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. Author manuscript; available in PMC: 2017 Sep 1.
Published in final edited form as: J Burn Care Res. 2016 Sep-Oct;37(5):273–277. doi: 10.1097/BCR.0000000000000356

Long-term administration of oxandrolone improves lung function in pediatric burned patients

Linda E Sousse 1,3, David N Herndon 1,3, Ronald P Mlcak 3, Jong O Lee 1,3, Clark R Andersen 1,3, Andrew Zovath 3, Celeste C Finnerty 1,2,3, Oscar E Suman 1,3
PMCID: PMC5014595  NIHMSID: NIHMS774553  PMID: 27171844

Abstract

Pulmonary dysfunction is a significant contributor to morbidity and mortality in the pediatric burned population. We have previously reported that the administration of a synthetic testosterone derivative, oxandrolone, significantly reduced hypermetabolism, and significantly increased height percentile, bone mineral content, lean body mass, and strength in pediatric burned patients.

Objective

We hypothesize that the administration of oxandrolone will improve pulmonary function in burned pediatric subjects.

Methods

A subset of severely burned pediatric subjects from a prospective clinical trial (n=222) were included in our study (n=54, 7-18 years, ≥30% total body surface area burn). The subjects were previously randomized to either the control arm (n=35), or the oxandrolone arm (0.1 mg/kg twice/day for 12 months, n=19). Maximum voluntary ventilation (MVV), the ratio between forced expiratory volume and forced vital capacity, and diffusion capacity were measured six months following burn injury, and results were compared between burned subjects with and without oxandrolone administration. Maximum expired ventilation (VEMax) was also measured in a subset of burned subjects.

Results

Subjects treated with oxandrolone had a significantly higher MVV (98 ± 53 L/min vs 115 ± 56 with treatment, p=0.03). During maximal exercise, subjects treated with oxandrolone had a significantly higher VEMax compared to untreated subjects (32.0 ± 8.7 L/min vs 43.7 ± 13.6 with treatment, p=0.02).

Conclusions

The administration of oxandrolone was associated with improved lung function in pediatric burned patients.

Keywords: Oxandrolone, lung function, pediatric burn, spirometry, maximum voluntary ventilation, pulmonary function test, maximum expired ventilation

Introduction

Annually, approximately 450,000 burn injuries occur in the United States, resulting in 40,000 hospitalizations and 3,400 deaths [1]. Nearly 23,000 of these burn patients suffer concomitant lung injury following smoke inhalation [2]. Inhalation injury significantly contributes to overall mortality and morbidity in burn patients [3, 4].

We have previously found that oxandrolone improved patient outcomes in clinical trials from our burn center. Oxandrolone is a synthetic, orally-administered, nonaromatizable testosterone derivative that initiates protein synthesis and anabolism via androgen receptors in skeletal muscle. Oxandrolone is preferable to testosterone supplementation because oxandrolone has only 5% of the virilizing activity and lower hepatotoxicity of testosterone. Oxandrolone is the sole adrogenic steroid approved by the FDA to maintain body weight resulting from catabolic states, such as in Turner Syndrome, AIDS, major surgery, infections, malnutrition, and neuromuscular diseases.

We have previously shown in severely burned children that long-term administration of oxandrolone for one year began during the acute phase of burn injury significantly reduced hypermetabolism [5]. Oxandrolone also significantly decreased the percent of predicted resting energy expenditure six months post injury, increased the height percentile one- and two-years post burn, and increased bone mineral content in subjects ages 7-18 years 2-5 years post burn [5]. In addition, we showed significantly increased lean body mass in oxandrolone-treated subjects between 7-18 years of age who received exercise training when assessed 2-5 years post burn. The same subjects (7-18 years) receiving oxandrolone in addition to exercise training had increased strength at 9-24 months post burn [5].

It has been reported that surgical patients with respiratory failure receiving oxandrolone spent significantly more time on a ventilator compared to untreated patients [6]. Considering that severely burned patients are already prone to pulmonary impairment, we examined subjects treated with oxandrolone for 6 months to assess the effects on lung function. Spirometry and lung volume measurements were performed to test the hypothesis that the administration of oxandrolone would increase pulmonary function in burned patients.

