Pharmacotherapy of Metabolic Modulation in Acute Burns

Mitchell J Daley, PharmD, FCCM, BCPSClinical 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 (2nd-3rd 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 RCTOxandrolone

N = 46PlaceboN = 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

ASTN = 114

ALTN = 110

ASTN = 119

ALTN = 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))

0.250.24

Significant hepatic damage(>100 mg/dL)- AST, n (%)- ALT, n (%)

11 (9.6)21 (19.1)

9 (7.6)6 (5.1)

0.74<0.05

N = Number of levels drawn per groupAST: Aspartate aminotransferaseALT: Alanine aminotransferase

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

Oxandrolone

(n=11)

10 mg Q12H

vs

Placebo (n=9)

Adult patients ≥ 18

years of age with 40-

70% TBSA burn with at

least 20% requiring

grafts

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

Oxandrolone is superior

to placebo for

decreasing weight and

net nitrogen losses and

increasing donor site

wound healing.

Pharm TN, et al.

J Burn Care Res

2008;29:902.

Observational

Single center

Oxandrolone

dose undefined

(n=59)

vs

Placebo (n=58)

Started within 7

days of injury

Adult patients ≥ 18

years of age with more

than 20% TBSA burn

No other concurrent

trauma

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

Oxandrolone may be

associated with

improved survival in

severe burn injury.

Further validation with a

RCT is needed.

Cochran A, et al.

Burns

2013;39:1374.

Retrospective

Multicenter

Oxandrolone

dose undefined

(n=38)

vs

Placebo (n=129)

Started within 7

days of injury

Adult patients ≥ 18

years of age with more

than 15% TBSA burn

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

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

Propranolol RCT Design Study Population

Single center, prospective, randomized, blinded trial

N = 81

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

Inclusion- Adult patients 16-60 years of age with 20 –

50% TBSA burns- Started on the 4th day after HD stable

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

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

Survival Differences?

Mortality 13.5% Propranolol vs. 14.28% Control (p=0.92)

No difference in sepsis either

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 Interventio

n

Patient Population Results Conclusion

Ali A, et al.

Crit Care

2015;19:217.

RCT

Single center

Propranolol

(n=35)

vs

Placebo

(n=37)

Adult patients ≥ 18 years

of age with 30% TBSA,

treatment with at least

one surgical skin graft

Propranolol unclear starting dose

Adjusted to decrease resting HR by 20%

(maximum 4 mg/kg/day)

Started on day 2

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)

Brown DA, et al.

J Burn Care Res

2016;37:218.

Retrospective

Single center

Propranolol

(n=35)

Adults (18-65) with

acute burn injuries >

20%

Excluded: pre-admission

beta-blocker

Propranolol 10 mg q6h NG/PO

Adjusted to decrease maxHR by 20%

• 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 beta-blocker/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

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 (2nd-3rd 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 Adjuncts?Oxandrolone Propranolol

Why Stimulates anabolism Inhibits catecholamine surge

Who More than 20% TBSA, individualize based on pt characteristics

When 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

Pharmacotherapy of Metabolic Modulation in Acute Burns

Mitchell J Daley, PharmD, FCCM, BCPSClinical 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