Propranolol in burn patients

Overview

Propranolol is a nonselective beta-1/beta-2 adrenergic receptor antagonist that has become the most widely used anticatabolic therapy in burn care ^[1][2]. The rationale for its use is rooted in the pathophysiology of the postburn hypermetabolic response: sustained catecholamine elevations of up to 50-fold drive tachycardia, increased cardiac work, peripheral lipolysis, skeletal muscle catabolism, and elevated resting energy expenditure ^[3][11]. By blocking beta-adrenergic signaling, propranolol attenuates multiple downstream effects of catecholamine excess. The landmark 2001 randomized trial by Herndon et al. in the New England Journal of Medicine established the foundation for its clinical use ^[3].

Mechanism of action

Propranolol blocks beta-1 and beta-2 adrenergic receptors, reducing heart rate, cardiac output, and myocardial oxygen consumption (beta-1 effects) while attenuating peripheral lipolysis and thermogenesis (beta-2 effects) ^[4]. Blears et al. explored the paradox that while synthetic beta-adrenergic agonists promote muscle growth, propranolol (a beta blocker) also improves muscle protein balance in burn patients ^[4]. The resolution lies in the pathologic context: in the setting of massive catecholamine excess after burns, beta-blockade reduces the catabolic drive rather than simply blocking anabolic signaling ^[4]. Bieerkehazhi et al. demonstrated in a murine model that propranolol attenuates burn-induced adverse adipose tissue changes including endoplasmic reticulum stress, lipolysis, and subcutaneous white adipose tissue browning ^[5].

Clinical evidence

Landmark trial

Herndon et al. (2001) conducted a randomized trial in 25 children with burns greater than 40% TBSA ^[3]. Propranolol, dosed to reduce resting heart rate by 20%, significantly decreased resting energy expenditure compared with baseline (P = 0.01) and controls (P = 0.001) ^[3]. Net muscle protein balance increased by 82% over baseline in the propranolol group while decreasing by 27% in controls ^[3]. Fat-free mass was preserved in the propranolol group but decreased by 9 +/- 2% in controls (P = 0.003) ^[3].

Systematic reviews and meta-analyses

Flores et al. conducted a systematic review and meta-analysis of 10 trials and found that propranolol significantly decreased resting energy expenditure (g = -0.64; 95% CI -0.8 to -0.5; P < 0.001), trunk fat (g = -0.3; P < 0.001), and insulin resistance (g = -1.35; P < 0.001) while improving peripheral lean mass (g = 0.45; P < 0.001) ^[6]. Adverse events were not significantly different between treated patients and controls ^[6]. Nunez-Villaveira et al. reviewed 15 randomized clinical trials through December 2013 and confirmed that propranolol at doses of 4 to 6 mg/kg/day reduces supraphysiological thermogenesis, cardiac work, resting energy expenditure, and peripheral lipolysis ^[7].

Safety

Jeschke et al. studied 245 patients (143 controls, 102 propranolol) in a prospective intent-to-treat study and found that propranolol did not increase infections, sepsis, or inflammatory markers ^[8]. Mortality was 6% in the control group and 5% in the propranolol group ^[8]. Propranolol significantly decreased serum TNF and IL-1beta compared with controls (P < 0.05) ^[8]. Ojeda et al. reported on 104 burn-injured children treated with propranolol for 1 to 2 years in the outpatient setting, documenting safe and effective long-term use with no adverse effects noted ^[9].

Wound healing

Cheema et al. conducted a randomized controlled trial in 70 adult burn patients (20-40% TBSA) and found that propranolol accelerated wound healing in both superficial burns (13.20 +/- 1.90 vs. 20.34 +/- 2.32 days; P < 0.001) and deep burns (23.87 +/- 2.36 vs. 33.64 +/- 3.15 days to readiness for grafting; P < 0.001) ^[10]. Mid-arm circumference was significantly preserved in the propranolol group, indicating attenuation of muscle wasting ^[10].

