no time during the studywere significant differences found between the treatment groupsin the complete blood count, liver function tests, creatinine, cal-cium, cholesterol, triglycerides, sodium, glycosylated hemoglobin,or fructosamine. In two or more weekly determinations through-out the study, mean levels of urea and potassium were significantlylower in patients receiving somatropin than in control patients. Incontrast, mean phosphorus levels were higher in the somatropin-treated group, with significant differences being found in one ofthe weekly determinations (Table 5).

Growth hormone levels were higher in the somatropin-treatedgroup compared to the placebo group. Twenty-four hour analysisof GH profiles demonstrated levels to be significantly higher inthe somatropin group throughout the day, although there was atendency for these levels to diminish during the 12 hours followingadministration of the drug (Fig. 1). The pharmacokinetic curves ofGH clearance were very similar on the second and eighth days ofstudy drug administration. Mean IGF-I levels were also higher inthe group receiving somatropin, with this difference being signif-icant starting on the second day of treatment (89.33 ng/ml in theplacebo group and 178.31 ng/ml in the somatropin group; Fig. 2).Mean IGFBP-3 levels were similar between the groups, with

Table 5. Glucose, potassium, phosphorus, and urea blood values, mean (SD).

Test Day 0 Day 7 Day 14 Day 21 Day 28 Day 35

Glucose (mg/dl)Placebo 120 (35) 105 (25) 103 (18) 101 (14) 107 (21) 105 (17)Somatropin 101 (14) 180 (81)* 155 (71)* 118 (26) 139 (69) 105 (18)Normal 70–110 mg/dl

Potassium (mEq/L)Placebo 4.2 (0.6) 4.6 (0.3) 4.5 (0.3) 4.4 (0.2) 4.5 (0.1) 4.5 (0.2)Somatropin 4.4 (0.3) 4.3 (0.2) 4.2 (0.4) 3.8 (0.3)* 3.9 (0.4)* 4.3 (0.4)Normal 3.5–4.4 mEq/L

Phosphorus (mg/dl)Placebo 3.8 (0.5) 4.5 (0.6) 4.7 (0.4) 4.6 (0.6) 4.9 (0.7) 4.9 (0.3)Somatropin 3.5 (1.1) 4.1 (1.2) 4.9 (0.9) 4.7 (0.8) 5.1 (0.9) 5.8 (0.7)*Normal 3–4.5 mg/dl

Urea (mg/dl)Placebo 36 (12) 33 (5) 30 (7) 33 (7) 33 (7) 39 (10)Somatropin 40 (11) 26 (6)* 28 (7) 25 (4)* 25 (4) 27 (4)*Normal 10–40 mg/dl

*p � 0.05 compared to placebo.

4 World J. Surg. Vol. 26, No. 1, January 2002

significant differences occurring only in two of the weekly deter-minations (Fig. 3).

Mean TSH levels were stable and within the normal rangethroughout the study in both groups. With respect to carbohy-

drate metabolism, during the first 2 weeks of treatment meanglucose levels were significantly higher in the group treated withsomatropin (Table 5). Mean insulin and C-peptide levels weresignificantly elevated in the group treated with somatropin (Table6; Fig. 4). Ten of the thirteen patients treated with somatropinand none of those receiving placebo presented with hyperglyce-mia. Seven of these ten patients required variable doses of insulin(69 � 48 units/24 hours; range: 24 to 124 units/24 hours) duringvariable lengths of time (31.8 � 30 days; range: 7 to 93 days).Within 3 days after termination of somatropin treatment, insulinwas no longer required to control the hyperglycemia.

The main adverse effects seen during the study are summarizedin Table 7. Other than hyperglycemia, there were no significantdifferences between the groups in the rest of these events. Onepatient in the placebo group died as a result of sepsis and multipleorgan failure 7 days after randomization. None of the patientspresented signs of benign intracranial hypertension during thestudy. There were no differences between the two groups in thedaily clinical parameters such as temperature, blood pressure, andpulse.

