Systematic review of the effect of propanolol on hypermetabolism in burn injuries

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Núñez-Villaveirán, M. Sánchez, P. Millán, A. García-de-Lorenzo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "T." "apellidos" => "Núñez-Villaveirán" "email" => array:1 [ 0 => "tnuvi@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M." "apellidos" => "Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "P." "apellidos" => "Millán" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "A." 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In severe burn patients the energy expenditure can be up to twice as high as the estimated resting energy expenditure.<a class="elsevierStyleCrossRefs" href="#bib0260">1,2</a>Such hypermetabolism is accompanied by increased muscle metabolism,<a class="elsevierStyleCrossRefs" href="#bib0265">2–4</a> in an attempt to provide the body with the nutrients required by the high energy demands. This situation has a negative impact upon organ's and system's function and structure, including skeletal muscle, skin, the immune system, and membrane transport. As a result, hypermetabolism can lead to multiorgan dysfunction and even death.<a class="elsevierStyleCrossRef" href="#bib0280">5</a>The metabolic and inflammatory changes persist up to three years after injury.<a class="elsevierStyleCrossRef" href="#bib0285">6</a> The duration and magnitude of the hypermetabolic response are major determinants of burn patient morbidity.<a class="elsevierStyleCrossRef" href="#bib0290">7</a> The prolonged catabolic response conditions body changes such as loss of muscle mass and bone mineral content that slow patient recovery and reincorporation to daily life.<a class="elsevierStyleCrossRefs" href="#bib0285">6,8,9</a>An increase in non-protein energy supply does not reduce the loss of lean body mass. Overfed patients tend to store the extra calories in the form of fat, without modifying lean mass catabolism.<a class="elsevierStyleCrossRefs" href="#bib0305">10,11</a>Different drugs for reducing catabolism or improving burn patient anabolism have been investigated in recent years. Their use would allow the provision of fewer calories, reducing the risks associated to overfeeding (liver steatosis, accumulation of peripheral adipose tissue and increased production of CO2).<a class="elsevierStyleCrossRef" href="#bib0315">12</a>The most important drugs used in this respect include anabolic hormones (growth hormone, insulin, IGF-1, combinations of IGF-1 and IGFBP-3, oxandrolone and testosterone) and anticatabolic agents such as adrenergic antagonists (propranolol or metoprolol)<a class="elsevierStyleCrossRef" href="#bib0320">13</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The use of propranolol has been proposed in burn patients for different reasons. On one hand, endogenous catecholamines are primary mediators of the hypermetabolic response,<a class="elsevierStyleCrossRefs" href="#bib0265">2,14</a> and blocking their action logically can be expected to reduce this response at least in part. On the other hand, propranolol improves recycling of the intracellular free amino acids, thus increasing the efficiency of protein synthesis in muscle,<a class="elsevierStyleCrossRef" href="#bib0330">15</a> reducing peripheral lipolysis<a class="elsevierStyleCrossRef" href="#bib0335">16</a> and increasing liver free fatty acid secretion efficiency.<a class="elsevierStyleCrossRef" href="#bib0320">13</a>The present study offers a review of the studies that analyze the effects of the administration of propranolol in both pediatric and adult burn patients.Materials and methodsThe articles considered in this review were identified based on a PubMed search. The key words “propranolol”, “beta-blocker”, “burns” and “thermal injury” were used in combination (“propranolol”+“thermal injury”; “beta-blocker”+“thermal injury”; “propranolol”+“burns”; “beta-blocker”+“burns”) to retrieve the relevant publications. We selected studies in humans published in English and Spanish up to December 2013.ResultsThe search without filters identified 131 articles. After applying the filters referred to language (English and Spanish) and studies in humans, and eliminating duplicated articles and studies in which “burns” was the name of an author, as well as publications not referred to treatment with beta-blockers in burn patients, the total number of articles was reduced to 42.A total of 15 randomized clinical trials were identified (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The rest of the articles (n=27) were non-randomized clinical trials or studies in which randomization was not specified, cohort studies, review articles, editorials and letters to the editor.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>We also retrieved 7 studies in animals designed to investigate the mechanism of action of propranolol and to evaluate possible alterations in its absorption. These articles were identified from the references cited in the articles found in our PubMed search.Justification of the use of beta-blockers in burn patientsEndogenous catecholamines are primary mediators in the hypermetabolic response observed in burn patients.<a class="elsevierStyleCrossRefs" href="#bib0265">2,14</a> This systemic response is characterized by hyperdynamic circulation, increased basal energy expenditure, and increased muscle protein catabolism. Blocking of the beta-adrenergic stimulus reduces supraphysiological thermogenesis,<a class="elsevierStyleCrossRef" href="#bib0340">17</a> cardiac work and resting energy expenditure (REE)<a class="elsevierStyleCrossRef" href="#bib0345">18</a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Beta-blockers moreover reduce peripheral lipolysis through β2-receptor block,<a class="elsevierStyleCrossRef" href="#bib0335">16</a> and increase liver efficiency in secreting free fatty acids. Propranolol also has an effect upon lean body mass. On one hand, it improves recycling of the intracellular free amino acids, thus increasing the efficiency of protein synthesis in muscle. These intracellular amino acids derived from protein catabolism are again incorporated to proteins without leaving the muscle cell. On the other hand, propranolol also stimulates the expression of genes involved in muscle metabolism and reduces the activation of genes involved in gluconeogenesis, thereby resulting in a decrease in net catabolism.<a class="elsevierStyleCrossRef" href="#bib0320">13</a>For these reasons the use of propranolol has been suggested in burn patients. Although most of the existing studies have been carried out in pediatric patients, with confirmation of its beneficial effects, it must be mentioned that the differences in beta-blocker prescription practice among different centers attending pediatric burn patients indicate that this drug has not yet been accepted as standard treatment in the pediatric population.<a class="elsevierStyleCrossRef" href="#bib0350">19</a> The scant information on the effects of the drug in adult burn patients underscores the need for further studies in this population group.Mechanism of action of propranololThe cellular mechanisms by which propranolol accelerates muscle protein synthesis are not clear. However, it has been seen that β1-agonists such as clenbuterol also promote muscle anabolism.<a class="elsevierStyleCrossRef" href="#bib0355">20</a> In this section we offer a summarized description of the most recent studies on the effects of propranolol at molecular and genetic expression levels.The activation of poly-(ADP-ribose) polymerase (PARP) promotes cell energy collapse and cell necrosis, and possibly contributes to the inflammatory responses and cell dysfunction seen in burn patients. Peak activation is observed in the third week after burn injury, and in some cases activation persists even one year later. Muscle biopsy studies have shown PARP activation to occur mainly in the vascular endothelial cells and in some mononuclear cells. However, the muscle biopsies of pediatric patients treated with propranolol show marked suppression of PARP activation. Possibly some of the clinical benefits of propranolol in burn patients are related to this suppressive effect upon PARP activation–increasing the net protein balance and reducing lean mass catabolism by preventing skeletal muscle necrosis following severe burns.<a class="elsevierStyleCrossRef" href="#bib0360">21</a>It has been seen that pediatric burn patients subjected to treatment with propranolol exhibit increased expression of the genes implicated in muscle metabolism (such as heat shock protein 70 [HSP70] or dynein), and decreased expression of fructose-1,6-biphosphatase, an important enzyme involved in gluconeogenesis and insulin resistance, as well as of VEGF and other genes. This increase in the expression of genes implicated in muscle metabolism is well correlated to the increase in net protein balance measured by isotopic studies with phenylalanine.<a class="elsevierStyleCrossRef" href="#bib0365">22</a> The administration of propranolol also reduces the expression of genes related to lipid metabolism in adipose tissue.<a class="elsevierStyleCrossRef" href="#bib0370">23</a>In murine models it has been observed that burns, through catecholamine release, induce stress response on the part of the endoplasmic reticulum (ER). This response in turn leads to the activation of c-Jun N-terminal (JNK) kinase, the suppression of insulin receptor signaling via phosphorylation of insulin receptor substrate 1 (IRS-1) and subsequent insulin resistance.<a class="elsevierStyleCrossRef" href="#bib0375">24</a> The administration of propranolol attenuates the ER stress response and the activation of JNK. This implies increased insulin sensitivity, as has been determined by activation of the hepatic phosphatidylinositol 3-kinase/Akt signaling cascade via the phosphorylation of IRS-1. Propranolol therefore has the potential to suppress the hypermetabolic response, preventing hepatic ER stress and increasing insulin sensitivity.<a class="elsevierStyleCrossRef" href="#bib0380">25</a>Another model in rats has shown that burns result in cardiomyocyte activation of mitogen-activated protein kinase (p38 MAPK) and JNK, and translocation of nuclear factor (NF)-κB. These molecules are important in transduction of the signals that induce the biosynthesis of inflammatory cytokines. MAPK participates in cardiomyocyte secretion of TNF-α, which increases the risk of cardiac dysfunction and promotes the nuclear translocation of NF-κB, and consequently the transcription of genes. Alpha-agonists also increase the activity of p38 MAPK and JNK. However, beta-agonists have no effect in this animal model. Alpha-antagonists inhibit the burn-mediated activation of p38 MAPK and JNK, and the translocation of NF-κB, though these phenomena are curiously also inhibited by beta-blockers. This may be due to propranolol-mediated inhibition of the phospholipase D pathway, which activates MAPK.<a class="elsevierStyleCrossRef" href="#bib0385">26</a>Dosing of propranololWhen used at adequate doses, propranolol is effective in reducing the resting heart rate (HR) by 15–20% of the HR recorded upon admission. However, neither the propranolol dose needed to achieve this decrease in HR nor the pharmacokinetics of the drug in the burn population is precisely known.<a class="elsevierStyleCrossRef" href="#bib0390">27</a>Some studies in pediatric patients have used initial doses of 2mg/kg/day (0.33mg/kg/4h or 0.5–1.5mg/kg/6h), followed by increments until achieving a decrease in HR of 20% with respect to the basal HR<a class="elsevierStyleCrossRefs" href="#bib0395">28,29</a>–with mean doses of 6.3mg/kg/day at the end of hospital stay.<a class="elsevierStyleCrossRef" href="#bib0330">15</a> In a randomized prospective trial in children, Williams et al. determined the dose per kg body weight of oral propranolol required to achieve adequate attenuation of cardiac work. They also studied the kinetics of the drug. Propranolol dosing was started as 1mg/kg/day via the enteral route (every 6h), and was adjusted to reduce the HR by 15–20%. The treatment was started once the patients were stabilized with fluids, about 24–72h after admission. The initial dose of 1mg/kg/day was enough to lower the HR by 10–15%, but had to be increased to 4mg/kg/day in order to achieve and maintain a HR decrease of 15%. There were no differences in dose requirement according to patient's age or gender. However, on comparing the patients according to burned body surface, those patients with 60–80% burns required doses of between 4 and 6mg/kg/day, while those with burns affecting less than 60% or more than 80% of the body surface required a dose of 4mg/kg/day. The effective therapeutic propranolol concentration was 50ng/ml. The peak drug levels were reached 30min to 1h after administration in pediatric burn patients, with trough levels within 1–2h. The half-life of the drug was 4–6h. Patients with burns affecting 80–100% of the body surface showed much greater dose variability than the patients with less extensive injuries. A number of factors probably influence such variability, since these patients are in a more critical condition, with greater resuscitation and surgery times that cause delays in the propranolol dose increments. Regarding the pharmacokinetics of the drug, pediatric burn patients usually do not reach adequate drug levels, and require dose escalation either because of tachyphylaxis or due to a maintained hypermetabolic response flow phase. Furthermore, these patients present such intense hypermetabolism that they reach peak levels earlier than expected. In such situations dosing with shorter intervals may be required. The principal metabolite, 4-hydroxypropranolol, is also active and may be more potent than propranolol. This would explain the decrease in HR even with low plasma propranolol concentrations.