Materials and Methods

Subject Population

Patients 7 to 18 years of age at the time of the burn, with ≥30% of total body surface area (TBSA) burned, and the need for at least one surgical intervention were included in the study. Exclusion criteria were the decision not to treat due to severity of the burn injury; anoxic brain injury; presence of pre-existing conditions such as HIV, AIDS, hepatitis, 5-year history of malignancy, or diabetes; and an inability to obtain informed consent. Administration of oxandrolone was started within 48 hours after the first operation. Oxandrolone was given orally at a dosage of 0.1 mg/kg twice a day for 6 months (BTG Pharmaceuticals, West Conshohocken, PA). This study was part of a larger clinical trial (www.clinicaltrials.gov, NCT00675714) to assess the long-term outcomes of burn survivors following administration of therapeutic agents such as oxandrolone, propranolol, insulin, and the combination of oxandrolone and propranolol. Informed written consent to a protocol approved by the Institutional Review Board of the University of Texas Medical Branch was obtained from a legal guardian before enrollment in the study. Children older than 7 years assented to participate.

Patient Demographics and Injury Characteristics

Subject age, sex, and TBSA burned were recorded at the time of admission. Age-appropriate diagrams were used to determine burn size [7]. Patients received the standard of care in the acute period as previously described [5].

Pulmonary Function Testing (PFT)

As part of the long-term assessment of our patients, lung volumes and spirometry were assessed in 54 burned subjects during scheduled outpatient clinic visits 6 months post-burn.

The PFT study variables included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow rate between 27-75% of the FVC (FEF25-75), FEV1/FVC ratio expressed as a percentage (FEV1/FVC%), total lung capacity (TLC), functional residual capacity (FRC), carbon monoxide diffusion capacity (DLCO), and maximum voluntary ventilation (MVV). MVV requires a subject to exert significant effort to breathe a maximum volume of air over a 12-15 second period. All spirometry measurements were made with a pulmonary function testing system (Medical Graphics PF/DX, St. Paul, MN) with the subject in an upright position [8]. Lung volumes were corrected to body temperature and atmospheric pressure. Subjects correctly performed at least two practice forced maximal inhalations and exhalations before any spirograms were documented. All expected values were obtained using validated-general population equations, and normal predicted values were obtained from Knudson, et al. [9].

The procedures were performed in accordance with the guidelines from the American Thoracic Society [10]. The criteria that was used to determine whether the subjects performed the maximal spirometry maneuvers included (A) appropriate curve shape, (B) lack of artifacts in results such as coughing, premature termination of the test, or delayed onset of measurement, (C) sustained expiration for a minimum of 3 seconds, and (D) performance deemed satisfactory by the tester [8].

Statistical Analysis

Multiple linear regression models were used to model the relation between the various outcome variables with four predictor variables including treatment group (oxandrolone versus control), sex, age, and percent of TBSA burned. In addition, TBSA burned, MVV, and DLCO were log-transformed to better approximate a normal distribution. Regression parameter estimates, reverse-transformed as appropriate, were tabulated along with associated 95% confidence intervals and p-values. The Welch test was used to model higher maximum expired ventilation (VEMax). All statistical tests assumed a 95% level of confidence. Analyses were performed using R statistical software [11].

Results

Demographics

A total of 2,821 patients were admitted to the Shriners Hospital for Children-Galveston between 2000-2010. Of these patients, 2,305 did not meet studies of interventions to attenuate the hypermetabolic response, leaving 516 subjects enrolled in the six arms of the larger clinical trials. Two hundred and twenty-two subjects were included in this analysis of control (n=152) compared to oxandrolone (n=70, 0.1 mg/kg twice a day for 6 months). All patients between the ages of 7-18 years with reliable pulmonary function tests in our study were included (n=54, Figure 1) because PFTs are generally considered reliable beginning from the age of 7 years due to the ability to follow specific instructions. The characteristics of the subjects randomized to oxandrolone and control groups were not significantly different (Table 1).

Figure 1.

Figure 1

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The consort diagram depicts patient allocation into this study. Subjects were included in our analyses if he/she had ≥30% TBSA burned, were between the ages of 7-18 years, and completed a pulmonary function test at the six-month time point.

Table 1. Subject Demographics.