Discussion

Many attempts have been made to reverse the catabolic changesthat occur in burn patients. In this regard, the metabolic effects ofsomatropin on improving the nitrogen balance in catabolic pa-tients have been demonstrated before [11]. However, there is alack of evidence of benefit in clinically relevant end-points incritically ill subjects, with the exception of children with largeburns [6]. Moreover, a recent report has clearly indicated anincrease in mortality among critically ill patients treated withgrowth hormone [12, 13]. Placebo-controlled, randomized, pro-spective studies have demonstrated that clinical parameters im-prove in children with extensive burns treated with somatropin [6,8]. However, no similar studies exist in the literature confirmingthese results in adult patients. In the present study we evaluate, ina randomized and controlled manner, the effects of somatropin onhealing of the graft donor site and, as a secondary end-point, onthe time spent in the burn unit in adults with severe burns.

Although patients treated with somatropin systematicallyhealed faster than those receiving placebo did, we could notdemonstrate a statistically significant effect of this drug on thegraft donor site healing time. In burn patients, the length ofhospital stay is determined by, among other things, whether thegraft donor sites are healed. In previous studies in severely burnedchildren, there was an association between these two factors suchthat reduction of the healing time of the graft donor site by twodays resulted in a 30% reduction in the length of hospital stay [6].In our study, we also failed to see a significant reduction in thetime spent in the burn unit. This parameter was also analyzed inrelation to the percentage of total body surface burned and thepercentage of third-degree burns, factors that clearly influencelength of stay. However, analyzing the data in this manner did notmodify the results, and there were still no differences between thesomatropin and placebo groups.

The dosage of somatropin used in the present study is similar tothat employed in previous studies [6, 7] of both pathology surger-ies in general [14] and burn patients. It resulted in a significantelevation of circulating IGF-I levels throughout the study period.One difference between this study and previous reports on the use

Fig. 1. Serum growth hormone levels (mean � SEM) taken the secondday of treatment with somatropin or placebo at 8, 10, 12, 16, 20, 24, and8� hours. Study drug (0.075 mg/kg per dose) was administered at 8 and 20hours. GH: growth hormone.

Fig. 2. Morning (8 AM) serum insulin-like growth factor I (IGF-I) levelsin the somatropin and placebo groups at baseline, 2, 7, 14, 21, 28, and 35days after randomization. Number of patients in each group at each timepoint is shown at the bottom of the graph. Values are means � SEM.Shaded area represents the normal range.

Fig. 3. Morning (8 AM) serum insulin-like growth factor binding pro-tein-3 (IGFBP-3) levels in the somatropin and placebo groups at baseline,2, 7, 14, 21, 28, and 35 days after randomization. Number of patients ineach group at each time point is shown at the bottom of the graph. Valuesare means � SEM. Shaded area represents the normal range.


of somatropin in catabolic situations in humans is that we havedivided the total daily dosage into two equal doses. This regimenwas suggested by Herndon et al. in order to eliminate the declinein plasma GH levels observed 12 hours after somatropin admin-istration [6]. Using this protocol, we were able to maintain highGH levels 24 hours a day (Fig. 1) and because GH is thought tohave both direct effects and paracrine effects, these processesshould be additive with those mediated by IGF-I. However, thisdid not result in a greater anabolic effect than that seen in childrenreceiving a single daily dose [6, 8].

The number of patients included in this study is based onprevious publications that demonstrate a significant effect on graftdonor site healing time and length of hospital stay. Theoretically,and in retrospect, sufficient statistical power was present to ob-

serve a significant difference between placebo and the study drug[6–8]. The obvious major difference between our patients andthose of previous studies is their age [6–8]. Therefore, it ispossible that the response of young burn patients is different, butthis has not been demonstrated in a study of patients from a wideage range.

We also observed a discrepancy between our results and thoseof various studies in the number of days needed to heal the graftdonor site in patients treated with placebo. In our study between6 and 7 days were needed, whereas up to 8 or 9 days were reportedin studies of children [6–8]. Hence, it is possible that this param-eter may be inadequate for analyzing treatment efficacy.

Published results of clinical trials in adult burn patients treatedwith somatropin are controversial. The only two published pro-spective studies [10, 15] have limitations in their study design.Shernan et al. [10] demonstrated a reduction in the time necessaryfor healing the graft donor site in a small, heterogeneous popu-lation. However, only a subgroup included burn patients, and nospecific nutritional analysis was done. Belcher et al. [15] did notfind any effect of treatment, but the somatropin dose used was low

Fig. 4. Morning (8 AM) serum C-peptide levels in the somatropin andplacebo groups at baseline, 2, 7, 14, 21, 28, and 35 days after randomiza-tion. Number of patients in each group at each time point is shown at thebottom of the graph. Values are means � SEM. Shaded area representsthe normal range.

