Pharmacotherapy of Metabolic Modulation in Acute Burns Mitchell J Daley, PharmD, FCCM, BCPS

Pharmacotherapy of Metabolic Modulation in Acute Burns Mitchell J Daley, PharmD, FCCM, BCPS Clinical Pharmacy Specialist, Critical Care Dell Seton Medical Center at the University of Texas and Seton Healthcare Family Clinical Adjunct Faculty University of Texas College of Pharmacy

Objectives 1. Review the mechanism and clinical evidence for oxandrolone, propranolol and insulin for metabolic modulation following acute burn injury in adult patients 2. Devise a pharmacotherapy plan for metabolic modulation following acute burns in adult patients

Patient Case DR is a 32 yo M admitted to DSMC after burn from water heater blast accident at home (weight 76 kg) 40% TBSA burned by flame (2 nd -3 rd degree) Face, posterior, neck, anterior trunk, upper and lower extremities Early excision and grating on Day 5 DR is now at DSMC 10 days after his burn 10 days post burn, he is now: Loosing significant weight (76 kg -> 68 kg) His graft sites are not healing well His HR is consistently ~120 bpm His ALT is 3x ULN Blood glucose 140-160 mg/dl responsive to inulin sliding scale

What Adjuncts? Which of the following is the optimal adjunct for efficacy and safety in this patient? A. Oxandrolone 10 mg PO q12h B. Propranolol 5 mg PO q6h C. Metformin 500 mg PO q12h D. Testosterone 400 mg IM q2weeks

Metabolic Modulation: Flow Phase Begins after initial stabilization Imbalance of catabolism and anabolism Decreased growth hormones and testosterone Sustained increase in catecholamine and cortisol release (10x) Hyperglycemia and insulin resistance Impaired immune function, lean muscle breakdown Resting energy expenditure: 180-200% Proportional to size and severity of burn May persists for months to 3 years Complications include: lean muscle loss (1 lb/day), decreased bone density and impaired wound healing, fatty liver Anesthesiology 2015;122:448-64

Oxandrolone Anabolic steroid and synthetic testosterone derivative Binds to intracellular androgen receptor in skeletal muscle Oxandrolone/androgen receptor complex migrate to nucleus and binds to DNA Stimulates protein synthesis and anabolism Increases muscle growth and reduces weight loss

Oxandrolone RCT Design Study Population Outcomes Multicenter, prospective, randomized, double-blinded trial N = 81 Treatment Group (n = 46) Oxandrolone 10 mg twice daily Control Group (n = 35) Placebo Inclusion - Adult patients 18 years of age with 20 60% TBSA burns - Ability to begin oral or enteral nutrition within 5 days of injury - No concurrent injuries apart from burn/inhalation injury that could produce long-term disabilities Exclusion - Primary chemical or electrical injury - Pregnancy - History of chronic liver disease, renal failure, or cancer - Recent or current use of glucocorticoids or anabolic steroids Primary - Length of stay Secondary - Number of ventilator days - Number of surgical procedures - Discharge to home - Total hospital costs - Complications - Hepatic dysfunction Follow-up continued to discharge J Burn Care Res 2006;27:131-139.

Oxandrolone RCT Oxandrolone N = 46 Placebo N = 35 p value Length of stay (days, M ± SD) 32.0 ± 3.1 45.3 ± 5.4 0.04 Number of ventilator days (M ± SD) 13 ± 3 18 ± 4 0.28 Number of surgical procedures (per subject, M ± SD) 2.2 ± 0.3 4.0 ± 0.6 0.02 Discharge to home, n (%) 32 (69.6) 20 (57.1) 0.42 Total hospital costs ($, M ± SD) 227,588 ± 30,086 262,671 ± 57,442 0.62 Complications, n (%) 24 (52.2) 20 (57.1) 0.85 M ± SD: Mean ± Standard deviation J Burn Care Res 2006;27:131-139.

Hepatic Transaminases Oxandrolone Placebo p value AST N = 114 ALT N = 110 AST N = 119 ALT N = 118 Outside of normal range (5 30 mg/dl) - AST, n (%) - ALT, n (%) 69 (60.5) 52 (47.3) 62 (52.1) 66 (55.9)) 0.25 0.24 Significant hepatic damage (>100 mg/dl) - AST, n (%) - ALT, n (%) N = Number of levels drawn per group AST: Aspartate aminotransferase ALT: Alanine aminotransferase 11 (9.6) 21 (19.1) 9 (7.6) 6 (5.1) 0.74 <0.05 J Burn Care Res 2006;27:131-139.

