The Journal of TRAUMA Injury, Infection, and Critical Care

Propranolol Does Not Increase Inflammation, Sepsis,

or Infectious Episodes in Severely Burned Children
Marc G. Jeschke, MD, PhD, William B. Norbury, MD, Celeste C. Finnerty, PhD, Ludwik K. Branski, MD,
and David N. Herndon, MD
Background: Propranolol, a nonselective 12 antagonist, attenuates hypermetabolism and catabolism in severely
burned patients. However, recent data
suggest that propranolol impairs immune
function and enhances inflammation. The
purpose of the present study was to determine the effect of propranolol administration on infection, sepsis, and inflammation
in severely burned pediatric patients.
Patients: A prospective, intent-totreat study was performed; patient demographics (age, gender, burn size, and
mortality); infectious episodes (colony
count greater then 105); and sepsis
(guidelines by the society of critical care

medicine) were determined. Hypermetabolic response was determined by resting

energy expenditure (REE), and the inflammatory response was determined by
measuring serum cytokine expression.
Results: Two hundred forty-five patients (143 controls, 102 propranolol) were
included into the study. There were no
differences between the control and propranolol groups for age, gender distribution, burn size, third degree burn, and
length of stay. Mortality was 6% in the control group and 5% in the propranolol
group. Propranolol significantly decreased
REE and predicted REE during acute hospital stay. Forty-three patients developed

infections in the control group (30%),

whereas 21 developed infections in the
propranolol group (21%). The incidence
of sepsis was 10% for controls and 7% for
propranolol. Analysis of the cytokine expression profile in 20 patients in each
group revealed that propranolol significantly decreased serum tumor necrosis
factor and interleukin-1 compared with
controls ( p < 0.05).
Conclusion: Propranolol treatment
attenuates hypermetabolism and does not
cause increased incidence of infection and
sepsis.
Key Words: Burns, Sepsis, Betablockade, Pediatric, Inflammation.
J Trauma. 2007;62:676 681.

ndogenous catecholamines are primary mediators of the

hypermetabolic response to trauma or burn.1 Levels of
these fight-or-flight stress hormones are increased approximately 10-fold shortly after severe blunt trauma or a
burn of over 30% to 40% total body surface area (TBSA).2 4
This highly conserved systemic response to injury is characterized by development of a hyperdynamic circulation,5 resetting of the hypothalamic temperature regulation point,4,6
elevated basal energy expenditure,7 peripheral insulin resistance with hyperglycemia,8 10 increased peripheral lipolysis,9 altered immune function,11 and skeletal muscle protein
catabolism.12 We and others have attenuated supraphysiologic thermogenesis,12 tachycardia,13 cardiac work,14 and
resting energy expenditure16 with administration of a nonselective 1/2-blocking agent (propranolol) after severe burn.
Decreased cardiac morbidity and diminished overall mortality have been documented in non-trauma patients who were
Submitted for publication October 2, 2006.
Accepted for publication December 14, 2006.
Copyright 2007 by Lippincott Williams & Wilkins, Inc.
From the Department of Surgery, Shriners Hospitals for Children,
University Texas Medical Branch, Galveston, Texas.
Supported by the Shriners Hospital for Children grants 8660, 8760, and
9145, NIH R01-GM56687, T32 GM008256, P50 GM60338, and NIDRR
H133A020102.
Address for reprints: Marc G. Jeschke, MD, PhD, Shriners Hospitals
for Children, Galveston Burns Unit, 815 Market Street, Galveston, TX
77550; email: majeschk@utmb.edu.
DOI: 10.1097/TA.0b013e318031afd3

676

given -blockers for control of tachycardia after iatrogenic

tissue trauma inflicted by a major surgical procedure.16 In a
later study, propranolol was administered at a dose that reduced heart rate by approximately 15% to 20% from basal
levels; propranolol decreased resting energy expenditure, improved skeletal muscle protein kinetics, and preserved fatfree and lean body mass.15 However, there is evidence that
propranolol decreases immune function and is detrimental
during infectious episodes or septicemia.17,18 The purpose of
the present study was to determine the effect of propranolol
administration on infection, sepsis, and inflammation in severely burned pediatric patients.