Control (n=35) Oxandrolone (n=19) p-Value
Age (Years) 13 ± 3 12 ± 4 0.46
Gender (M:F) 24:11 15:4 0.62
Ethnicity (Hispanic, %) 29 (83%) 18 (95%) 0.39
TBSA Burned [Median] 60 ± 15 [58] 61 ± 17 [55] 0.97
3rd Degree TBSA Burned [Median] 47 ± 24 [46] 32 ± 22 [30] 0.06
Inhalation Injury (%) 16 (46%) 9 (47%) 1.00
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Oxandrolone improves MVV

Subjects treated with oxandrolone had significantly higher MVV compared to untreated subjects at 6 months post burn (Untreated: 98 ± 53 L/min, Oxandrolone: 115 ± 56 L/min, p=0.025). Table 3 shows the model summaries of MVV for the four predictor variables: the treatment groups, gender, age, and TBSA burned. The significant variables include the differences between oxandrolone-treated and untreated groups (Factor: 1.327) and age (Factor: 1.047). Figure 2 illustrates the 33% increase in MVV in oxandrolone-treated subjects compared to untreated subjects. Additionally, every one-year increase in age was associated with a 5% increase in the log of MVV.

Table 3. Maximum Voluntary Ventilation (MVV).

Factor 95% CI p-Value
Oxandrolone/Control 1.327 1.044 to 1.686 0.025*
Male/Female 1.192 0.918 to 1.548 0.190
Age 1.047 1.009 to 1.086 0.020*
TBSA Burned [Log] 0.869 0.532 to 1.418 0.580
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Figure 2.

Figure 2

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Oxandrolone significantly improves maximum voluntary ventilation (MVV). The means with confidence intervals of MVV between burned subjects with and without oxandrolone treatment are shown in Figure 2. (*) represents significance of p<0.05 compared to control.

Oxandrolone administration had no effect on FEV1/FVC and DLCO when measured 6 months post burn (FEV1/FVC: Untreated: 1 ± 0, Oxandrolone: 1 ± 0, p=0.816; DLCO: Untreated: 102 ± 39, Oxandrolone: 111 ± 26, p=0.684). Tables 4 and 5 show the model summaries of both pulmonary variables for the four predictor variables.

Table 4. Forced Expiratory Volume/Forced Vital Capacity (FEV1/FVC).

Adjusted Mean Standard Error p-Value
Oxandrolone-Control 0.035 0.020 0.082
Male-Female -0.044 0.022 0.054
Age 0.0001 0.003 0.967
TBSA Burned [Log] 0.058 0.042 0.169
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Table 5. Diffusion Capacity (DLCO).

Factor Standard Error p-Value
Oxandrolone/Control 0.067 0.160 0.684
Male/Female -0.040 0.224 0.862
Age -0.038 0.030 0.224
TBSA Burned [Log] 0.359 0.331 0.296
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Exercise maximal minute ventilation is higher with oxandrolone

Twelve control subjects and twelve oxandrolone-treated subjects underwent a maximal exercise treadmill test. There were no statistical differences between their gender, ethnicity, or TBSA burned within the cohorts (Table 2). Subjects treated with oxandrolone had significantly higher maximum expired ventilation (VEMax) compared to untreated subjects 6 months after burn (Untreated: 32 ± 9 L/min, Oxandrolone: 44 ± 14 L/min, p=0.02, Figure 3).

Table 2. Demographics of Subjects in Subset of Study with Exercise Testing.

Control (n=12) Oxandrolone (n=12) p-Value
Age (Years) 11 ± 4 13 ± 3 0.21
Gender (M:F) 9:3 10:2 1.00
Ethnicity (Hispanic, %) 12 (100%) 12 (100%) 1.00
TBSA Burned [Median] 50 ± 8 [48] 59 ± 18 [54] 0.15
3rd Degree TBSA Burned [Median] 43 ± 16 [45] 36 ± 19 [32] 0.36
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Figure 3.

Figure 3

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Exercise maximal minute ventilation (VEMax) significantly increases with oxandrolone. Means with standard deviations of VEMax between burned subjects with and without oxandrolone treatment are shown in Figure 3. (*) represents significance of p<0.05 compared to control.