Table 6. Hormonal values, mean (SD).

Test Day 0 Day 7 Day 14 Day 21 Day 28 Day 35

GHPlacebo 1.4 (0.9) 1.5 (0.8) 2.1 (1.8) 1.9 (2.0) 1.8 (1.3) 1.4 (0.7)Somatropin 1.9 (1.6) 5.3 (4.2)* 7.3 (5.6)* 3.8 (1.9)* 4.9 (3.7)* 4.2 (1.4)*Normal 0.2–5 ng/mL

IGF-IPlacebo 104 (59) 147 (78) 164 (91) 179 (91) 201 (100) 159 (76)Somatropin 104 (37) 450 (211)* 601 (206)* 554 (237)* 574 (244)* 572 (197)*Normal 48–400 ng/mL

IGFBP-3Placebo 1.8 (1) 2.1 (1.2) 2.3 (1.2) 2.6 (1.6) 3.1 (1.6) 2.6 (1.1)Somatropin 1.8 (0.6) 3.5 (1.4)* 4.7 (2.5)* 3.5 (1.4) 3.8 (1.5) 3.9 (1.1)Normal 1.15–4.75 �g/mL

InsulinPlacebo 15.2 (7.1) 14.7 (5.1) 13.3 (5.1) 19.3 (9.8) 13.4 (6) 12.6 (3)Somatropin 13.2 (8.8) 71.4 (48)* 82 (42)* 104 (46)* 51 (26)* 37 (19)*Normal 0–30 �IU/mL

C-PeptidePlacebo 3.4 (0.6) 3.4 (1.5) 3.3 (1.5) 3.6 (2.5) 2.9 (0.8) 3.1 (0.8)Somatropin 3.8 (1.5) 9.0 (4.1)* 8.8 (2.5)* 7.3 (5.1) 6.8 (2.4)* 5.5 (3.0)Normal 0.66–2.5 ng/mL

TSHPlacebo 2.3 (1.6) 3.2 (1.4) 2.6 (1.5) 2.3 (1.4) 2.1 (1.4) —Somatropin 3.4 (1.7) 3.0 (1.7) 2.8 (1.5) 3.2 (1.6) 2.7 (1.9) —Normal 0.17–5 mIU/L

GH: growth hormone; IGF-I: insulin-like growth factor I; IGFBP-3; insulin-like growth factor binding protein-3; TSH: thyroid-stimulatinghormone.

*Significance accepted at p � 0.05 compared to placebo.

Table 7. Main adverse events.

EventPlacebo group(n � 11)

Somatropin group(n � 13)

Hyperglycemia* 0 10Arterial hypertension 3 5a

Graft infection 4 6Urinary tract infection 4 3Sepsis 4 3Death 1 0

aTwo cases required 50% dose reduction.*p � 0.0001.


and clearly insufficient to rise serum IGF-I levels higher thanthose found in the control group. This is not the case in our study,because the somatropin dose used was clearly higher. In a retro-spective study employing both test and control subjects, a reduc-tion in graft donor site healing time, as well as mortality, was seenin adult burn patients treated with somatropin compared to thecontrol group [16].

Mean IGFBP-3 levels were significantly elevated in the groupreceiving somatropin compared to controls in only two of thevarious determinations performed throughout the study. Al-though there is a well-known relationship between GH and IG-FBP-3, at least in this type of patient it is possible that thisparameter is less useful than IGF-I level in evaluating the effect ofpharmacological doses of somatropin [17].

We observed an increase in the basal metabolic rate of patientstreated with somatropin in comparison with the control group,and this is in accordance with previous studies [14]. Furthermore,we found no significant differences between the two groups ingeneral clinical analyses with the exception of urea levels, whichwere lower in patients treated with somatropin. This could be dueto water retention induced by the hormone treatment. Potassiumlevels were also lower in the somatropin treatment group, possiblyas a consequence of the lower level of protein degradation and theadded effect of hyperinsulinemia in this group [2]. The increase inphosphorus has been described in previous publications and at-tributed to the increase in renal absorption [18].