PATIENTS AND METHODS

An intent-to-treat study was performed (intent-to-treat
means patients were randomized to control or propranolol
and received it for more than 3 days). We did not divide
patients based on the length of propranolol administration or
between responders and nonresponders. This study was approved by the University of Texas Medical Branch Institutional Review Board. Informed written consent was obtained
from each patients guardian before enrollment in the study.
Inclusion criteria were children younger than 18 years of age
and TBSA burns of greater than 40%. From 1996 to 2006,
severely burned patients with burns over 40% TBSA were
randomized into two groups: controls (no anabolic agent
treatment) and propranolol (0.51.5 mg/kg by mouth every 6
hours).
March 2007

Propranolol and Infections

We have a randomization list at our institution and, after
receiving consent, patients were randomized according to that
list. In this study, all patients received the same standard
acute burn care. Within 48 hours of admission, each patient
underwent total burn wound excision and grafting with autograft skin and allograft. Patients returned to the operating
room when autograft donor sites healed and became available
for reharvest (usually 6 8 days from the last operation).
Sequential, staged surgical procedures for repeat excision and
grafting were performed until the wounds were healed. Each
patient received enteral nutrition via a nasoduodenal tube
with Vivonex TEN (Sandoz Nutritional Corp., Minneapolis,
MN). The composition of Vivonex is 82% carbohydrate, 15%
protein, and 3% fat. Daily caloric intake was given at a rate
calculated to deliver 1,500 kcal/m2 TBSA burned 1,500
kcal/m2 TBSA. This feeding regimen was started at admission and continued at a constant rate until the wounds were
healed. Caloric intake was based on resting energy expenditure (REE). REE was determined weekly and patients received the caloric amount (1.4 times REE).
Burned patients were connected to an Emtek vitals signs
tracking system (Eclipsys, Rockville, MD) by standard echocardiogram leads. Heart rate was measured hourly and verified by each patients nurse. The average heart rate for each
entire 24-hour period was determined throughout the hospital
stay. Clinical data were prospectively collected.
After a control period of 7 days, patients were randomized to either receive normal saline or propranolol at a dose of
0.5 to 1.5 mg/kg by mouth every 6 hours. Patients were
closely monitored for heart rate and blood pressure. Patients
did not receive any other anabolic or anticatabolic agent. All
patients received insulin if necessary (blood glucose 210
mg/dL) to decrease blood glucose below 210 mg/dL, with a
target blood glucose of 140 to 160 mg/dL.

Indirect Calorimetry
All patients underwent REE measurements within 1
week after hospital admission and weekly thereafter during
their acute hospitalization. For the present study, we chose
the first metabolic study and compared it to the metabolic
study at discharge. The studies were performed between
midnight and 5 AM while the patients were asleep and receiving continuous feeding. REE was measured using a SensorMedics Vmax 29 metabolic cart (Yorba Linda, CA). Subjects
were tested in a supine position while under a large, clear,
ventilated hood. The REE was calculated from the oxygen
consumption and carbon dioxide production by equations. All
REE measurements were made at ambient temperatures of
30 C, which is the standard environmental setting for all
patient rooms in our acute burn intensive care unit. The REE
measurements were used to guide nutritional management
and to assess the level of metabolism. The discharge REE
measurement was used to determine the level of hypermetabolism when the burn wounds were 95% healed, and were
included as part of this study. Measured values were comVolume 62 Number 3

Table 1 Criteria Used to Diagnose Sepsis

At least three of the following:
Delirium
Temperature 38.5 or 36.5 C
Tachycardia (120 BPM in adults, 150 BPM in children)
Tachypnea
White blood cell count 12,000 or 4,000
Refractory hypotension (systolic blood pressure 90 mm Hg)
Thrombocytopenia (platelets 50,000 mm3)
Hyperglycemia (serum glucose 240 mg/dl)
Enteral feeding intolerance (residuals 200 mL/h or diarrhea
1 L/d) and pathologic tissue source identified and 105
organisms/gram tissue

pared with predicted norms based on the Harris-Benedict

equation.

Infection Episodes and Sepsis

Diagnosis of infectious episodes was determined by colony counts of colony forming units (CFUs) greater than 105
CFUs, with the identification of the bacteria. Diagnosis of
sepsis was made through hospitalization, and final diagnosis
was confirmed by autopsy-demonstrated sepsis (presence and
identification of organisms and inflammatory response in
multiple organs). Because the hypermetabolic state induced
by a severe burn can mimic conditions typically used to
diagnose systemic inflammatory response syndrome or sepsis
as defined by the guidelines of the Society of Critical Care
Medicine, a modified list of criteria was used to diagnose
sepsis in the burn patient (Table 1). Although the patients
were alive, the presence of organisms in burn wound, blood,
or tissue biopsies was confirmed by colony counts; at the time
of autopsy, colony counts from organ cultures or histologic
detection were used to confirm presence of invasive organisms. Most patients were found to be infected with a combination of fungi and gram-negative and -positive bacteria.