<a class="elsevierStyleCrossRef" href="#bib0390">27</a> Herndon et al. proposed the use of doses in excess of 4mg/kg/day, since they produce few adverse effects and a high HR persists.<a class="elsevierStyleCrossRef" href="#bib0345">18</a> Adults receive a standard dose of 20mg every 6h, with increments as required, though dosing studies have not been made in this population.<a class="elsevierStyleCrossRef" href="#bib0390">27</a>Regarding the administration route, Neudeck et al. conducted a study in rats with burns affecting 30% of the body surface. Although the burns resulted in a decrease in the functional intestinal mucosal surface and a drop in glycoprotein-P content, no alteration in propranolol absorption was observed. This may be because propranolol is very lipophilic and is consequently easily absorbed. Moreover, a potential decrease in propranolol absorption could be countered by a lesser efflux of the drug, due to the lower glycoprotein-P content.<a class="elsevierStyleCrossRef" href="#bib0405">30</a>Clinical effects of propranolol in burn patientsIn 1974, Wilmore demonstrated that catecholamine levels were increased after thermal injury, and that beta-adrenergic block decreased the metabolic rate, HR, ventilation/min and free fatty acids in burn patients.<a class="elsevierStyleCrossRef" href="#bib0325">14</a> In 1987, Wolfe et al. described an increase in substrate (futile) cycles in burn patients, and showed that treatment with propranolol reduces triglyceride-free fatty acid substrate cycles.<a class="elsevierStyleCrossRef" href="#bib0410">31</a> Furthermore, on measuring the rate of appearance of glycerol and palmitate, these authors showed that propranolol also reduces lipolysis in burn patients.<a class="elsevierStyleCrossRef" href="#bib0415">32</a> One year later, Herndon et al. published a study in which adrenergic block was seen to reduce myocardial work in burn patients, maintaining adequate cardiac output and oxygen transport.<a class="elsevierStyleCrossRef" href="#bib0340">17</a> Over the following years it was shown that propranolol reduces the myocardial oxygen demands in burn patients, without affecting oxygen delivery or body oxygen consumption,<a class="elsevierStyleCrossRef" href="#bib0420">33</a> or patient's capacity to increase energy expenditure in cold environments.<a class="elsevierStyleCrossRef" href="#bib0425">34</a> The number of publications has continued to grow, particularly those of the Galveston group, in relation to the use of this drug in burn patients. In this regard, in 2001 the mentioned group demonstrated that propranolol reduces muscle protein catabolism in pediatric burn patients.<a class="elsevierStyleCrossRef" href="#bib0330">15</a> Further studies have been made on the effects of propranolol in burn patients; indeed, the drug is becoming increasingly popular in this patient population. The results of these studies are summarized below.In pediatric burn patients, treatment with propranolol results in decreased cardiac work from the second week of treatment, and this decrease is sustained over time.<a class="elsevierStyleCrossRefs" href="#bib0345">18,27,35</a> Furthermore, the treated patients have a greater measured stroke volume.<a class="elsevierStyleCrossRef" href="#bib0390">27</a> Likewise, the decrease in HR persists one year after burn injury if treatment with propranolol is continued. A decrease in heart rate-pressure product of approximately 15% also persists 6 months after injury.<a class="elsevierStyleCrossRef" href="#bib0345">18</a>Propranolol also improves skeletal muscle protein kinetics in children, exerting an anabolic effect upon muscle.<a class="elsevierStyleCrossRef" href="#bib0330">15</a> The drug improves the efficiency of protein synthesis, with a lesser loss of lean body mass or the preservation of lean mass.<a class="elsevierStyleCrossRefs" href="#bib0330">15,18,22</a> As has been commented, propranolol induces an increase in the intracellular recycling of free amino acids, i.e., intracellular free amino acids resulting from protein catabolism are reincorporated again to proteins without leaving the muscle cell.<a class="elsevierStyleCrossRef" href="#bib0330">15</a>Pediatric patients treated with propranolol for one year experience less accretion of central mass (organs and mesenteric fat) and of central fatty tissue. This is because propranolol reduces the central fat deposits, and is consistent with the findings (described further below) indicating that propranolol reduces mesenteric blood flow and peripheral lipolysis. Furthermore, the treated patients exhibit a greater increase in peripheral lean mass after 6 months of treatment. A minor percentage of the patients lose more than 5% of their bone mineral content and total body mass, compared with untreated patients. Increased bone resistance can also indirectly contribute to improve lean body mass.<a class="elsevierStyleCrossRef" href="#bib0345">18</a>Propranolol likewise reduces resting energy expenditure (REE) in pediatric patients,<a class="elsevierStyleCrossRefs" href="#bib0330">15,18,29</a> though the respiratory ratio experiences no significant variations.<a class="elsevierStyleCrossRef" href="#bib0330">15</a> If the treatment is maintained, the decrease in REE is also more pronounced between two weeks and 6 months after burn injury when compared with untreated patients.<a class="elsevierStyleCrossRef" href="#bib0345">18</a>However, propranolol does not appear to have an effect upon the inflammatory reaction in burn patients. During acute hospital admission, only minor differences have been observed between patients with and without propranolol treatment. Jeschke et al. found no differences in the expression of IL-6, IL-8, IL-10, MCP-1 or MIP-1β. Differences were recorded at a single timepoint in relation to the concentrations of TNF-α and IL-1β, which were seen to be lower in the treated group.<a class="elsevierStyleCrossRef" href="#bib0400">29</a>Likewise, no differences have been found between children with and without propranolol treatment in terms of mortality, the duration of hospital stay or multiorgan failure.<a class="elsevierStyleCrossRef" href="#bib0400">29</a> In any case, detecting differences in mortality in pediatric burn patients would require the conduction of multicenter studies with many patients, since the mortality rate in this population group is 4–6%.<a class="elsevierStyleCrossRef" href="#bib0400">29</a>The net fat balance through the liver is conditioned to the uptake of fatty acids from plasma, the intrahepatic oxidation of fatty acids, and the release of triglycerides bound to very low density lipoproteins (VLDL).<a class="elsevierStyleCrossRefs" href="#bib0395">28,36</a> Propranolol reduces the availability of free fatty acids for the liver. By reducing the release of fatty acids from the periphery in burn patients (peripheral lipolysis)<a class="elsevierStyleCrossRefs" href="#bib0335">16,28</a> and reducing splanchnic blood flow, the liver receives a lesser supply of fatty acids.<a class="elsevierStyleCrossRef" href="#bib0435">36</a> Furthermore, the drug increases the efficiency of free fatty acid conversion to VLDL-bound triglycerides and their release from the liver.<a class="elsevierStyleCrossRef" href="#bib0395">28</a> Thus, in burn patients propranolol has the beneficial effect of reducing liver fat accumulation–a frequent problem in patients of this kind.<a class="elsevierStyleCrossRefs" href="#bib0370">23,28,36</a>Studies have also been made of the effect of propranolol upon wound healing. Zhang et al. investigated the effect of the administration of the drug upon healing of the partial thickness donor zones in rabbits. In the propranolol group the fractional protein synthesis rate in the wound was found to be greater, with a correlation between the protein synthesis rate and the percentage decrease in HR. In addition, propranolol increased the efficacy of amino acid utilization in wound catabolism for the synthesis of new proteins. The protein depositing rate and the concentrations of free essential amino acids were also greater in the propranolol group. Wound DNA synthesis, the expression of beta-adrenergic receptors, and the expression or activation of signaling cascade targets were not different between the treated and non-treated rabbits. However, the authors indicated that infusion of the drug can result in faster transition from shock condition to flow phase.<a class="elsevierStyleCrossRef" href="#bib0440">37</a>Romana-Souza et al. studied the effect of propranolol (6mg/kg/day p.o.) in a model of scalding third-degree burns affecting 10% of the total body surface in Wistar rats. Wound healing was found to be better in the treated group, which exhibited a lesser wound area after 63 days of treatment. This group also showed a decrease in local inflammatory response (with lesser inflammatory infiltration), improved contraction of the wound, greater reepithelization, cell proliferation, granulation tissue formation, collagen accumulation, myofibroblast density, and nitrite and metalloproteinase-2 levels, together with a lesser vessel density. Treatment with propranolol appeared to stimulate the development of less vascularized and more organized collagenous granulation tissue. The authors suggested that many of these effects were attributable to nitric oxide synthesis stimulated by propranolol.<a class="elsevierStyleCrossRef" href="#bib0445">38</a>Mohammadi et al. conducted a randomized, double-blind clinical trial in adult burn patients with or without propranolol treatment. In their series the patients were treated with delayed graft covering until the appearance of clean granulation tissue. The patients started treatment with propranolol at a dose of 1mg/kg/day p.o., followed by gradual elevation to 1.98mg/kg/day, adjusting the dose in order to lower the HR by 20% of the basal HR in each patient. The authors evaluated the time from admission to epithelization or preparation for skin grafting, as clinical indicators of burn healing time. The patients in the propranolol treatment group showed faster epithelization and a shorter time to graft bed suitability. Furthermore, the administration of propranolol reduced the size of the burn surface finally requiring grafting, as well as the duration of hospital stay.<a class="elsevierStyleCrossRef" href="#bib0450">39</a>Beta-blockers prevent memory reconsolidation, and have been administered to patients exposed to traumatic effects in order to prevent post-traumatic stress syndrome. However, the studies in this regard among children and adults have not shown beta-blocker administration to reduce the incidence of post-traumatic stress syndrome or acute distress disorders.<a class="elsevierStyleCrossRefs" href="#bib0455">40,41</a>Some studies have related beta-blockers to worsening of the benefits of training in non-burn patient populations. No such effect has been observed in pediatric burn patients, however. Porro et al. evaluated the effects of a 12-week aerobic exercise and resistance program in children over 7 years of age with burns affecting more than 30% of the total body surface and treated or not treated with propranolol. The authors recorded an increase in muscle resistance (by 50%), lean body mass and peak VO2 (oxygen consumption) in both groups when compared with children not enrolled in the exercise program. The group treated with propranolol moreover showed greater peak VO2, possibly as a result of slower capillary blood flow in the muscle, thereby allowing for greater tissue oxygen extraction.