Discussion

The pulmonary function changes seen in burned pediatric patients may be caused by a combination of airway and lung inflammation, scar formation, and decreased compliance from chest wall and loss of muscle strength. We have previously reported continued lung dysfunction in the forms of obstructive and/or restrictive disease processes at 2- and 8-years post-burn injury [12, 13]. Previously we suggested that permanent cardiopulmonary impairment was a possible complication in pediatric burn patients [14], and we have shown that severely burned children have significantly improved pulmonary function through regular exercise training [15]. In our current study, we have shown that subjects treated with oxandrolone had a significantly higher MVV compared to untreated subjects (Figure 2), and that subjects treated with oxandrolone had a significantly higher VEMax compared to untreated subjects during maximal exercise (Figure 3).

In a study by Przkora et al of oxandrolone and exercise in pediatric burn patients, it was reported that both the subjects with exercise training and subjects with oxandrolone and exercise training had significantly increased peak oxygen consumption [16]. Additionally, in a study of oxandrolone's effects on adult tetraplegia patients, Spungen et al found a significant combined improvement in measures of spirometry [17]. Oxandrolone has been shown to increase net muscle protein synthesis in healthy men [18] and in burned children [19], which may explain the beneficial effects of oxandrolone on lung physiology.

While studies have shown the benefits of oxandrolone on overall recovery in burn patients, a study by Bulger et al concluded that ventilator-dependent adult surgical trauma patients treated with oxandrolone spent a significantly longer time on mechanical ventilation [6]. In a response to this, Pereira et al discuss the consideration that oxandrolone's blocking of glucocorticoid signaling, lowering of plasma triglycerides, and effects on lipid metabolism decreased surfactant production, a factor that could be accounted for in future implementation [20].

Spirometry is primarily performed at rest and is largely effort dependent. Previous resting pulmonary function studies have shown degrees of impaired gas exchange and residual pulmonary pathology. However, we did not find differences in the FEV1/FVC and DLCO between the oxandrolone-treated group and the control group. It is important to note that a maximal exercise treadmill test requires the pulmonary system to perform at a peak level; thus, this test allows the assessment of pulmonary function beyond resting levels. The dynamic measurements of pulmonary function, MVV (Figure 2; p=0.025) and VEmax (Figure 3; p=0.02), were significantly higher in oxandrolone-treated subjects compared to untreated subjects at 6 months post burn.

We speculate that the administration of oxandrolone may have increased the strength of respiratory accessory muscles. Our results also suggest that lung function should not be looked at simply with static tests such as the pulmonary function tests, but also with dynamic tests performed during exercise. Future studies will measure the maximum expiratory and inspiratory pressures in our subject population, and will measure pulmonary function one year after burn injury. In conclusion, the long-term administration of oxandrolone may be a safe and effective therapy to alleviate lung dysfunction.

Acknowledgments

This work was supported by Grants P50GM060338, R01GM056687, R01HD049471, H133A120091, and T32GM008256 from the National Institute of Health; Grants 84080, 79135, 71009, 80100, and 71008 from the Shriners Hospitals for Children; Grant W81XWH-12-10429 from the Department of Defense; and the ‘Remembering the 15’ Research Education Endowment Fund. This study was also conducted with the support of the Institute for Translation Sciences at UTMB, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Sciences (NIH). Additionally, this study is registered at clinicaltrials.gov, No. NCT00675714.

The authors would like to thank the staff of Shriners Hospitals for Children-Galveston for their valuable assistance, especially Tabatha Elliot, Noe Rodriguez, Becky Whitlock, and the Respiratory Therapy Team. The following individuals assisted with the conduct of the oxandrolone clinical trial and/or study measurements: Deborah Benjamin, Wes Benjamin, Maria Cantu, Mario Celis, Kathryn Epperson, Holly Goode, Joanna Huddleston, Sylvia Ojeda, Cathy Reed, Lucile Robles, and Judith Underbrink. The authors also thank Dr. Daniel Traber for consultation.

Footnotes

Disclosures: No conflicts of interest exist with the authors.