Insulin and C-peptide were clearly elevated in the group treatedwith somatropin. Although the high insulin levels cannot be con-sidered significant, because various patients required exogenousinsulin to control their hyperglycemia, the clear increase in pep-tide-C levels is indicative of a state of insulin resistance producedby the high somatropin doses. This is a transient effect that tendsto normalize at 2 weeks of treatment. Hyperglycemia was ob-served in ten of the thirteen patients treated with somatropin andseven of them needed high doses of insulin. This treatment ade-quately controlled glucose levels, because neither glycosylatedhemoglobin nor fructosamine levels were modified. The percent-age of adult patients that suffered hyperglycemia is greater thanthat observed in children, probably because of the greater pan-creatic reserve found in children [6–8].

In general the treatment was well tolerated by the patients. Thedeath of one patient in the control group who developed sepsis isnot surprising because this is a relatively frequent complication inpatients with extensive burns. Of interest, the mortality rate in thegrowth hormone-treated group was zero, even in this high-riskpopulation, confirming previous safety results in severely burnedchildren. These results are in clear contrast with the increase inmortality among critically ill patients treated with growth hor-mone reported in two large clinical trials by Takala et al. [12]. Wecan hypothesize that one reason for this discrepancy might bethat, in our study, therapy with the study drug was initiatedapproximately 2 weeks after the burn injury (Table 1), in contrastwith the earlier intervention (5 to 7 days after injury) reported byTakala et al. [12]. Days 5 to 7 after injury are concurrent with thepeak inflammatory and systemic responses to stress, which couldbe exacerbated by the pharmacological effects of growth hormone[13]. Of course, another major difference in the study designs arethe patient populations (severely burned subjects versus patientswith major thoraco-abdominal surgery, multiple trauma, or acute

respiratory failure), which could account for the discrepancy inthe mortality results.

The incidence of infection, hypertension, and sepsis was similarbetween the two groups. In contrast with a previous study ofsurgery patients [19], we found no reduction in the incidence ofinfection as a result of somatropin treatment.

Cases of benign intracranial hypertension have been describedin pediatric patients treated with somatropin [20]. Therefore, wedesigned a systematic prospective study that included both clinicalneurological and funduscopic examinations of our patients. Al-though high doses of somatropin were used, no complications ofthis type were observed. Likewise, there was no increased inci-dence of hypothyroidism, another possible complication related tosomatropin treatment, as TSH levels did not vary between the twostudy groups.

In conclusion, we present the first prospective, randomized,placebo-controlled study to evaluate the effect of a somatropindose sufficient to significantly increase IGF-I levels and influencethe healing time of the graft donor site and the length of stay inthe burn unit in adult patients with severe burns. Because wefound no significant differences between the treatment and con-trol groups, we were unable to confirm results previously reportedfrom a similar study in a pediatric population. We can, however,confirm the excellent safety profile of this therapy in severelyburned pediatric and adult patients [6, 10, 15].

Résumé. Les brûlures sévères provoquent un catabolisme accéléré avec unbilan azoté hautement négatif, ce qui peut aggraver le pronostic. On adémontré que le traitement par somatropine améliore ce bilan dans dessituations hypercataboliques. De plus, chez l’enfant ayant eu des brûluresétendues, ce traitement réduit également la durée de cicatrisation de lazone de prélèvement de greffes cutanées ainsi que la durée del’hospitalisation. Dans la littérature il n’existe aucune étude clinique,prospective, contrôlée qui confirme ces données chez l’adulte. Notre but aété de démontrer l’efficacité d’une hormone de croissance recombinante(somatropine) dans la réduction de la durée de cicatrisation des sites deprélèvement de greffes cutanées, ainsi que dans la durée de séjour dansune unité des brûlures graves des adultes. une étude randomiséecontrôlée par placebo en double aveugle a été menée chez 24 patientsadultes gravement brûlés (atteinte de plus de 40% de leur surfacecorporelle et/ou plus de 15% de la surface en brûlures atteignant toutesles couches de la peau). Les patients ont reçu soit un placebo (n � 11) soitde la somatropine (n � 13) à un dosage de 0.15 mg/kg/jour, divisé en deuxdoses égales (toutes les 12 heures) par injection intramusculaire. On acommencé le traitement le même jour que la première autogreffe et on l’aterminé le jour de sortie de l’unité des brulés. Le nombre moyen (� ET)de greffes par patient ne différait pas de façon significative dans les deuxgroupes (4.2 � 1.8 vs. 3.4 � 1.8, respectivement, dans les groupes placeboet somatropine). Aucune réduction dans la durée de cicatrisation du sitede prélèvement de greffe cutanée n’a été observée dans le groupe desomatropine comparée au groupe placebo. De même, la durée passée dansl’unité des brûlés ne différait pas de façon significative que ce soit ennombre absolu de jours (36.2 � 19.7 vs 30.1 � 16.8 dans les groupesplacebo et somatropine, respectivement) ou par rapport aux pourcentagesde la surface corporelle totale brûlée ou la surface brûlée sur toutel’épaisseur. L’hormone de croissance et les taux de facteur de croissanceinsulin-like-I (IGF-I) étaient trois à cinq fois plus élevés dans le groupesomatropine comparé au groupe placebo. Dix patients traités parsomatropine ont eu une hypoglycémie, parmi lesquels sept ont nécessitéune insulinothérapie. Aucune effet secondaire n’a été observé excepté chezun patient dans le groupe placebo qui est décédé suite à un sepsis et unedéfaillance multiviscérale. La somatropine, telle qu’utilisée aux dosesspécifiées dans cette étude, n’a réduit ni la durée de cicatrisation des sitesde prélèvement de greffes de peau, ni la durée d’hospitalisation dansl’unité des grands brûlés adultes.