<a class="elsevierStyleCrossRef" href="#bib0465">42</a>There are few studies on the effects of propranolol in adult burn patients. Arbabi et al. published a retrospective study comparing the prognosis of adult burn patients treated with beta-blockers from before admission and with continued treatment during admission versus non-treated burn patients matched for percentage burn surface area and age. The authors identified a total of 21 patients treated with beta-blockers for different reasons (arterial hypertension in 20 cases and migraine in one patient), and included 42 controls. Most of the patients received treatment with β1-antagonists, including metoprolol, esmolol and atenolol. Two patients were treated with labetalol and one with propranolol. Although the patients receiving treatment had a higher prevalence of heart disease and arterial hypertension, they showed lesser mortality (5% versus 13%), shorter healing times, and a tendency toward shorter stay in hospital and in Intensive Care.<a class="elsevierStyleCrossRef" href="#bib0470">43</a> The improvement in mortality may have been due in part to the cardioprotective effect of the beta-blockers. The authors suggested that a randomized prospective study is needed in order to confirm these findings.<a class="elsevierStyleCrossRef" href="#bib0470">43</a>The investigators of the abovementioned study furthermore propose the use of selective β1-antagonists such as metoprolol, because they could be used in patients with inhalation syndrome, with a lesser risk of bronchospasm.<a class="elsevierStyleCrossRef" href="#bib0470">43</a> Caution in this respect is required, however, since an increase in mortality has been observed among patients with arteriosclerosis treated with metoprolol during non-cardiac surgery.<a class="elsevierStyleCrossRef" href="#bib0475">44</a> However, the Herndon group recommends the use of propranolol instead of other more selective beta-blockers, since the effect upon lipid metabolism is mediated by β2-receptor block.<a class="elsevierStyleCrossRefs" href="#bib0335">16,45</a>Effects of jointly administered propranolol and growth hormone (rhGH)Combined treatment with propranolol and growth hormone (rhGH) has been studied in three clinical trials in children. The first study was a crossover clinical trial in 6 patients administered rhGH and the combination of rhGH and propranolol, during 6 days. As has been commented above, propranolol was seen to decrease peripheral lipolysis and maintained the VLDL-bound triglyceride secretion rate.<a class="elsevierStyleCrossRef" href="#bib0395">28</a>The second clinical trial found no differences between the net protein balance and REE over the short term with the combination treatment or with propranolol alone. This lack of effect of growth hormone is in contraposition to the observations of previous studies, though the authors speculated that it may have been due to the fact that the effects were measured over the short term (10 days). In this regard, the effects of growth hormone upon the increase in lean muscle mass in pediatric burn patients are seen when the hormone is administered over several months. Furthermore, it is possible that propranolol exerts a greater anabolic effect, or that there is an anabolic ceiling effect already reached when administering propranolol alone.<a class="elsevierStyleCrossRef" href="#bib0355">20</a>The most recent clinical trial showed the joint administration of rhGH and propranolol to attenuate the inflammatory cascade and therefore hypermetabolism during the acute phase in pediatric patients. In addition, it avoided the adverse effects of rhGH (hyperglycemia and free fatty acid elevation). The combination treatment reduced REE and HR, and preserved body mass by reducing the presence of inflammatory mediators such as TNF-α, IL-6, IL-8, MIP-1β, PCR and cortisol, and increasing the levels of IL-7, which stimulates the proliferation of early and mature T cells and B cells. Likewise, the treatment increased total bone mineral density and liver and muscle protein synthesis, and decreased the transaminase (ALT and AST) concentrations.<a class="elsevierStyleCrossRef" href="#bib0485">46</a> However, the mentioned study did not compare the administration of these two drugs in combination versus propranolol alone. The comparisons were made with a group of controls receiving no drug treatment.Side effects of propranolol in burn patientsThe treatment of burn patients with propranolol at doses that lower the HR by 20% with respect to the HR upon admission appears to be safe.<a class="elsevierStyleCrossRefs" href="#bib0330">15,27,28,39</a> However, blood pressure monitoring of the treated patients is required.<a class="elsevierStyleCrossRef" href="#bib0330">15</a>Few side effects were reported in the study published in 2012 by Herndon et al. on the effects of propranolol in 90 pediatric burn patients treated with the drug during one year. Overall, there were two episodes of bradycardia, one episode of hypoglycemia, one cardiac arrhythmia and two episodes of breathing problems. There were no cases of hypotension, however. Five deaths were documented in the control group (89 patients), versus four in the active treatment group. There were no significant differences between the two groups in terms of mortality, which was due to sepsis in all the cases.<a class="elsevierStyleCrossRef" href="#bib0345">18</a>A case of colon pseudo-obstruction (Ogilvie syndrome) has been reported in a patient treated with oral propranolol. Conservative management resolved the problem successfully after suspending propranolol.<a class="elsevierStyleCrossRef" href="#bib0490">47</a>Murine studies have reported that non-selective beta-adrenergic block during episodes of septicemia increases mortality.<a class="elsevierStyleCrossRef" href="#bib0495">48</a> However, no differences have been observed in relation to episodes of infection or sepsis, or mortality, between patients with or without propranolol treatment.<a class="elsevierStyleCrossRefs" href="#bib0330">15,29,39</a> Moreover, sepsis is characterized by changes similar to those observed in burns, with the development of a catabolic state, increased lipid and glucose metabolism, changes in cardiac output, immune modulating effects, increased REE, hyperglycemia and a loss of muscle mass. The attenuation of this response is associated to lesser mortality. A key mediator of the response to sepsis is the rapid rise in catecholamine levels, with activation of the sympathetic autonomic nervous system. It therefore has been suggested that propranolol could be useful for modulating these responses to sepsis, including a decrease in energy expenditure, inversion of catabolism, reduction of lipolysis, restoration of blood glucose control, and attenuation of the immune suppression caused by catecholamine action.<a class="elsevierStyleCrossRef" href="#bib0500">49</a>Studies in murine models have shown that burn-related sepsis is characterized by sympathetic stimulation that leads to monocytosis, though it suppresses monocyte inflammatory response. Beta-adrenergic block reduces such monocytosis induced by sepsis in burn cases. Furthermore, it increases the percentage of inflammatory monocytes, granulocytosis and the production of TNF-α on the part of the circulating granulocytes.<a class="elsevierStyleCrossRef" href="#bib0505">50</a>Type M1 monocytes (producers of IL-12 but not IL-10) are important effector cells in the first line of antibacterial defense within the context of innate immune responses. However, this subtype is not a manifest in burn patients, which show a predominance of type M2 monocytes (producers of IL-10 but not IL-12), which in turn inhibits the conversion of resident monocytes to type M1 cells. Specifically, subtype M2b is seen to predominate. The type M2 cells appear after catecholamine binding to beta-receptors of the resident monocytes, and possess a lesser antibacterial capacity. Burn patients treated with propranolol show a greater conversion of resident monocytes to type M1 cells. Since the M1 subtype affords greater resistance to infections produced by Staphylococcus aureus and to the translocation of Enterococcus faecalis, the susceptibility of severe burn patients to such infections could be influenced by treatment with propranolol.<a class="elsevierStyleCrossRef" href="#bib0510">51</a>ConclusionsMost of the studies on the effects of propranolol in burn patients have been carried out in children, with very promising results. Given the enormous potential benefits for adult burn patients, further studies are needed on the effects and dosing protocols of propranolol in this particular population group.Conflict of interestThe authors declare that they have received no financial support or grants for this study, and have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres452113" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Main results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec475077" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres452112" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados principales" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec475076" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Justification of the use of beta-blockers in burn patients" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Mechanism of action of propranolol" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Dosing of propranolol" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Clinical effects of propranolol in burn patients" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Effects of jointly administered propranolol and growth hormone (rhGH)" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Side effects of propranolol in burn patients" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflict of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-03-31" "fechaAceptado" => "2014-08-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec475077" "palabras" => array:3 [ 0 => "Burns/metabolism" 1 => "Burns/drug therapy" 2 => "Propranolol/therapeutic use" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec475076" "palabras" => array:3 [ 0 => "Quemados/metabolismo" 1 => "Quemados/terapia farmacológica" 2 => "Propranolol/uso terapéutico" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundThe use of propranolol has been proposed to reduce the hypermetabolic response of patients with burn injuries. ObjectivesTo review the studies published up to December 2013 on the effects of propranolol in burn patients. MethodsA PubMed search was conducted using the terms “burns”, “thermal injury”, “beta-blocker” and “propranolol”, with the filters “human” and “English” and “Spanish”. A total of 42 citations were retrieved, 15 of which were randomized clinical trials. The main results are summarized. Main resultsPropranolol at doses adjusted to decrease the heart rate by 20% of the baseline value (4–6mg/kg/day p.o.) reduces supraphysiological thermogenesis, cardiac work, resting energy expenditure and peripheral lipolysis. It likewise increases the efficiency of muscular protein synthesis and reduces central mass accretion. Most studies have been conducted in pediatric burn patients. ConclusionsPropranolol reduces the hypermetabolic response in pediatric burn patients. More studies on its effects in adult burn patients are needed." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Main results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesEl uso de propranolol se ha propuesto para atenuar la respuesta hipermetabólica del paciente quemado. ObjetivosRevisar los estudios publicados hasta diciembre de 2013 que analizan los efectos del propranolol en el paciente quemado. MétodosSe aplicaron los términos «burns», «thermal injury», «betablocker» y «propranolol», con los filtros «human» y «English» y «Spanish» en el buscador Pubmed. Se identificaron 42 artículos de los que 15 eran ensayos clínicos aleatorizados. Se resumen los resultados principales de estos artículos. Resultados principalesEl propranolol ajustado para lograr una frecuencia cardiaca un 20% menor a la basal (4–6mg/kg/día por vía enteral) disminuye la termogénesis suprafisiológica, el trabajo cardiaco, el gasto energético en reposo y la lipólisis periférica. Aumenta la eficiencia de la síntesis proteica muscular y disminuye la acreción de masa central. La mayor parte de estudios han sido realizados en niños. ConclusionesEl propranolol atenúa la respuesta hipermetabólica del paciente quemado pediátrico. Son necesarios más estudios sobre su efecto en la población adulta." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados principales" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Núñez-Villaveirán T, Sánchez M, Millán P, García-de-Lorenzo A. Revisión sistemática del efecto del propranolol sobre el hipermetabolismo del quemado. Med Intensiva. 2015;39:101–113." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anabolic agents \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticatabolic drugs \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Growth hormone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Beta-blockers \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Insulin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Metformin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">IGF-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Combinations of IGF-1 and IGFBP-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Oxandrolone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Testosterone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab700678.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Drugs that attenuate the hypermetabolic response in burn patients." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "FAs, fatty acids; FFAs, free fatty acids; CO, cardiac output; REE, resting energy expenditure; CHs, carbohydrates; i.v., intravenous; MIP, macrophage inflammatory protein; n.s., non-significant; MBP, mean blood pressure; PARP, poly-(ADP-ribose) polymerase; rhGH, recombinant human growth hormone; s.c., subcutaneous; BBS, burned body surface; NGT, nasogastric tube; TGs, triglycerides; p.o., oral route." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Place of study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study objectives \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Propranolol dose and route \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Findings \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Herndon et al. (1994)<a class="elsevierStyleCrossRef" href="#bib0335">16</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the effect of β1 block upon the cardiovascular system and lipid and protein kinetics in burn patients– To show that the metabolic effects of catecholamines in burn patients are mediated by β2 receptors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 pediatric patients and adolescents (>40% BBS)– 8 receive metoprolol– 8 receive propranolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol 2mg/kg/day i.v., every 8h, during 5 days. Dose later adjusted for HR 20% less than basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– No significant difference between REE of day 1 and day 5– Both drugs: decrease in HR and HR-pressure product (p<0.05)– Propranolol reduces lipolysis; metoprolol does not (p<0.05)– Neither propranolol nor metoprolol alter protein kinetics \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Aarsland et al. (1996)<a class="elsevierStyleCrossRef" href="#bib0395">28</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the effect of propranolol upon peripheral lipolysis in pediatric burn patients receiving treatment with rhGH– To determine whether there are alterations in VLDL-bound triglyceride secretion rate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cross-over clinical trial in 6 children (third-degree burns >30% BBS)– 6 patients receive treatment with rhGH and with rhGH+propranolol– 6 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 days of combined treatment with rhGH (0.2mg/kg/day s.c.) and propranolol (2mg/kg/day i.v.). Dose later adjusted for HR 20% less than basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– rhGH increases release of FFAs in pediatric major burn patients– Propranolol reduces release of FFAs, but maintains VLDL-bound TG secretion rate (greater efficiency of FFA conversion to VLDL-bound TGs and release from liver) (p<0.05)– No significant difference in REE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Herndon et al. (2001)<a class="elsevierStyleCrossRef" href="#bib0330">15</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the effect of propranolol upon REE and muscle catabolism in severe burn patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">25 pediatric patients and adolescents (>40% BBS)– 13 receive propranolol– 12 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">After second surgery: propranolol 0.33mg/kg/4h through NGT. Dose later adjusted for HR 20% less than basal. Maintained at least 14 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol reduces REE (−422±197kcal/day after 2 weeks [p=0.001]) and lean mass catabolism in pediatric severe burn patients (net muscle protein balance 82% greater than basal (p=0.002) versus 27% less in control group (n.s.)) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hart et al. (2002)<a class="elsevierStyleCrossRef" href="#bib0355">20</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether combination treatment with GH+propranolol exerts additive effects upon the reduction of burn-induced catabolism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">56 pediatric patients and adolescents (>40% BBS)– n=12: rhGH– n=12: propranolol– n=12: rhGH+propranolol– n=20: controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol 0.33mg/kg/4h p.o. Dose later adjusted for HR 20–25% less than basal. Maintained at least 10 daysrhGH 0.2mg/kg/day s.c. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Propranolol: accelerates protein synthesis in early hypercatabolic period in pediatric major burn patients, and reduces REE (p<0.05)– rhGH exerts no additive effect upon muscle protein accretion or REE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Morio et al. (2002)<a class="elsevierStyleCrossRef" href="#bib0435">36</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To quantify components of the splanchnic metabolism of FAs and VLDL-TGs in order to understand the mechanisms underlying fatty liver development in severe burn patients– To determine whether propranolol can reduce the accumulation of FAs in the liver, over the short and long term \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 adult and pediatric patients (BBS>55%)– All 8 receive propranolol i.v. in the first study and serve as their own controls– 4: propranolol 3 weeks– 4: controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol i.v. (bolus: 1.5mg/kg and then perfusion 0.04μmol/kg/min)Propranolol p.o. 2mg/kg/day every 4h during 3 weeks. Dose later adjusted for HR 25% less than basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Liver fat is stored in burn patients with diet rich in CHs, due to low FA oxidation rate and secretion in form of VLDL-TGs– Propranolol: reduces availability of FAs and liver storage of TGs (p<0.05).– The effect of propranolol persists after 3 weeks of treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Herndon et al. (2003)<a class="elsevierStyleCrossRef" href="#bib0365">22</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the effect of propranolol upon protein metabolism of pediatric burn patients– To define the genetic and phenotypic events associated to beta-adrenergic block \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 pediatric patients and adolescents (BBS >40%)– 14 receive propranolol– 23 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">After second surgery, propranolol 0.3–1mg/kg/4–6h through NGT. Dose later adjusted for HR 10–15% less than basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Balance between protein synthesis and protein catabolism: −14.3±12.9nmol/min/100ml in controls; +69.3±34.9nmol/min/100ml in propranolol group (p<0.012)– Increase of 9 genes implicated in muscle metabolism and decrease of 5 genes implicated in gluconeogenesis and insulin resistance in the propranolol group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Barrow et al. (2006)<a class="elsevierStyleCrossRef" href="#bib0370">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether propranolol can be beneficial in pediatric major burn patients by attenuating peripheral lipolysis, portal blood flow and hepatomegalia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98 pediatric patients and adolescents (BBS>40%)– 44 receive propranolol– 54 receive placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">After second surgery, propranolol 0.3–1mg/kg/4–6h through NGT adjusted for HR 12–15% less than basal. Maintained until healing of 95% of the surface \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Propranolol prevents or attenuates the increase in weight and liver size in pediatric major burn patients (p<0.001)– Propranolol reduces the expression of genes related to lipid metabolism in adipose tissue \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Jeschke et al. (2007)<a class="elsevierStyleCrossRef" href="#bib0400">29</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine the effect of propranolol upon infections, sepsis and inflammation in severe burn patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">245 pediatric patients and adolescents (BBS >40%)– 102 receive propranolol– 143 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol 0.5–1.5mg/kg/6h enteral route started after 7 days. Intent-to-treat: all administered for at least 3 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– No significant difference between groups in terms of mortality (6% controls, 5% treated), incidence of infections (30% controls, 21% propranolol) or sepsis (10% controls, 7% propranolol)– Propranolol: decrease in REE, TNF-α and IL-1β (p<0.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Jeschke et al. (2008)<a class="elsevierStyleCrossRef" href="#bib0485">46</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether combined treatment with rhGH+propranolol improves hypermetabolism, the hepatic acute phase response, and the inflammatory response in severe burn patients, without adverse effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 pediatric patients and adolescents (BBS >40%)– n=15: propranolol+rhGH– n=15: controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Treatment started on day 7–10 of admission with rhGH (0.2mg/kg/day s.c.) and propranolol (0.5mg/kg/4h, adjusted for HR 10–15% less than basal). Treatment maintained for 25 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– REE −5±8% of predicted value in treated versus 35<±20% in controls (p<0.05)Treated group (p<0.05):– Decrease in C-reactive protein, cortisone, GPT, GOT, FFAs, IL-6, IL-8 and MIP-1– Increase in IGF-I, IGFBP-3, GH, prealbumin and IL-7– Without side effects of rhGH alone \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Mohammadi et al. (2009)<a class="elsevierStyleCrossRef" href="#bib0450">39</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shiraz Burn Research Center (Iran) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether propranolol shortens healing time in burn patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">79 patients (16–60 years; 20–50% BBS)– 37 receive propranolol– 42 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Treatment started on day 4 of admission with propranolol 1mg/kg/day every 4h enteral route, adjusting for HR 20% less than basal (maximum 1.98mg/kg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Treated group:– Shorter superficial burn epithelization time (16.13±7.4 versus 21.52±7.94 days; p<0.004)– Shorter graft bed preparation time in deep burns (28.23±8.43 versus 33.46±9.17 days; p<0.007) and greater reduction of size of burn area for grafting (treated: mean BBS 31.42% – require grafting 13.75%; controls: mean BBS 33.61% – require grafting 18.72% [p<0.006])– Shorter stay (24.41±8.11 versus 30.95±8.44 days, p<0.05)– No significant difference in mortality or sepsis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Williams et al. (2011)<a class="elsevierStyleCrossRef" href="#bib0390">27</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine the propranolol dose that reduces HR by 15% with respect to HR upon admission and improves cardiac function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">340 pediatric patients and adolescents (>30% BBS)– 125 with propranolol (n=80 BBS 30–60%; n=33 BBS 60–80%; n=12 BBS >80%)– 215 controls (n=139 BBS 30–60%; n=58 BBS 60–80%; n=18 BBS>80%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">From 24 to 72h until end of admission, propranolol every 6h via enteral route. Start with 1mg/kg/day. Dose later adjusted for HR 15–20% less than basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Propranolol at dose of 1mg/kg/day reduces HR 15% with respect to basal. The dose must increase to 4mg/kg/day the first 10 days in order to maintain the effect (4–6mg/kg/day in the BBS 60–80% group)– Effective plasma concentration in pediatric burn patients within 30min (50ng/ml). Half-life: 4h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Kobayashi (2011)<a class="elsevierStyleCrossRef" href="#bib0510">51</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether propranolol reduces M2b monocytes in peripheral blood \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– First part: 22 pediatric patients (BBS>30%) and 6 healthy volunteers– Second part: randomization to two groups of 15 patients (8 receive propranolol and 7 placebo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol 4mg/kg/day enteral route during 7–17 days, starting 2–5 days after injury \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– M2b: predominate in non-treated pediatric burn patients– Patients with propranolol: no predominance of M2b (p<0.001) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Olah et al. (2011)<a class="elsevierStyleCrossRef" href="#bib0360">21</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the activation of PARP in burn patients and the effect of propranolol upon such activation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– First part: 16 vastus lateralis muscle biopsies in different burn stages versus 3 cleft palate/lip biopsies in controls– Second part: 21 patients (0–17 years, BBS>40%)– 9 receive propranolol– 12 do not receive propranolol \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol 4mg/kg/day enteral route from admission and during 10±1 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Burn patients showed activation of PARP– Propranolol: suppresses activation of PARP in the muscle biopsies of the patients (p<0.