Dosing and administration

The standard approach is to titrate propranolol to achieve a 15-20% reduction in resting heart rate from baseline. LeCompte et al. surveyed ABA-listed burn centers and found that 60.5% use propranolol, with 82% of those using it in both adult and pediatric patients ^[2]. The majority initiate in patients with greater than 20% TBSA burns ^[2]. Dosing ranges from 10-40 mg in adults and 0.1-5 mg/kg in pediatric patients, administered two to four times daily ^[2]. Ojeda et al. reported age-specific mean doses: 0-3 years 5.2 +/- 2.8 mg/kg/day, 4-10 years 4.2 +/- 1.8 mg/kg/day, and 11-18 years 2.9 +/- 1.4 mg/kg/day ^[9]. Propranolol dose requirements decrease as time from burn injury increases ^[9].

Duration of therapy

Duration of propranolol therapy varies substantially across centers. LeCompte et al. found that most centers continue propranolol only during hospitalization for adults (43%), while 17.6% continue long-term outpatient use in pediatric patients ^[2]. Ojeda et al. treated patients for 1 to 2 years in the outpatient setting with documented safety ^[9]. The optimal duration remains undefined and likely depends on the magnitude and persistence of the individual patient's hypermetabolic response.

Controversies and Evidence Gaps

The majority of high-quality evidence comes from pediatric burn populations, and adult data are comparatively limited ^[2][7]. A wide variation in dosing, timing, and duration of propranolol therapy exists across burn centers, highlighting the need for consensus guidelines ^[2]. Whether propranolol should be initiated in patients with burns less than 20% TBSA is not established. The interaction between propranolol and other anticatabolic/anabolic agents (insulin, oxandrolone) needs further characterization. Long-term cardiovascular effects of beta-blockade in burn survivors are not well studied. The role of selective beta-1 blockers (atenolol, metoprolol) versus nonselective blockade has not been adequately compared in burn patients.

References

[1] Stanojcic M et al. "Anabolic and anticatabolic agents in critical care." Curr Opin Crit Care 2016;22:325-331. PMID: 27272101 [2] LeCompte MT et al. "A survey of the use of propranolol in burn centers: Who, what, when, why." Burns 2016;43:121-126. PMID: 27575676 [3] Herndon DN et al. "Reversal of catabolism by beta-blockade after severe burns." N Engl J Med 2001;345:1223-1229. PMID: 11680441 [4] Blears E et al. "The impact of catecholamines on skeletal muscle following massive burns: Friend or foe?" Burns 2021;47:756-764. PMID: 33568281 [5] Bieerkehazhi S et al. "Beta-Adrenergic blockade attenuates adverse adipose tissue responses after burn." J Mol Med (Berl) 2024;102:1245-1254. PMID: 39145814 [6] Flores O et al. "The efficacy and safety of adrenergic blockade after burn injury: A systematic review and meta-analysis." J Trauma Acute Care Surg 2016;80:146-155. PMID: 26517779 [7] Nunez-Villaveira T et al. "Systematic review of the effect of propranolol on hypermetabolism in burn injuries." Med Intensiva 2015;39:101-113. PMID: 25305241 [8] Jeschke MG et al. "Propranolol does not increase inflammation, sepsis, or infectious episodes in severely burned children." J Trauma 2007;62:676-681. PMID: 17414346 [9] Ojeda S et al. "The Safety and Efficacy of Propranolol in Reducing the Hypermetabolic Response in the Pediatric Burn Population." J Burn Care Res 2018;39:963-969. PMID: 29757441 [10] Cheema SA et al. "Effects of Propranolol in Accelerating Wound Healing and Attenuation of Hypermetabolism in Adult Burn Patients." J Coll Physicians Surg Pak 2020;30:46-50. PMID: 31931932 [11] Williams FN et al. "What, how, and how much should patients with burns be fed?" Surg Clin North Am 2011;91(3):609-29. PMID: 21621699.