|Year : 2015 | Volume
| Issue : 1 | Page : 19-25
Modulation of hypermetabolism in burn patient by administration of propranolol in the first two weeks and assessing its effect by using clinical and biochemical parameters
Ajay Lunawat, Avinash Vishwani, Sanjay Datey, Vikramaditya Singh
Department of Surgery, Sri Aurobindo Medical College and Postgraduate Institute, Indore, Madhya Pradesh, India
|Date of Web Publication||11-Dec-2015|
Dr. Ajay Lunawat
Department of Surgery, Sri Aurobindo Medical College and Postgraduate Institute, Indore, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Background: India being a developing country has a high incidence of thermal injuries. Severe burn injury is followed by a state of hypermetabolism, which causes increased cardiac workload and increased resting energy expenditure causing muscle wasting, leading to increased morbidity. The aim of this study is to test the effect of propranolol in modulating the state of hypermetabolism in the acute postburn phase using various clinical and laboratory parameters. Materials and Methods: This is a prospective case-control study which includes 50 cases of thermal injuries with total burn surface area 20-60% conducted at burn unit of a Tertiary Care Center over a period of 1-year. The patients were divided into test (propanolol) and control groups. Similar burn treatment was continued in both groups and change in the laboratory, and clinical parameters were noted. Results were compared within the groups using paired t-test and in between the groups using unpaired t-test. Result: This study shows a significant reduction of 20% in the heart rate and 28% in the sleeping pulse rate with 2 weeks of propranolol therapy (P < 0.0001). There was a 2.5% increase in the weight along with 6% increase in mid-arm circumference. There was a 5% increase in total serum albumin concentration and resolution of pedal edema by the end of 2 weeks of therapy. C-reactive protein was found to be reduced by 10% (P < 0.0001). Conclusion: The results prove propranolol as an effective modulator of hypermetabolism by counteracting the effect of catecholamine, reducing infection and inflammation hence improving the overall outcome of severe burn patients.
Keywords: Hypermetabolism, mid-arm circumference, propranolol, sleeping pulse rate, thermal burns
|How to cite this article:|
Lunawat A, Vishwani A, Datey S, Singh V. Modulation of hypermetabolism in burn patient by administration of propranolol in the first two weeks and assessing its effect by using clinical and biochemical parameters. Indian J Burns 2015;23:19-25
|How to cite this URL:|
Lunawat A, Vishwani A, Datey S, Singh V. Modulation of hypermetabolism in burn patient by administration of propranolol in the first two weeks and assessing its effect by using clinical and biochemical parameters. Indian J Burns [serial online] 2015 [cited 2019 Dec 7];23:19-25. Available from: http://www.ijburns.com/text.asp?2015/23/1/19/171636
| Introduction|| |
Burn injury is always associated with a state of hypermetabolism. Severe thermal injury, defined as burns involving over 30% of a patient's total body surface area (TBSA), is followed by a pronounced hypermetabolic response that may last up to 1-2 years postburn. Burn-induced stress response stimulates secretion of endogenous catecholamine, which are thought to be primary mediators of hypermetabolism after stress due to injury. 
The hypermetabolic response is associated with a hyperdynamic circulation, hyperthermia, and skeletal muscle and fat breakdown. During this time, the metabolic and energy requirements are vast, necessitating recruitment of proteins and amino acids to sustain healing and recovery. This, in turn, increases protein turnover and produces a negative nitrogen balance. The accompanying reductions in lean body mass (LBM) and bone density produce weakness and impair wound healing. 
Although the hypermetabolic response undoubtedly evolved to aid survival from burns, this physiologic response also has maladaptive consequences that can negatively affect survival and hinder recovery.  The 10-50-fold increase in catecholamine levels induce increased myocardial oxygen consumption, increased resting energy expenditures (REEs), and contribute greatly to the profound catabolism after severe burn injury.  Successful blockade of beta-adrenergic stimulation and the effects of elevated levels of catecholamine after severe injury decrease cardiac work, tachycardia, metabolic rates, and thermogenesis.  Beta-antagonist treatment reduces the rate of cardiac complications and decreases mortality after severe trauma.  Propranolol prevents increased peripheral lipolysis in thermally injured patients by impeding the activation of the beta-2-adernergic receptors. It significantly decreases fatty infiltration of the liver compared to untreated severely burned children.  Propranolol increases LBM and decreases skeletal muscle wasting as proven by stable isotope and body composition studies.  Treatment, at a dose of 0.5-4 mg/kg/day to reduce heart rates 15-20% of admitting heart rates, did not effect inward transport of amino acids, but did effectively increase the efficiency of muscle protein synthesis.  It enhances the availability of free amino acids for muscle protein synthesis. 