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Herndon et al. (2012)<a class="elsevierStyleCrossRef" href="#bib0345">18</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To determine whether the long-term administration of propranolol improves cardiac function, REE and body composition \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">179 pediatric patients and adolescents (BBS>30%)– 90 receive propranolol– 89 controls \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol started 3±2 days after admission, at dose required to reduce HR 15% (mean dose 4mg/kg/day p.o.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– Low mortality in both groups (5 controls, 4 treated), without significant differences. All deaths due to sepsis– Propranolol: few adverse effects (0 hypotension, 2 bradycardia, 1 hypoglycemia, 1 cardiac arrhythmia, 2 respiratory problems)– Propranolol reduces HR and cardiac work. The drug reduces central body mass and trunk fat, improves lean body mass and bone mineral density (p<0.001–0.02) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Porro et al. (2013)<a class="elsevierStyleCrossRef" href="#bib0465">42</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Shriners Burns Institute (USA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– To assess the effect of aerobic and resistance exercise during 12 weeks together with propranolol treatment in pediatric major burn patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">46 pediatric patients and adolescents (7–18 years, BBS>30%)– n=27: propranolol+exercise– n=31: only exercise \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Propranolol adjusting to reduce HR by 15–20% versus basal (4–8mg/kg/day p.o.). Start in first 48h of admission and maintained until end of physical training (within 6 months after injury) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– 50% increase in muscle strength after training in all children– Increase in peak O2 consumption greater in patients with propranolol (36% versus 22%; p<0.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab700677.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Randomized clinical trials." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Physiopathology and particularities of burn patients \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Effects of propranolol in burn patients or animal burn models \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Primary mediators of hypermetabolic response: catecholamines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-selective β-adrenergic receptor block \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Hyperdynamic circulation and increased cardiac output \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Decreases heart rate and cardiac work \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Increased basal energy expenditure \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduces supraphysiological thermogenesis and resting energy expenditure \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Increased muscle protein catabolism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Favors recycling of intracellular free amino acids in muscleStimulates the expression of genes implicated in muscle metabolism and reduces the activation of genes implicated in gluconeogenesis, with reduction of net catabolism \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Increased peripheral lipolysisFat accumulation in liver \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduces peripheral lipolysisIncreases efficiency of liver free fatty acid secretionReduces mesenteric blood flow \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Need for healing of burns and graft donor zones \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increased fractional protein synthesis in woundIncreased efficacy in use of amino acids from wound catabolism for synthesizing new proteinsIncreased protein accumulation and free amino acid concentrations in the woundImproved healing and epithelization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">In sepsis, increased monocytosis with suppression of inflammatory response of monocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction of monocytosis induced by sepsis in burns, increase in percentage of inflammatory monocytes, granulocytosis and production of TNF-α \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Predominance of type M2 monocytes, with lesser antibacterial capacity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Increase in type M1 monocytes, with possibly greater resistance to certain infections (S. aureus, E. faecalis) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab700676.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Effects of propranolol in burn patients." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib0260" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Energy expenditure of major burns" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C. 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Systematic review of the effect of propanolol on hypermetabolism in burn injuries

Revisión sistemática del efecto del propranolol sobre el hipermetabolismo del quemado

T. Núñez-Villaveirána,

Corresponding author

tnuvi@hotmail.com

Corresponding author.

, M. Sánchezb, P. Millánb, A. García-de-Lorenzob

a Servicio de Cirugía Plástica y Reparadora, Hospital Universitario La Paz, Madrid, Spain

b Servicio de Medicina Intensiva, Hospital Universitario La Paz, Madrid, Spain

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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Revisi&#243;n sistem&#225;tica del efecto del propranolol sobre el hipermetabolismo del quemado"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Severe burns are the type of injury exhibiting the greatest degree of hypermetabolism in humans&#46; In severe burn patients the energy expenditure can be up to twice as high as the estimated resting energy expenditure&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Such hypermetabolism is accompanied by increased muscle metabolism&#44;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">2&#8211;4</span></a> in an attempt to provide the body with the nutrients required by the high energy demands&#46; This situation has a negative impact upon organ&#39;s and system&#39;s function and structure&#44; including skeletal muscle&#44; skin&#44; the immune system&#44; and membrane transport&#46; As a result&#44; hypermetabolism can lead to multiorgan dysfunction and even death&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The metabolic and inflammatory changes persist up to three years after injury&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">6</span></a> The duration and magnitude of the hypermetabolic response are major determinants of burn patient morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">7</span></a> The prolonged catabolic response conditions body changes such as loss of muscle mass and bone mineral content that slow patient recovery and reincorporation to daily life&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">6&#44;8&#44;9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">An increase in non-protein energy supply does not reduce the loss of lean body mass&#46; Overfed patients tend to store the extra calories in the form of fat&#44; without modifying lean mass catabolism&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Different drugs for reducing catabolism or improving burn patient anabolism have been investigated in recent years&#46; Their use would allow the provision of fewer calories&#44; reducing the risks associated to overfeeding &#40;liver steatosis&#44; accumulation of peripheral adipose tissue and increased production of CO<span class="elsevierStyleInf">2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The most important drugs used in this respect include anabolic hormones &#40;growth hormone&#44; insulin&#44; IGF-1&#44; combinations of IGF-1 and IGFBP-3&#44; oxandrolone and testosterone&#41; and anticatabolic agents such as adrenergic antagonists &#40;propranolol or metoprolol&#41;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">13</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The use of propranolol has been proposed in burn patients for different reasons&#46; On one hand&#44; endogenous catecholamines are primary mediators of the hypermetabolic response&#44;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">2&#44;14</span></a> and blocking their action logically can be expected to reduce this response at least in part&#46; On the other hand&#44; propranolol improves recycling of the intracellular free amino acids&#44; thus increasing the efficiency of protein synthesis in muscle&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> reducing peripheral lipolysis<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a> and increasing liver free fatty acid secretion efficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The present study offers a review of the studies that analyze the effects of the administration of propranolol in both pediatric and adult burn patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Materials and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">The articles considered in this review were identified based on a PubMed search&#46; The key words &#8220;propranolol&#8221;&#44; &#8220;beta-blocker&#8221;&#44; &#8220;burns&#8221; and &#8220;thermal injury&#8221; were used in combination &#40;&#8220;propranolol&#8221;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#8220;thermal injury&#8221;&#59; &#8220;beta-blocker&#8221;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#8220;thermal injury&#8221;&#59; &#8220;propranolol&#8221;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#8220;burns&#8221;&#59; &#8220;beta-blocker&#8221;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#8220;burns&#8221;&#41; to retrieve the relevant publications&#46; We selected studies in humans published in English and Spanish up to December 2013&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The search without filters identified 131 articles&#46; After applying the filters referred to language &#40;English and Spanish&#41; and studies in humans&#44; and eliminating duplicated articles and studies in which &#8220;burns&#8221; was the name of an author&#44; as well as publications not referred to treatment with beta-blockers in burn patients&#44; the total number of articles was reduced to 42&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">A total of 15 randomized clinical trials were identified &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The rest of the articles &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41; were non-randomized clinical trials or studies in which randomization was not specified&#44; cohort studies&#44; review articles&#44; editorials and letters to the editor&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">We also retrieved 7 studies in animals designed to investigate the mechanism of action of propranolol and to evaluate possible alterations in its absorption&#46; These articles were identified from the references cited in the articles found in our PubMed search&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Justification of the use of beta-blockers in burn patients</span><p id="par0065" class="elsevierStylePara elsevierViewall">Endogenous catecholamines are primary mediators in the hypermetabolic response observed in burn patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">2&#44;14</span></a> This systemic response is characterized by hyperdynamic circulation&#44; increased basal energy expenditure&#44; and increased muscle protein catabolism&#46; Blocking of the beta-adrenergic