References

  • 1.Association AB. Burn Incidence and Treatment in the United States: 2013 Fact Sheet. 2013 March 9, 2015]; Available from: http://www.ameriburn.org/resources_factsheet.php.
  • 2.Alcorta R. Smoke inhalation & acute cyanide poisoning. Hydrogen cyanide poisoning proves increasingly common in smoke-inhalation victims. JEMS. 2004;29(8) suppl:6–15. quiz suppl 16-7. [PubMed] [Google Scholar]
  • 3.Mlcak R, et al. Lung function following thermal injury in children--an 8-year follow up. Burns. 1998;24:213–216. doi: 10.1016/s0305-4179(98)00012-6. [DOI] [PubMed] [Google Scholar]
  • 4.Finnerty CC, et al. Proteomics improves the prediction of burns mortality: results from regression spline modeling. Clin Transl Sci. 2012;5(3):243–9. doi: 10.1111/j.1752-8062.2012.00412.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Porro LJ, et al. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg. 2012;214(4):489–502. doi: 10.1016/j.jamcollsurg.2011.12.038. discussion 502-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Bulger EM, et al. Oxandrolone does not improve outcome of ventilator dependent surgical patients. Ann Surg. 2004;240(3):472–8. doi: 10.1097/01.sla.0000137131.22608.e2. discussion 478-80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Mlcak R, Buffalo M. Pre-hospital management, transport, and emergency care. In: Herndon DN, editor. Total Burn Care. Saunders; Philadelphia: 2007. pp. 81–92. [Google Scholar]
  • 8.Suman OE, Mlcak RP, Herndon DN. Effects of exogenous growth hormone on resting pulmonary function in children with thermal injury. J Burn Care Rehabil. 2004;25(3):287–93. doi: 10.1097/01.bcr.0000124792.22931.d7. [DOI] [PubMed] [Google Scholar]
  • 9.Knudson RJ, et al. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age. Am Rev Respir Dis. 1976;113(5):587–600. doi: 10.1164/arrd.1976.113.5.587. [DOI] [PubMed] [Google Scholar]
  • 10.Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3):1107–36. doi: 10.1164/ajrccm.152.3.7663792. [DOI] [PubMed] [Google Scholar]
  • 11.Team RC. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing 2012 [Google Scholar]
  • 12.Petroff PA, et al. Pulmonary function studies after smoke inhalation. Am J Surg. 1976;132(3):346–51. doi: 10.1016/0002-9610(76)90391-3. [DOI] [PubMed] [Google Scholar]
  • 13.Mlcak R, et al. Lung function following thermal injury in children--an 8-year follow up. Burns. 1998;24(3):213–6. doi: 10.1016/s0305-4179(98)00012-6. [DOI] [PubMed] [Google Scholar]
  • 14.Mlcak RP, et al. Increased physiological dead space/tidal volume ratio during exercise in burned children. Burns. 1995;21(5):337–9. doi: 10.1016/0305-4179(94)00017-4. [DOI] [PubMed] [Google Scholar]
  • 15.Suman OE, Mlcak RP, Herndon DN. Effect of exercise training on pulmonary function in children with thermal injury. J Burn Care Rehabil. 2002;23(4):288–93. doi: 10.1097/00004630-200207000-00013. discussion 287. [DOI] [PubMed] [Google Scholar]
  • 16.Przkora R, Herndon DN, Suman OE. The effects of oxandrolone and exercise on muscle mass and function in children with severe burns. Pediatrics. 2007;119(1):e109–16. doi: 10.1542/peds.2006-1548. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Spungen AM, et al. Treatment with an anabolic agent is associated with improvement in respiratory function in persons with tetraplegia: a pilot study. Mt Sinai J Med. 1999;66(3):201–5. [PubMed] [Google Scholar]
  • 18.Sheffield-Moore M, et al. Short-term oxandrolone administration stimulates net muscle protein synthesis in young men. J Clin Endocrinol Metab. 1999;84(8):2705–11. doi: 10.1210/jcem.84.8.5923. [DOI] [PubMed] [Google Scholar]
  • 19.Hart DW, et al. Anabolic effects of oxandrolone after severe burn. Ann Surg. 2001;233(4):556–64. doi: 10.1097/00000658-200104000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Pereira CT, Jeschke MG, Herndon DN. Use of oxandrolone in ventilator dependent surgical patients. Ann Surg. 2005;241(6):1030–1. doi: 10.1097/01.sla.0000165781.09660.ad. author reply 1031-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

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