Drugs that block this catecholamine surge have been shown to be effective at countering catecholamine-induced sequelae after severe burns.  Propranolol, a nonspecific beta-1, beta-2-adrenergic receptor antagonist that has been studied extensively, holds promise for the reduction of the postburn hypermetabolic response. The role of beta-blockers has been extensively studied in pediatric, and adolescent age group with proven efficacy, ,, but there are only a few studies to show the effect of propranolol in the adult burn. ,
| Materials and Methods|| |
The study is a prospective case-control study set up at a tertiary care hospital over a period of 1-year (December 2012 to November 2013). This study includes 50 cases of burn (thermal injuries) having TBSA (total burn surface area) from 20% to 60%. All the research and interventions were conducted at the burn unit in Department of Surgery of the Institute. The study has been approved by Institutional Ethical Committee of the institute. Informed written consent was obtained from all the patients. Fifty cases were chosen and were randomly divided into two groups keeping patients of similar age group and TBSA in both the groups to reduce the error in results.
- Age = 18-60 years
- Admission within 3 days of burn
- TBSA = 20-60%
- Flame (gas) burns
- Chemical burns
- Kerosene burns
- Electric burns
- Pregnant females
- Cardiac failure cases
- Diabetic patients
- <18 years age and >60 years age
- Known case of hypertension on beta blocker therapy previously
Cases were divided into two groups
- Test group
- Control group
Each group consists of 25 patients. Randomization was done by generating random number table generated using online tool http://www.graphpad.com/quickcalcs/randomn1.cfm as per Graph 1.
The test group was given propranolol in a dose of 0.5-1.5 mg/kg body weight (achieving a reduction in the heart rate by 20%) per day (6-8 hourly) orally for 2 weeks along with the standard burn care and treatment while the control group will be given only the standard burn care and treatment. Adequate analgesia and similar external environment were given to all the patients and adequate feeding was given to meet the individual's calorie requirement.
Physiotherapy, wound care which includes moist dressing, biological dressings, collagen dressings, early excision and grafting were done in all the patients as a part of standard protocol for management of burn patients. After stabilizing the patient, early excision and grafting was done within 1 st week and maximum of 10-15% TBSA was excised and grafted in one sitting.
All the patients were subjected to routine investigations prior to starting propranolol therapy. These investigations included complete blood count, serum electrolytes, chest X-ray, and electrocardiography. Propranolol therapy was given to the patients for 15 days and the results were assessed on various clinical and laboratory parameters. The study was planned to be stopped on patients who showed features of hypersensitivity, cardiac changes or increased morbidity.
Propranolol was continued in the patients even after 15 days, as a part of ongoing long-term study.
- Heart rate
- Sleeping heart rate
- Blood pressure
- Mid-arm circumference.
- Serum albumin concentration
- Serum concentration on C-reactive protein (CRP)
All the above parameters were assessed on 1 st , 7 th , and 14 th day and the results were compared. Paired t-test was used to compare data within the group and unpaired t-test to compare data between the groups.
| Results|| |
Same numbers of patients were compared in both the groups with similar age and sex distribution, according to TBSA (total burn surface area) to improve the accuracy of results as per [Table 1]. Patient wise distribution of TBSA in test and control group is shown in [Figure 1] and [Figure 2] respectively.
There is a significant reduction in the number of hospital days required in test group as compared to control group. There was less number of surgical procedures required in test group as well as lesser mortality in the test group as per [Table 2].
|Table 2: Mortality, average hospital stay and procedure required in discharged patients in relation to TBSA|
Click here to view
Rectal temperature charting was done every day, 6 hourly, and the average temperature was noted. Results were compared between the two groups on 1 st , 7 th , and 14 th day.