stimulus reduces supraphysiological thermogenesis&#44;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">17</span></a> cardiac work and resting energy expenditure &#40;REE&#41;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Beta-blockers moreover reduce peripheral lipolysis through &#946;2-receptor block&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a> and increase liver efficiency in secreting free fatty acids&#46; Propranolol also has an effect upon lean body mass&#46; On one hand&#44; it improves recycling of the intracellular free amino acids&#44; thus increasing the efficiency of protein synthesis in muscle&#46; These intracellular amino acids derived from protein catabolism are again incorporated to proteins without leaving the muscle cell&#46; On the other hand&#44; propranolol also stimulates the expression of genes involved in muscle metabolism and reduces the activation of genes involved in gluconeogenesis&#44; thereby resulting in a decrease in net catabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">13</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">For these reasons the use of propranolol has been suggested in burn patients&#46; Although most of the existing studies have been carried out in pediatric patients&#44; with confirmation of its beneficial effects&#44; it must be mentioned that the differences in beta-blocker prescription practice among different centers attending pediatric burn patients indicate that this drug has not yet been accepted as standard treatment in the pediatric population&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">19</span></a> The scant information on the effects of the drug in adult burn patients underscores the need for further studies in this population group&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Mechanism of action of propranolol</span><p id="par0080" class="elsevierStylePara elsevierViewall">The cellular mechanisms by which propranolol accelerates muscle protein synthesis are not clear&#46; However&#44; it has been seen that &#946;<span class="elsevierStyleInf">1</span>-agonists such as clenbuterol also promote muscle anabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a> In this section we offer a summarized description of the most recent studies on the effects of propranolol at molecular and genetic expression levels&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The activation of poly-&#40;ADP-ribose&#41; polymerase &#40;PARP&#41; promotes cell energy collapse and cell necrosis&#44; and possibly contributes to the inflammatory responses and cell dysfunction seen in burn patients&#46; Peak activation is observed in the third week after burn injury&#44; and in some cases activation persists even one year later&#46; Muscle biopsy studies have shown PARP activation to occur mainly in the vascular endothelial cells and in some mononuclear cells&#46; However&#44; the muscle biopsies of pediatric patients treated with propranolol show marked suppression of PARP activation&#46; Possibly some of the clinical benefits of propranolol in burn patients are related to this suppressive effect upon PARP activation&#8211;increasing the net protein balance and reducing lean mass catabolism by preventing skeletal muscle necrosis following severe burns&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">It has been seen that pediatric burn patients subjected to treatment with propranolol exhibit increased expression of the genes implicated in muscle metabolism &#40;such as heat shock protein 70 &#91;HSP70&#93; or dynein&#41;&#44; and decreased expression of fructose-1&#44;6-biphosphatase&#44; an important enzyme involved in gluconeogenesis and insulin resistance&#44; as well as of VEGF and other genes&#46; This increase in the expression of genes implicated in muscle metabolism is well correlated to the increase in net protein balance measured by isotopic studies with phenylalanine&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">22</span></a> The administration of propranolol also reduces the expression of genes related to lipid metabolism in adipose tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In murine models it has been observed that burns&#44; through catecholamine release&#44; induce stress response on the part of the endoplasmic reticulum &#40;ER&#41;&#46; This response in turn leads to the activation of c-Jun N-terminal &#40;JNK&#41; kinase&#44; the suppression of insulin receptor signaling via phosphorylation of insulin receptor substrate 1 &#40;IRS-1&#41; and subsequent insulin resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">24</span></a> The administration of propranolol attenuates the ER stress response and the activation of JNK&#46; This implies increased insulin sensitivity&#44; as has been determined by activation of the hepatic phosphatidylinositol 3-kinase&#47;Akt signaling cascade via the phosphorylation of IRS-1&#46; Propranolol therefore has the potential to suppress the hypermetabolic response&#44; preventing hepatic ER stress and increasing insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Another model in rats has shown that burns result in cardiomyocyte activation of mitogen-activated protein kinase &#40;p38 MAPK&#41; and JNK&#44; and translocation of nuclear factor &#40;NF&#41;-&#954;B&#46; These molecules are important in transduction of the signals that induce the biosynthesis of inflammatory cytokines&#46; MAPK participates in cardiomyocyte secretion of TNF-&#945;&#44; which increases the risk of cardiac dysfunction and promotes the nuclear translocation of NF-&#954;B&#44; and consequently the transcription of genes&#46; Alpha-agonists also increase the activity of p38 MAPK and JNK&#46; However&#44; beta-agonists have no effect in this animal model&#46; Alpha-antagonists inhibit the burn-mediated activation of p38 MAPK and JNK&#44; and the translocation of NF-&#954;B&#44; though these phenomena are curiously also inhibited by beta-blockers&#46; This may be due to propranolol-mediated inhibition of the phospholipase D pathway&#44; which activates MAPK&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Dosing of propranolol</span><p id="par0105" class="elsevierStylePara elsevierViewall">When used at adequate doses&#44; propranolol is effective in reducing the resting heart rate &#40;HR&#41; by 15&#8211;20&#37; of the HR recorded upon admission&#46; However&#44; neither the propranolol dose needed to achieve this decrease in HR nor the pharmacokinetics of the drug in the burn population is precisely known&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Some studies in pediatric patients have used initial doses of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day &#40;0&#46;33<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4<span class="elsevierStyleHsp" style=""></span>h or 0&#46;5&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;6<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; followed by increments until achieving a decrease in HR of 20&#37; with respect to the basal HR<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">28&#44;29</span></a>&#8211;with mean doses of 6&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day at the end of hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> In a randomized prospective trial in children&#44; Williams et al&#46; determined the dose per kg body weight of oral propranolol required to achieve adequate attenuation of cardiac work&#46; They also studied the kinetics of the drug&#46; Propranolol dosing was started as 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day via the enteral route &#40;every 6<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; and was adjusted to reduce the HR by 15&#8211;20&#37;&#46; The treatment was started once the patients were stabilized with fluids&#44; about 24&#8211;72<span class="elsevierStyleHsp" style=""></span>h after admission&#46; The initial dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day was enough to lower the HR by 10&#8211;15&#37;&#44; but had to be increased to 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day in order to achieve and maintain a HR decrease of 15&#37;&#46; There were no differences in dose requirement according to patient&#39;s age or gender&#46; However&#44; on comparing the patients according to burned body surface&#44; those patients with 60&#8211;80&#37; burns required doses of between 4 and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; while those with burns affecting less than 60&#37; or more than 80&#37; of the body surface required a dose of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; The effective therapeutic propranolol concentration was 50<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; The peak drug levels were reached 30<span class="elsevierStyleHsp" style=""></span>min to 1<span class="elsevierStyleHsp" style=""></span>h after administration in pediatric burn patients&#44; with trough levels within 1&#8211;2<span class="elsevierStyleHsp" style=""></span>h&#46; The half-life of the drug was 4&#8211;6<span class="elsevierStyleHsp" style=""></span>h&#46; Patients with burns affecting 80&#8211;100&#37; of the body surface showed much greater dose variability than the patients with less extensive injuries&#46; A number of factors probably influence such variability&#44; since these patients are in a more critical condition&#44; with greater resuscitation and surgery times that cause delays in the propranolol dose increments&#46; Regarding the pharmacokinetics of the drug&#44; pediatric burn patients usually do not reach adequate drug levels&#44; and require dose escalation either because of tachyphylaxis or due to a maintained hypermetabolic response flow phase&#46; Furthermore&#44; these patients present such intense hypermetabolism that they reach peak levels earlier than expected&#46; In such situations dosing with shorter intervals may be required&#46; The principal metabolite&#44; 4-hydroxypropranolol&#44; is also active and may be more potent than propranolol&#46; This would explain the decrease in HR even with low plasma propranolol concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a> Herndon et al&#46; proposed the use of doses in excess of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; since they produce few adverse effects and a high HR persists&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a> Adults receive a standard dose of 20<span class="elsevierStyleHsp" style=""></span>mg every 6<span class="elsevierStyleHsp" style=""></span>h&#44; with increments as required&#44; though dosing studies have not been made in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding the administration route&#44; Neudeck et al&#46; conducted a study in rats with burns affecting 30&#37; of the body surface&#46; Although the burns resulted in a decrease in the functional intestinal mucosal surface and a drop in glycoprotein-P content&#44; no alteration in propranolol absorption was observed&#46; This may be because propranolol is very lipophilic and is consequently easily absorbed&#46; Moreover&#44; a potential decrease in propranolol absorption could be countered by a lesser efflux of the drug&#44; due to the lower glycoprotein-P content&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Clinical effects of propranolol in burn patients</span><p id="par0120" class="elsevierStylePara elsevierViewall">In 1974&#44; Wilmore demonstrated that catecholamine levels were increased after thermal injury&#44; and that beta-adrenergic block decreased the metabolic rate&#44; HR&#44; ventilation&#47;min and free fatty acids in burn patients&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">14</span></a> In 1987&#44; Wolfe et al&#46; described an increase in substrate &#40;futile&#41; cycles in burn patients&#44; and showed that treatment with propranolol reduces triglyceride-free fatty acid substrate cycles&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">31</span></a> Furthermore&#44; on measuring the rate of appearance of glycerol and palmitate&#44; these authors showed that propranolol also reduces lipolysis in burn patients&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">32</span></a> One year later&#44; Herndon et al&#46; published a study in which adrenergic block was seen to reduce myocardial work in burn patients&#44; maintaining adequate cardiac output and oxygen transport&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">17</span></a> Over the following years it was shown that propranolol reduces the myocardial oxygen demands in burn patients&#44; without affecting oxygen delivery or body oxygen consumption&#44;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">33</span></a> or patient&#39;s capacity to increase energy expenditure in cold environments&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">34</span></a> The