Resumen. Los pacientes con quemaduras extensas exhiben catabolismoacelerado con elevados balances negativos de nitrógeno, fenómenos quepueden empeorar su pronóstico. El tratamiento con somatotropina hademostrado mejorar este balance negativo en diferentes condicioneshipercatabólicas. Además, en niños con grandes quemaduras, tambiénacorta el periodo de cicatrización del sitio donante de piel y reduce eltiempo de hospitalización. En la literatura disponible no se encuentranestudios clínicos prospectivos en pacientes adultos que confirmen taleshallazgos. Nuestro propósito fue demostrar la eficacia de la hormona decrecimiento recombinante (somatotropina) en la reducción tanto deltiempo de cicatrización del sitio donante como de la estancia en la Unidadde Quemados en pacientes adultos con quemaduras graves. se realizó unestudio aleatorizado y doble ciego en 24 pacientes adultos conquemaduras extensas (más del 40% de la superficie corporal y/o más del15% de quemaduras de espesor total). Los pacientes recibieron placebo (n� 11) o somatotropina (n � 13) en cantidad de 0.15 mg/Kg/día, divididaen dos dosis iguales administradas cada 12 horas por vía intramuscular.El tratamiento se inició el día en que se practicó el primer autoinjerto depiel, y fue concluido el día en que el paciente egresó de la Unidad deQuemados. El número de injertos de piel por paciente fue similar en losdos grupos (4.2 � 1.8 vs. 3.4 � 1.8 en el grupo placebo y en el grupo desomatotropina, respectivamente). No se observó disminución en el tiempode cicatrización del sitio donante en el grupo de somatotropina encomparación con el grupo placebo. Tampoco resultó significativamentediferente el tiempo de permanencia en la Unidad de Quemados ni elnúmero absoluto de días de hospitalización (36.2 � 19.7 vs. 30.1 � 16.8días en los grupos placebo y somatotropina, respectivamente), ni en lorelativo al porcentaje total de la superficie corporal o al de la quemadurade espesor total. Los niveles de hormona de crecimiento y de factor decrecimiento similar a la insulina-I (IGF-I) aparecieron tres a cinco vecessuperiores, respectivamente, en el grupo somatotropina en comparacióncon el grupo placebo. Diez de los pacientes tratados con somatotropinaexhibieron hiperglicemia, y siete de ellos requirieron la administración deinsulina. No se observaron otros efectos, excepto que un paciente en elgrupo placebo murió como resultado de sepsis y falla orgánica múltiple.La somatotropina en el régimen de tiempo y dosificación utilizado en esteestudio, no logró reducir el tiempo de cicatrización del sitio donante ni dela estancia en la Unidad de Quemados en pacientes adultos conquemaduras graves.

Acknowledgments

We thank the staff of the Burn Unit at the University HospitalVirgen del Rocío, Seville, and Ms. Mercedes Martínez and Ms.Inmaculada Carpio, clinical research assistants at the MedicalResearch Department of Lilly S.A., Spain, for their invaluablehelp in the design and performance of this study. This work wassupported by Lilly, S.A.

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effects of human recombinant growth hormone on donor-site healing in burned adults

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