The average temperature in the test group was 99.1 ± 0.78°F on day 1 and 98.5 ± 0.21°F on day 14, whereas in the control group patients the mean body temperature was 99.1 ± 0.80°F on day 1 and 98.95 ± 0.7°F at the end of 2 weeks (P < 0.0001) as per [Figure 3].
Heart rate was recorded 4 hourly using monitor. Results were compared on 1 st , 7 th , and 14 th day. In the test group, dose of propranolol was adjusted so as to bring down the heart rate by 20%, which is within safe limits of propranolol use. [Figure 4] shows doses of propranolol in relation to the day of hospitalization. The average heart rate was 131 ± 9.36 on day 1 and 94.52 ± 6.65 on day 14, in the test group while it was 130.32 ± 8.67 on day 1 and 115.04 ± 9.93 on day 14 in control group (P < 0.0001) as per [Figure 5].
Sleeping pulse rate was measured using the monitor while the patient was fast asleep and results were compared on every 7 th day. Baseline sleeping pulse rate was found to be 7-10% lower than heart rate in all the patients. The test group had a significant reduction in heart rate up to 28% while it was only 12% in control group. Thus, the above values show a reduction in REE and reduction in cardiac workload. The average sleeping pulse rate was 121.36 ± 9.01 on day 1 and 88 ± 5.69 on day 14, in the test group while it was 121.52 ± 8.06 on day 1 and 107.36 ± 10.06 on day 14, in control group after 2 weeks (P < 0.0001) as per [Figure 6].
Mid-arm circumference was measured in centimeters using inch tape every 7 th day. Point where the measurement was done was marked to reduce errors. Mean mid-arm circumference was 25.42 ± 2.69 cm in test group on day 1, which increased to 27.09 ± 3.05 cm on day 14 hence 6.1% increase in mid-arm circumference was seen in test group while in control group the average values were 25.4 ± 2.66 on day 1 and 23.64 ± 2.82 on day 14, thus 6.9% decrease was noted in the control group at the end of 2 weeks with a P < 0.0001 as per [Figure 7].
Weight of every patient was measured in kilograms on a digital weighing scale on the day of admission and on the 14 th day. The mean values on day 1 in test group were 60.6 ± 11.18 and on day 14 were 62.38 ± 11.31, hence 2.58% increase in the weight of the patients on an average in the test group was noted while in the control group the mean values on day 0 were 61.06 ± 10.39 on day 1 whereas the were 59.65 ± 10.25 on day 14, showing decrease in weight by 2.24% (P < 0.0001) as per [Figure 8].
Serum albumin concentration was investigated every 7 th day and the mean values were 3.58 ± 0.40 on day 1 and 3.75 ± 0.39 on day 14, hence 5% increase in albumin concentration was seen in test group while in control group mean values were 3.62 ± 0.29 on day 1 and 2.95 ± 0.19 on day 14 hence 22% reduced albumin levels were noted in the control group (P < 0.0001) as per [Figure 9].
CRP was measured every 7 th day and mean values in test group on day 1 were 12.24 ± 0.88 and on day 14 the mean values were 10.4 ± 1.11 showing a 10% reduction whereas in the control group the mean values on day 1 were 14.24 ± 1.28 on day 1 and 19.44 ± 1.23 on day 14 showing a rise of 20% in the control group. These values suggest significant reduction of infection in the patients receiving propranolol (P < 0.0001) as per [Figure 10].
In addition to the above observations, improved wound healing was also observed in patients receiving propranolol.
| Discussion|| |
The hypermetabolic response is thought to be due to postburn elevation of endogenous catecholamines and cortisol. Supraphysiologic levels of stress hormones contribute to the long-lasting tachycardia, catabolism, and immune suppression that characterize the hypermetabolic response. Catecholamines and corticosteroids are the primary mediators of the hypermetabolic response following burns >40% TBSA. There is a 10-50-fold surge of plasma catecholamine and corticosteroid levels that last up to 9 months postburn. Burn patients have increased REEs, increased cardiac work, increased myocardial oxygen consumption, marked tachycardia, severe lipolysis, liver dysfunction, severe muscle catabolism, increased protein degradation, insulin resistance, and growth retardation.  The loss of LBM can drive detrimental responses in burn. Hypermetabolism can be quantitated by analyzing REE, consumption of oxygen and glucose, and CO 2 production. REE remains elevated at 130-140% of the predicted value for 3 years after burn injury. 