Serum Cytokines
Blood was collected from the burn patients at the time of
admission, preoperatively, and 5 days postoperatively for 4
weeks for serum cytokine analysis. Blood was drawn in a
serum-separator collection tube and centrifuged for 10 minutes at 1,320 rpm; the serum was removed and stored at 70
C until assayed. The Bio-Plex Human Cytokine 17-Plex
panel was used with the Bio-Plex Suspension Array System
(Bio-Rad, Hercules, CA) to profile expression of seventeen
inflammatory mediators (interleukin [IL]-1, IL-2, IL-4,
IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17, granulocyte colony-stimulating factor, granulocyte-macrophage
colony stimulating factor, interferon-gamma, monocyte chemoattractant protein-1, macrophage inflammatory protein
1-beta, and tumor necrosis factor [TNF]). The assay was
performed according to the manufacturers instructions. Serum samples were briefly thawed and then centrifuged at
4,500 rpm for 3 minutes at 4 C. Serum samples were then
677

The Journal of TRAUMA Injury, Infection, and Critical Care

incubated with microbeads labeled with specific antibodies to
one of the aforementioned cytokines for 30 minutes. After a
wash step, the beads were incubated with the detection antibody cocktail, with each antibody specific to a single cytokine. After another wash step, the beads were incubated with
streptavidin-phycoerythrin for 10 minutes, washed, and the
concentrations of each cytokine were determined using the
array reader.

Statistical Analysis
One-way analysis of variance, with Bonferronis post
hoc correction (cytokine analysis) and paired and unpaired
Students t tests (demographics, REE, infections) were used
to compare the two groups. Data are expressed as percentages
or means standard error of the mean, where appropriate.
Significance was accepted at p 0.05.

RESULTS
Two hundred forty-five patients (143 controls, 102 propranolol) were included into the study. There were no differences between the control and propranolol groups for age,
gender distribution, burn size, third degree burn, inhalation
injury, and length of stay. Mortality was 6% in the control
group and 5% in the propranolol group (Table 2).

Resting Energy Expenditure

Patients receiving propranolol demonstrated a significant
change in REE and predicted REE compared with control
patients ( p 0.05) (Fig. 1). Although control patients had an
increase in REE and percent predicted REE during the acute
stay, propranolol patients showed a decreased change in REE
and percent predicted REE ( p 0.05) (Fig. 1).

Infection Episodes and Sepsis

Forty-three patients (30%) had infectious episodes with
CFUs 105 during the acute hospital stay, whereas 21 patients (21%) in the propranolol group showed signs of infection, which was not significantly different (Fig. 2). Similarly,

Table 2 Demographic Data for Control and

Propranolol Patients
Number
Age (years)
Gender (F/M)
Time from burn to admit (days)
TBSA (%)
3rd degree burns (%)
Length of ICU stay (days)
Length of ICU/TBSA (days/%)
Inhalation injury (%)
Multi Organ Failure (%)
Mortality (%)

Control

Propranolol

143
7.8 0.4
83/119
61
55 1
43 2
32 2
0.56 0.02
35
9
6

102
7.2 0.6
43/59
61
54 2
44 3
30 2
0.54 0.02
39
6
5

Data presented as mean SEM.

TBSA, total body surface area; ICU, intensive care unit.

678

Fig. 1. Resting energy expenditure (REE) and predicted REE. Although control patients had an increase in REE and percent predicted REE during the acute stay, propranolol patients showed a
decreased change in REE and percent predicted REE. *Significant
difference between control and propranolol (p 0.05).

in 14 (10%) control patients, the diagnosis of sepsis was

made, whereas the incidence of sepsis was 7% in the propranolol group. There was no significant difference between
the two groups (Fig. 2). Furthermore, incidence of specific
infections did not vary between groups.

Serum Cytokines
Analysis of the cytokine expression profile in 20 patients
from each group revealed only minor differences. Propranolol administration significantly decreased serum TNF and
IL-1, at one time point when compared with controls ( p
0.05) (Fig. 3). We found no differences between the propranolol and control groups for IL-6, IL-8, IL-10, monocyte
March 2007

Propranolol and Infections

Fig. 2. Forty-three control patients (30%) had infectious episodes

with colony forming units 105 during the acute hospital stay,
whereas 21 patients (21%) showed signs of infections in the propranolol group, which was not significantly different. In 14 control
patients (10%), the diagnosis of sepsis was made; the incidence of
sepsis was 7% in the Propranolol group. There was no significant
difference between the two groups.

chemoattractant protein-1, and macrophage inflammatory

protein 1- during acute hospital stay (Fig. 3).