Wolf (2006): Authors Conclusions Oxandrolone is associated with shorter length of stay in severe burn injury Study stopped halfway due to significant difference between groups at planned interim analysis Reasons for decreased length of stay not defined in study Hepatic transaminases should be monitored Significantly greater incidence of increased serum transaminases in treatment group Clinical relevance of increased serum transaminases unknown Increased transaminases not associated with increases in length of stay or other complications J Burn Care Res 2006;27(2):131-9 J Burn Care Res 2006;27:131-139.

Study /Design Intervention Patient Population Results Conclusion Demling RH, et al. J Crit Care 2000;15:12. RCT Single center Pharm TN, et al. J Burn Care Res 2008;29:902. Observational Single center Cochran A, et al. Burns 2013;39:1374. Retrospective Multicenter Oxandrolone (n=11) 10 mg Q12H vs Placebo (n=9) Oxandrolone dose undefined (n=59) vs Placebo (n=58) Started within 7 days of injury Oxandrolone dose undefined (n=38) vs Placebo (n=129) Started within 7 days of injury Adult patients 18 years of age with 40-70% TBSA burn with at least 20% requiring grafts Adult patients 18 years of age with more than 20% TBSA burn No other concurrent trauma Adult patients 18 years of age with more than 15% TBSA burn Oxandrolone reduced : Net weight loss (3 kg vs. 8 kg; p<0.05) Net nitrogen loss (4 g vs. 13 g; p<0.05) Time to epithelialization of donor site (9 days vs. 13 days; p<0.05) No liver dysfunction or hirsutism was noted Mean duration of oxandrolone 43 days Oxandrolone was associated with reduced morality (OR 0.1; 95% CI 0.02-0.7; p<0.02) in adjusted analysis Oxandrolone did not appear to reduce the number of surgical procedures, number of units transfused, number of ventilator days, LOS, nosocomial infections or multiple organ failure 1:1 matching for CSI, age and TBSA burn Oxandrolone reduced the LOS (33.6 days vs. 43.4 days; p=0.03) Oxandrolone is superior to placebo for decreasing weight and net nitrogen losses and increasing donor site wound healing. Oxandrolone may be associated with improved survival in severe burn injury. Further validation with a RCT is needed. Oxandrolone is associated with shorter length of stay in severe burn injury while controlling for CSI, TBSA, and age.

Oxandrolone Considerations ABA Guidelines: not addressed, most ABA centers use Consider Oxandrolone 10 mg Q12H if >20% TBSA Initiate following fluid resuscitation and initial stabilization Use with caution: concurrent edema or fluid retention issues, concurrent glucocorticoids, history of coronary artery disease or hyperlipidemia, active bleeding Avoid: Carcinoma of prostate or breast, hepatic impairment, pregnancy, nephrosis, hypercalcemia Monitor: LFT and serum calcium at baseline and weekly, adrenergic side effects Continue until discharge to hospital or rehab or wound closure J Burn Care Research 2008;29:257-266

Propranolol Attenuates excessive cardiovascular and catabolic response Modulates metabolic response oxygen demand resting energy expenditure Reduces catecholamine induced muscle breakdown and lipolysis Modifies immune response Majority of data in peds Austin J Emergency & Crit Care Med 2015;2:1032

Design Single center, prospective, randomized, blinded trial N = 81 Propranolol RCT Study Population Inclusion - Adult patients 16-60 years of age with 20 50% TBSA burns - Started on the 4 th day after HD stable Treatment Group (n = 37) Propranolol 1 mg/kg/day in 6 divided doses (max 1.98 mg/kg/day) Adjusted to decrease resting HR by 20% Control Group (n = 42) Placebo Exclusion - Cardiac, endocrine, PVD - History of asthma - SBP <90, HR <60 after resuscitation - Inhalation injury J Burn Care Res 2009;30:1013-1017.

Propranolol RCT J Burn Care Res 2006;27:131-139.

Propranolol RCT Survival Differences? Mortality 13.5% Propranolol vs. 14.28% Control (p=0.92) No difference in sepsis either J Burn Care Res 2006;27:131-139.