In addition to decreasing tachycardia, cardiac work, REE, and hepatic, beta blockade with propranolol reduces breakdown of peripheral muscle and increases protein synthesis.  In 2007, Jeschke et al. found that propranolol attenuated the hypermetabolic response, as indicated by a significant decrease in REE during acute hospitalization, without increasing the incidence of infection and sepsis.  The role of propranolol in the treatment of burn injuries goes beyond modulating metabolism. Systemic administration of propranolol has been shown to enhance wound healing and decrease the surface area requiring skin grafting. 
The study design was a prospective case-control study which was similar to the studies performed by Herndon et al. and Segu et al. and Herndon et al. ,, This study included patient with 20-60% TBSA compared to 25-40% TBSA in the study by Segu et al. more than 40% TBSA in the study by Herndon et al. and >30% for study by Herndon et al. ,,
The dose of propranolol was adjusted to reduce the heart rate by 20% which was similar to the dose used in study by Segu et al. and Herndon et al. and Williams and 18% reduction in the study by Hart et al. in 2002. ,,, In our study 27% reduction in baseline heart rate was seen by the end of 14 days in patients receiving propranolol therapy while only 11% reduction was seen in control cases and tachycardia still persisted.
Results were assessed on clinical parameters which included heart rate, sleeping pulse rate, weight and mid-arm circumference. The results were similar to the study by Segu et al.  with a P < 0.001 and null hypothesis is rejected.  Body temperature after propranolol therapy was found to be near normal while patients were still febrile in the control group. Even laboratory parameters gave a significant positive result with a P < 0.002.
A 2.2% increase in the weight of the patients receiving propranolol was noted while the weight of the control group was found to be reduced by 2.5%. A significant decrease in REE in blockade (P < 0.05) and muscle anabolism has been reported in the study by Hart et al. in 2002.  This indirectly provides evidence to prove increase in weight and mid-arm circumference. Though the mid-arm circumference may not to an absolutely precise parameter to assess anabolism because the mid-arm circumference results vary in patients who have sustained burn injuries in their arm unilaterally or bilaterally.
The effects of treatment on the net balance of muscle protein synthesis and breakdown during propranolol administration have been demonstrated in the study by Hart et al.  In this study, anabolism was achieved and the protein net balance was significantly greater after treatment than in the untreated, baseline period (P < 0.05). In our study the serum albumin concentration in patients receiving propranolol was increased by 5% at the end of 2 weeks while a reduction of 22% was seen in the control group, which was synchronous with the pedal edema found in patients. Similarly in the study by Segu et al., the serum albumin concentration has increased from 3.5 mg% to 4 mg% within 2 weeks of propranolol therapy while it was reduced from 3.5 mg% to 2.9 mg% in patients not receiving propranolol. 
The values of CRP after 2 weeks of propranolol therapy was found to be reduced by 10% while it was increased by 20% in the control group. Similar results have been demonstrated in the study by Segu et al. with a P < 0.01, these values suggest a decreasing titer of infection in the body with propranolol therapy and hence improving immunity.  A study by Póvoa et al. suggests CRP to be a good marker for assessment of sepsis.
No adverse effects of propranolol was observed with the given doses and there was never a requirement to withdraw due to any untoward effects. 
| Conclusion|| |
The above results clearly show the effect of propranolol on reducing cardiac workload and reduction of catabolism. Improvement in albumin concentration, mid-arm circumference and body weight implies improvement in LBM.
A severe burn injury is invariably followed by a state of hypermetabolism causing increased morbidity and mortality. They counteract the effect of catecholamines and thus reduce infection and inflammation, thus reducing morbidity and eventually improving the long-term outcome of burn patients. Beta blockers are safe and efficient drugs in burn management can be included in the basic burn treatment protocol, provided a large group multicentric randomized control trial proves the similar results in adults.
Limitation of the study
Long-term multicenter studies are required to determine if propranolol administration has any lasting or long-term effects on cardiac function, growth, strength, exercise capacity and return to work, especially in adult burn patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
[Table 1], [Table 2]