number of publications has continued to grow&#44; particularly those of the Galveston group&#44; in relation to the use of this drug in burn patients&#46; In this regard&#44; in 2001 the mentioned group demonstrated that propranolol reduces muscle protein catabolism in pediatric burn patients&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> Further studies have been made on the effects of propranolol in burn patients&#59; indeed&#44; the drug is becoming increasingly popular in this patient population&#46; The results of these studies are summarized below&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In pediatric burn patients&#44; treatment with propranolol results in decreased cardiac work from the second week of treatment&#44; and this decrease is sustained over time&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">18&#44;27&#44;35</span></a> Furthermore&#44; the treated patients have a greater measured stroke volume&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a> Likewise&#44; the decrease in HR persists one year after burn injury if treatment with propranolol is continued&#46; A decrease in heart rate-pressure product of approximately 15&#37; also persists 6 months after injury&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Propranolol also improves skeletal muscle protein kinetics in children&#44; exerting an anabolic effect upon muscle&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> The drug improves the efficiency of protein synthesis&#44; with a lesser loss of lean body mass or the preservation of lean mass&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#44;18&#44;22</span></a> As has been commented&#44; propranolol induces an increase in the intracellular recycling of free amino acids&#44; i&#46;e&#46;&#44; intracellular free amino acids resulting from protein catabolism are reincorporated again to proteins without leaving the muscle cell&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Pediatric patients treated with propranolol for one year experience less accretion of central mass &#40;organs and mesenteric fat&#41; and of central fatty tissue&#46; This is because propranolol reduces the central fat deposits&#44; and is consistent with the findings &#40;described further below&#41; indicating that propranolol reduces mesenteric blood flow and peripheral lipolysis&#46; Furthermore&#44; the treated patients exhibit a greater increase in peripheral lean mass after 6 months of treatment&#46; A minor percentage of the patients lose more than 5&#37; of their bone mineral content and total body mass&#44; compared with untreated patients&#46; Increased bone resistance can also indirectly contribute to improve lean body mass&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Propranolol likewise reduces resting energy expenditure &#40;REE&#41; in pediatric patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#44;18&#44;29</span></a> though the respiratory ratio experiences no significant variations&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a> If the treatment is maintained&#44; the decrease in REE is also more pronounced between two weeks and 6 months after burn injury when compared with untreated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">However&#44; propranolol does not appear to have an effect upon the inflammatory reaction in burn patients&#46; During acute hospital admission&#44; only minor differences have been observed between patients with and without propranolol treatment&#46; Jeschke et al&#46; found no differences in the expression of IL-6&#44; IL-8&#44; IL-10&#44; MCP-1 or MIP-1&#946;&#46; Differences were recorded at a single timepoint in relation to the concentrations of TNF-&#945; and IL-1&#946;&#44; which were seen to be lower in the treated group&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Likewise&#44; no differences have been found between children with and without propranolol treatment in terms of mortality&#44; the duration of hospital stay or multiorgan failure&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a> In any case&#44; detecting differences in mortality in pediatric burn patients would require the conduction of multicenter studies with many patients&#44; since the mortality rate in this population group is 4&#8211;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The net fat balance through the liver is conditioned to the uptake of fatty acids from plasma&#44; the intrahepatic oxidation of fatty acids&#44; and the release of triglycerides bound to very low density lipoproteins &#40;VLDL&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">28&#44;36</span></a> Propranolol reduces the availability of free fatty acids for the liver&#46; By reducing the release of fatty acids from the periphery in burn patients &#40;peripheral lipolysis&#41;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;28</span></a> and reducing splanchnic blood flow&#44; the liver receives a lesser supply of fatty acids&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a> Furthermore&#44; the drug increases the efficiency of free fatty acid conversion to VLDL-bound triglycerides and their release from the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a> Thus&#44; in burn patients propranolol has the beneficial effect of reducing liver fat accumulation&#8211;a frequent problem in patients of this kind&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">23&#44;28&#44;36</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Studies have also been made of the effect of propranolol upon wound healing&#46; Zhang et al&#46; investigated the effect of the administration of the drug upon healing of the partial thickness donor zones in rabbits&#46; In the propranolol group the fractional protein synthesis rate in the wound was found to be greater&#44; with a correlation between the protein synthesis rate and the percentage decrease in HR&#46; In addition&#44; propranolol increased the efficacy of amino acid utilization in wound catabolism for the synthesis of new proteins&#46; The protein depositing rate and the concentrations of free essential amino acids were also greater in the propranolol group&#46; Wound DNA synthesis&#44; the expression of beta-adrenergic receptors&#44; and the expression or activation of signaling cascade targets were not different between the treated and non-treated rabbits&#46; However&#44; the authors indicated that infusion of the drug can result in faster transition from shock condition to flow phase&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">37</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Romana-Souza et al&#46; studied the effect of propranolol &#40;6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day p&#46;o&#46;&#41; in a model of scalding third-degree burns affecting 10&#37; of the total body surface in Wistar rats&#46; Wound healing was found to be better in the treated group&#44; which exhibited a lesser wound area after 63 days of treatment&#46; This group also showed a decrease in local inflammatory response &#40;with lesser inflammatory infiltration&#41;&#44; improved contraction of the wound&#44; greater reepithelization&#44; cell proliferation&#44; granulation tissue formation&#44; collagen accumulation&#44; myofibroblast density&#44; and nitrite and metalloproteinase-2 levels&#44; together with a lesser vessel density&#46; Treatment with propranolol appeared to stimulate the development of less vascularized and more organized collagenous granulation tissue&#46; The authors suggested that many of these effects were attributable to nitric oxide synthesis stimulated by propranolol&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">38</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Mohammadi et al&#46; conducted a randomized&#44; double-blind clinical trial in adult burn patients with or without propranolol treatment&#46; In their series the patients were treated with delayed graft covering until the appearance of clean granulation tissue&#46; The patients started treatment with propranolol at a dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day p&#46;o&#46;&#44; followed by gradual elevation to 1&#46;98<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; adjusting the dose in order to lower the HR by 20&#37; of the basal HR in each patient&#46; The authors evaluated the time from admission to epithelization or preparation for skin grafting&#44; as clinical indicators of burn healing time&#46; The patients in the propranolol treatment group showed faster epithelization and a shorter time to graft bed suitability&#46; Furthermore&#44; the administration of propranolol reduced the size of the burn surface finally requiring grafting&#44; as well as the duration of hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">39</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Beta-blockers prevent memory reconsolidation&#44; and have been administered to patients exposed to traumatic effects in order to prevent post-traumatic stress syndrome&#46; However&#44; the studies in this regard among children and adults have not shown beta-blocker administration to reduce the incidence of post-traumatic stress syndrome or acute distress disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">40&#44;41</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Some studies have related beta-blockers to worsening of the benefits of training in non-burn patient populations&#46; No such effect has been observed in pediatric burn patients&#44; however&#46; Porro et al&#46; evaluated the effects of a 12-week aerobic exercise and resistance program in children over 7 years of age with burns affecting more than 30&#37; of the total body surface and treated or not treated with propranolol&#46; The authors recorded an increase in muscle resistance &#40;by 50&#37;&#41;&#44; lean body mass and peak VO<span class="elsevierStyleInf">2</span> &#40;oxygen consumption&#41; in both groups when compared with children not enrolled in the exercise program&#46; The group treated with propranolol moreover showed greater peak VO<span class="elsevierStyleInf">2</span>&#44; possibly as a result of slower capillary blood flow in the muscle&#44; thereby allowing for greater tissue oxygen extraction&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">42</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">There are few studies on the effects of propranolol in adult burn patients&#46; Arbabi et al&#46; published a retrospective study comparing the prognosis of adult burn patients treated with beta-blockers from before admission and with continued treatment during admission versus non-treated burn patients matched for percentage burn surface area and age&#46; The authors identified a total of 21 patients treated with beta-blockers for different reasons &#40;arterial hypertension in 20 cases and migraine in one patient&#41;&#44; and included 42 controls&#46; Most of the patients received treatment with &#946;<span class="elsevierStyleInf">1</span>-antagonists&#44; including metoprolol&#44; esmolol and atenolol&#46; Two patients were treated with labetalol and one with propranolol&#46; Although the patients receiving treatment had a higher prevalence of heart disease and arterial hypertension&#44; they showed lesser mortality &#40;5&#37; versus 13&#37;&#41;&#44; shorter healing times&#44; and a tendency toward shorter stay in hospital and in Intensive Care&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> The improvement in mortality may have been due in part to the cardioprotective effect of the beta-blockers&#46; The authors suggested that a randomized prospective study is needed in order to confirm these findings&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The investigators of the abovementioned study furthermore propose the use of selective &#946;<span class="elsevierStyleInf">1</span>-antagonists such as metoprolol&#44; because they could be used in patients with inhalation syndrome&#44; with a lesser risk of bronchospasm&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">43</span></a> Caution in this respect is required&#44; however&#44; since an increase in mortality has been observed among patients with arteriosclerosis treated with metoprolol during non-cardiac surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">44</span></a> However&#44; the Herndon group recommends the use of propranolol instead of other more selective beta-blockers&#44; since the effect upon lipid metabolism is mediated by &#946;<span class="elsevierStyleInf">2</span>-receptor block&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">16&#44;45</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Effects of jointly administered propranolol and growth hormone &#40;rhGH&#41;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Combined treatment with propranolol and growth