Mohammadi (2009): Conclusions In severe burn, propranolol is associated with: Improved wound healing and decreased healing time Preservation of protein and amino acid stores Regeneration of epithelial cells and granulation tissue Shorter length of stay No apparent reduction in infectious complications or mortality Well tolerated (1 patient experience hypotension) J Burn Care Res 2006;27(2):131-9 J Burn Care Res 2006;27:131-139.

Study /Design Ali A, et al. Crit Care 2015;19:217. RCT Single center Brown DA, et al. J Burn Care Res 2016;37:218. Retrospective Single center Interventio n Propranolol (n=35) vs Placebo (n=37) Propranolol (n=35) Patient Population Results Conclusion Adult patients 18 years of age with 30% TBSA, treatment with at least one surgical skin graft Adults (18-65) with acute burn injuries > 20% Excluded: pre-admission beta-blocker Propranolol unclear starting dose Adjusted to decrease resting HR by 20% (maximum 4 mg/kg/day) Started on day 2 Propranolol 10 mg q6h NG/PO Adjusted to decrease max HR by 20% Median total daily dose 3.3 mg/kg/day for an average of 40 days Propranolol reduced : Mean daily HR by 11 BPM starting on day 2 Time between skin grafting (10 vs 17 days; p=0.02) Mean duration of propranolol 29 day Mean dose 0.46 mg/kg/d (min 0.24 to max 0.61) 72% experienced hypotension (MAP < 60, SBP < 90) 14.8% experience bradycardia (<60) 81.5% of patients had at least 1 dose held More common for ADR and to hold within first week and with older patients Acute HD events correlated with ICU LOS, duration of MV and OR procedures and use of ABX

How is Propranolol Used? J Burn Care Res 2006;27(2):131-9 LeCompte MT, et al. Burns 43;2017:121-126.

Propranolol Considerations ABA Guidelines: not addressed, most ABA centers use Consider Propranolol 5-10 mg Q6H if >20% TBSA Initiate following fluid resuscitation and initial stabilization (48 hrs-7 days) Use with caution: elderly, hepatic or renal dysfunction, chronic pulmonary conditions Avoid: HD unstable, bradyarrhythmia, HF, concurrent betablocker/antiarrhythmic Titrate by 5 mg/dose each day until a 15-20% reduction in resting HR (MAX 4 mg/kg/day) Monitor: Hold if HR <60, SBP<90 and restart 16 hours later at 50% of the dose Duration: Based on improved HD but wean over 2-4 days prior to discharge J Burn Care Research 2008;29:257-266

Metabolic Modulation Adjuncts? Oxandrolone Propranolol Why Stimulates anabolism Inhibits catecholamine surge Who When More than 20% TBSA, individualize based on pt characteristics After resuscitation phase when hemodynamically stable (e.g. 48 hours) Evidence 2 RCT, 2 retrospective (116 pts) Adult 2 RCT, 1 retrospective (107 pts) How 10 mg Q12H or 5 mg Q12H geri 5-10 mg Q6h, titrate to HR 20% Expected outcome LOS, wt loss,?mortality? wound healing Decreased wound healing, reduced time to grafting, LOS Monitor LFT, edema, Ca Hemodynamics, ADR (lipophilic) $ (50% tbsa, 80 kg) $10.48/tab 30 day $629 $0.31/tab 30 day $37.20

Hyperglycemia and Insulin Resistance Insulin has multiple mechanisms Mediates glucose uptake into adipose tissue & skeletal muscle Suppresses hepatic gluconeogenesis Increases DNA replication and protein synthesis via amino acid uptake, increasing fatty acid synthesis and decreasing proteolysis Insulin treatment can wound healing, protein balance (dose dependent) prevent infections and possibly reduce mortality Aim for euglycemia (start >150 mg/dl, maintain <130 to 150 mg/dl) Metformin may reduce hyperglycemia, insulin resistance and promotes protein synthesis Avoid if at risk for lactic acidosis (renal, hepatic dysfunction, tissue hypoxia) Diaz EC, et al. Burns 2015; 41:649-657.

Conclusion Metabolic modulation adjunct Oxandrolone: LOS,?mortality?, wt loss, wound healing Propranolol: LOS, wound healing, time to grafting Insulin for euglycemia: wound healing, infection,? mortality Data limited by high quality RCT Many trials ongoing, hopeful future