DISCUSSION
The systemic inflammatory response after burn is triggered by catecholamines and leads to hypermetabolism, and
thus to protein degradation and catabolism. Consequently, the
structure and function of essential organs such as the muscle,
skin, heart, immune system, and liver are compromised, contributing to multiple organ failure and mortality.19,20 Uncontrolled release of proinflammatory mediators such as IL-6,
IL-8, and acute-phase proteins trigger and enhance protein
Volume 62 Number 3

wasting and organ dysfunction.2125 Organ function breakdown can then lead to increased incidence of infection and
sepsis, ultimately leading to multiple organ failure and death.
This circulus vitiosus is very difficult to break and successful
therapy for sepsis has yet to be defined.
There is evidence in the literature that catecholamines
are beneficial to fighting infections and enhancing the immune system. For example, it has been recently shown that
epinephrine enhances platelet-neutrophil adhesion, which is
crucial for survival of critically ill patients.26 Ortega et al.27
showed that Norepinephrine stimulated phagocytosis induced
by moderate exercise. Garcia et al.28 showed in 2003 that
noradrenaline modulates the phagocytic process of macrophages and maintains the phagocytic functions at physiologically optimal levels. Modulation of chemotaxis is mainly
mediated by -receptors and phagocytosis needs both - and
-receptor stimulation. Based on these effects of catecholamines
on immune cells, the question arises as to whether nonselective
-blockade has a detrimental or adverse effect on the immune
system and function in severely burned pediatric patients. We
did not measure immune function directly; however, we suggest that the incidence of infections or sepsis can be used as
a marker for immune function. We found that there was no
difference in the incidence of infection or sepsis in severely
burned pediatric patients receiving placebo or propranolol
throughout the hospital stay. Both groups had an incidence
of infection of approximately 25% to 30% and incidence of
sepsis of 10% and 7%, respectively, and the incidence of
specific infections did not vary between groups. This data
indicate that propranolol has no adverse effects on infections and sepsis. There was also no difference between
groups regarding mortality, multiple organ failure, or length
of hospital stay. We did not look at pneumonia in the present
study and we might have missed differences in the incidence
of pneumonia between groups.
That propranolol was administered in the correct dose
can be seen in a decreased hypermetabolic response. In agreement with previous data, we found that propranolol decreased
REE and predicted REE in severely burned pediatric patients
when compared with controls. We hypothesized that an attenuated hypermetabolic response is associated with a decreased inflammatory response. We showed that propranolol
did not affect the inflammatory response as compared with
control patients. Propranolol decreased TNF and IL-1 concentration in the serum, but the biological significance is
questionable because levels were only decreased at one time
point. Therefore, we suggest that propranolol did not alter the
inflammatory reaction compared with controls.
In summary, we showed that a nonselective 1/2 antagonist does not affect the incidence of infections or sepsis in
severely burned pediatric patients, indicating that propranolol
has no adverse effect on the immune system and function.
Propranolol decreases REE, which is associated with a decrease in serum TNF and IL-1. We suggest that propranolol
treatment is beneficial in burn victims and may improve
679

The Journal of TRAUMA Injury, Infection, and Critical Care

Fig. 3. Analysis of the cytokine expression profile. Propranolol administration significantly decreased serum tumor necrosis factor and
interleukin (IL)-1 at one time point when compared with controls. We found no differences between propranolol and control for IL-6, IL-8,
IL-10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1- during the acute hospital stay. *Significant differences
between propranolol and control (p 0.05).

680

March 2007

Propranolol and Infections

11.

12.
13.

14.

15.

16.

17.

Fig. 3. Continued.
18.

survival. To detect differences in mortality, a large, multicenter trial would have to be performed, since mortality rates
in children are 4% to 6%.

REFERENCES
1.

2.

3.

4.
5.

6.
7.
8.
9.

10.

Wilmore DW, Long JM, Mason AD Jr, Skreen RW, Pruitt BA Jr.
Catecholamines: mediator of the hypermetabolic response to thermal
injury. Ann Surg. 1974;180:653 669.
Goodall M, Stone C, Haynes BW Jr. Urinary output of adrenaline
and noradrenaline in severe thermal burns. Ann Surg. 1957;145:
479 487.
Goodall MG. Sympathetic nerve and adrenal medullary response to
thermal burn. Clinical analysis of adrenaline and noradrenaline
depletion. Am Surg. 1966;32:448 452.
Wilmore DW, Aulick LH. Metabolic changes in burned patients.
Surg Clin North Am. 1978;58:11731187.
Asch MJ, Feldman RJ, Walker HL, et al. Systemic and pulmonary
hemodynamic changes accompanying thermal injury. Ann Surg.
1973;178:218 221.
Wilmore DW. Hormonal responses and their effect on metabolism.
Surg Clin North Am. 1976;56:999 1018.
Reiss E, Pearson E, Artz CP. The metabolic response to burns.
J Clin Invest. 1956;35:6277.
Wolfe RR, Durkot MJ, Allsop JR, Burke JF. Glucose metabolism in
severely burned patients. Metabolism. 1979;28:10311039.
Wolfe RR, Herndon DN, Peters EJ, Jahoor F, Desai MH, Holland
OB. Regulation of lipolysis in severely burned children. Ann Surg.
1987;206:214 221.
Wolfe RR, Miller HI, Spitzer JJ. Glucose and lactate kinetics in burn
shock. Am J Physiol. 1977;232:E415 418.

Volume 62 Number 3

19.

20.
21.

22.

23.

24.

25.
26.

27.

28.

Yurt RW, McManus AT, Mason AD Jr, Pruitt BA Jr. Increased

susceptibility to infection related to extent of burn injury. Arch Surg.
1984;119:183188.
Herndon DN, Tompkins RG. Support of the metabolic response to
burn injury. Lancet. 2004;363:18951902.
Minifee PK, Barrow RE, Abston S, Desai M, Herndon DN.
Improved myocardial oxygen utilization following propranolol
infusion in adolescents with postburn hypermetabolism. J Pediatr
Surg. 1989;24:806 810; discussion 810 811.
Baron PW, Barrow RE, Pierre EJ, Herndon DN. Prolonged use of
propranolol safely decreases cardiac work in burned children. J Burn
Care Rehabil. 1997;18:223227.
Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal
of catabolism by beta-blockade after severe burns. N Engl J Med.
2001;345:12231229.
Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on
mortality and cardiovascular morbidity after noncardiac surgery.
Multicenter Study of Perioperative Ischemia Research Group. N Engl
J Med. 1996;335:17131720.
Oberbeck R. Therapeutic implications of immune-endocrine
interactions in the critically ill patients. Curr Drug Targets Immune
Endocr Metabol Disord. 2004;4:129 139.
Oberbeck R, Schmitz D, Wilsenack K, et al. Adrenergic modulation
of survival and cellular immune functions during polymicrobial
sepsis. Neuroimmunomodulation. 2004;11:214 223.
Arnold J, Campbell IT, Samuels TA, et al. Increased whole body
protein breakdown predominates over increased whole body
protein synthesis in multiple organ failure. Clin Sci (Lond). 1993;
84:655 661.
Rennie MJ. Muscle protein turnover and the wasting due to injury
and disease. Br Med Bull. 1985;41:257264.
Jeschke MG, Barrow RE, Herndon DN. Extended hypermetabolic
response of the liver in severely burned pediatric patients. Arch
Surg. 2004;139:641 647.
Jeschke MG, Einspanier R, Klein D, Jauch KW. Insulin attenuates
the systemic inflammatory response to thermal trauma. Mol Med.
2002;8:443 450.
Jeschke MG, Herndon DN. Effect of growth factors as therapeutic
drugs on hepatic metabolism during the systemic inflammatory
response syndrome. Curr Drug Metab. 2004;5:399 413.
Jeschke MG, Rensing H, Klein D, et al. Insulin prevents liver
damage and preserves liver function in lipopolysaccharide-induced
endotoxemic rats. J Hepatol. 2005;42:870 879.
Moshage H. Cytokines and the hepatic acute phase response.
J Pathol. 1997;181:257266.
Horn NA, Anastase DM, Hecker KE, Baumert JH, Robitzsch T,
Rossaint R. Epinephrine enhances platelet-neutrophil adhesion in
whole blood in vitro. Anesth Analg. 2005;100:520 526.
Ortega E, Marchena JM, Garcia JJ, Barriga C, Rodriguez AB.
Norepinephrine as mediator in the stimulation of phagocytosis induced
by moderate exercise. Eur J Appl Physiol. 2005;93:714 718.
Garcia JJ, del Carmen Saez M, De la Fuente M, Ortega E. Regulation
of phagocytic process of macrophages by noradrenaline and its end
metabolite 4-hydroxy-3-metoxyphenyl-glycol. Role of alpha- and betaadrenoreceptors. Mol Cell Biochem. 2003;254:299 304.

681