hormone &#40;rhGH&#41; has been studied in three clinical trials in children&#46; The first study was a crossover clinical trial in 6 patients administered rhGH and the combination of rhGH and propranolol&#44; during 6 days&#46; As has been commented above&#44; propranolol was seen to decrease peripheral lipolysis and maintained the VLDL-bound triglyceride secretion rate&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">The second clinical trial found no differences between the net protein balance and REE over the short term with the combination treatment or with propranolol alone&#46; This lack of effect of growth hormone is in contraposition to the observations of previous studies&#44; though the authors speculated that it may have been due to the fact that the effects were measured over the short term &#40;10 days&#41;&#46; In this regard&#44; the effects of growth hormone upon the increase in lean muscle mass in pediatric burn patients are seen when the hormone is administered over several months&#46; Furthermore&#44; it is possible that propranolol exerts a greater anabolic effect&#44; or that there is an anabolic ceiling effect already reached when administering propranolol alone&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The most recent clinical trial showed the joint administration of rhGH and propranolol to attenuate the inflammatory cascade and therefore hypermetabolism during the acute phase in pediatric patients&#46; In addition&#44; it avoided the adverse effects of rhGH &#40;hyperglycemia and free fatty acid elevation&#41;&#46; The combination treatment reduced REE and HR&#44; and preserved body mass by reducing the presence of inflammatory mediators such as TNF-&#945;&#44; IL-6&#44; IL-8&#44; MIP-1&#946;&#44; PCR and cortisol&#44; and increasing the levels of IL-7&#44; which stimulates the proliferation of early and mature T cells and B cells&#46; Likewise&#44; the treatment increased total bone mineral density and liver and muscle protein synthesis&#44; and decreased the transaminase &#40;ALT and AST&#41; concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a> However&#44; the mentioned study did not compare the administration of these two drugs in combination versus propranolol alone&#46; The comparisons were made with a group of controls receiving no drug treatment&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Side effects of propranolol in burn patients</span><p id="par0210" class="elsevierStylePara elsevierViewall">The treatment of burn patients with propranolol at doses that lower the HR by 20&#37; with respect to the HR upon admission appears to be safe&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#44;27&#44;28&#44;39</span></a> However&#44; blood pressure monitoring of the treated patients is required&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Few side effects were reported in the study published in 2012 by Herndon et al&#46; on the effects of propranolol in 90 pediatric burn patients treated with the drug during one year&#46; Overall&#44; there were two episodes of bradycardia&#44; one episode of hypoglycemia&#44; one cardiac arrhythmia and two episodes of breathing problems&#46; There were no cases of hypotension&#44; however&#46; Five deaths were documented in the control group &#40;89 patients&#41;&#44; versus four in the active treatment group&#46; There were no significant differences between the two groups in terms of mortality&#44; which was due to sepsis in all the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">A case of colon pseudo-obstruction &#40;Ogilvie syndrome&#41; has been reported in a patient treated with oral propranolol&#46; Conservative management resolved the problem successfully after suspending propranolol&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">47</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Murine studies have reported that non-selective beta-adrenergic block during episodes of septicemia increases mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">48</span></a> However&#44; no differences have been observed in relation to episodes of infection or sepsis&#44; or mortality&#44; between patients with or without propranolol treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">15&#44;29&#44;39</span></a> Moreover&#44; sepsis is characterized by changes similar to those observed in burns&#44; with the development of a catabolic state&#44; increased lipid and glucose metabolism&#44; changes in cardiac output&#44; immune modulating effects&#44; increased REE&#44; hyperglycemia and a loss of muscle mass&#46; The attenuation of this response is associated to lesser mortality&#46; A key mediator of the response to sepsis is the rapid rise in catecholamine levels&#44; with activation of the sympathetic autonomic nervous system&#46; It therefore has been suggested that propranolol could be useful for modulating these responses to sepsis&#44; including a decrease in energy expenditure&#44; inversion of catabolism&#44; reduction of lipolysis&#44; restoration of blood glucose control&#44; and attenuation of the immune suppression caused by catecholamine action&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">49</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Studies in murine models have shown that burn-related sepsis is characterized by sympathetic stimulation that leads to monocytosis&#44; though it suppresses monocyte inflammatory response&#46; Beta-adrenergic block reduces such monocytosis induced by sepsis in burn cases&#46; Furthermore&#44; it increases the percentage of inflammatory monocytes&#44; granulocytosis and the production of TNF-&#945; on the part of the circulating granulocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">50</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Type M1 monocytes &#40;producers of IL-12 but not IL-10&#41; are important effector cells in the first line of antibacterial defense within the context of innate immune responses&#46; However&#44; this subtype is not a manifest in burn patients&#44; which show a predominance of type M2 monocytes &#40;producers of IL-10 but not IL-12&#41;&#44; which in turn inhibits the conversion of resident monocytes to type M1 cells&#46; Specifically&#44; subtype M2b is seen to predominate&#46; The type M2 cells appear after catecholamine binding to beta-receptors of the resident monocytes&#44; and possess a lesser antibacterial capacity&#46; Burn patients treated with propranolol show a greater conversion of resident monocytes to type M1 cells&#46; Since the M1 subtype affords greater resistance to infections produced by <span class="elsevierStyleItalic">Staphylococcus aureus</span> and to the translocation of <span class="elsevierStyleItalic">Enterococcus faecalis</span>&#44; the susceptibility of severe burn patients to such infections could be influenced by treatment with propranolol&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">51</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0240" class="elsevierStylePara elsevierViewall">Most of the studies on the effects of propranolol in burn patients have been carried out in children&#44; with very promising results&#46; Given the enormous potential benefits for adult burn patients&#44; further studies are needed on the effects and dosing protocols of propranolol in this particular population group&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that they have received no financial support or grants for this study&#44; and have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Resumen"
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              "titulo" => "Antecedentes"
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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              "identificador" => "sec0020"
              "titulo" => "Justification of the use of beta-blockers in burn patients"
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            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Mechanism of action of propranolol"
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              "identificador" => "sec0030"
              "titulo" => "Dosing of propranolol"
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              "identificador" => "sec0035"
              "titulo" => "Clinical effects of propranolol in burn patients"
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              "identificador" => "sec0040"
              "titulo" => "Effects of jointly administered propranolol and growth hormone &#40;rhGH&#41;"
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              "identificador" => "sec0045"
              "titulo" => "Side effects of propranolol in burn patients"
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          "titulo" => "Conclusions"
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    "fechaRecibido" => "2014-03-31"
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          "clase" => "keyword"
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          "palabras" => array:3 [
            0 => "Burns&#47;metabolism"
            1 => "Burns&#47;drug therapy"
            2 => "Propranolol&#47;therapeutic use"
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          "clase" => "keyword"
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          "palabras" => array:3 [
            0 => "Quemados&#47;metabolismo"
            1 => "Quemados&#47;terapia farmacol&#243;gica"
            2 => "Propranolol&#47;uso terap&#233;utico"
          ]
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The use of propranolol has been proposed to reduce the hypermetabolic response of patients with burn injuries&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To review the studies published up to December 2013 on the effects of propranolol in burn patients&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A PubMed search was conducted using the terms &#8220;burns&#8221;&#44; &#8220;thermal injury&#8221;&#44; &#8220;beta-blocker&#8221; and &#8220;propranolol&#8221;&#44; with the filters &#8220;human&#8221; and &#8220;English&#8221; and &#8220;Spanish&#8221;&#46; A total of 42 citations were retrieved&#44; 15 of which were randomized clinical trials&#46; The main results are summarized&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Main results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Propranolol at doses adjusted to decrease the heart rate by 20&#37; of the baseline value &#40;4&#8211;6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day p&#46;o&#46;&#41; reduces supraphysiological thermogenesis&#44; cardiac work&#44; resting energy expenditure and peripheral lipolysis&#46; It likewise increases the efficiency of muscular protein synthesis and reduces central mass accretion&#46; Most studies have been conducted in pediatric burn patients&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Propranolol reduces the hypermetabolic response in pediatric burn patients&#46; More studies on its effects in adult burn patients are needed&#46;</p></span>"
        "secciones" => array:5 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Objectives"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Main results"
          ]
          4 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El uso de propranolol se ha propuesto para atenuar la respuesta hipermetab&#243;lica del paciente quemado&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Revisar los estudios publicados hasta diciembre de 2013 que analizan los efectos del propranolol en el paciente quemado&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se aplicaron los t&#233;rminos &#171;burns&#187;&#44; &#171;thermal injury&#187;&#44; &#171;betablocker&#187; y &#171;propranolol&#187;&#44; con los filtros &#171;human&#187; y &#171;English&#187; y &#171;Spanish&#187; en el buscador Pubmed&#46; Se identificaron 42 art&#237;culos de los que 15 eran ensayos cl&#237;nicos aleatorizados&#46; Se resumen los resultados principales de estos art&#237;culos&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados principales</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El propranolol ajustado para lograr una frecuencia cardiaca un 20&#37; menor a la basal &#40;4&#8211;6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#237;a por v&#237;a enteral&#41; disminuye la termog&#233;nesis suprafisiol&#243;gica&#44; el trabajo cardiaco&#44; el gasto energ&#233;tico en reposo y la lip&#243;lisis perif&#233;rica&#46; Aumenta la eficiencia de la s&#237;ntesis proteica muscular y disminuye la acreci&#243;n de masa central&#46; La mayor parte de estudios han sido realizados en ni&#241;os&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">El propranolol aten&#250;a la respuesta hipermetab&#243;lica del paciente quemado pedi&#225;trico&#46; Son necesarios m&#225;s estudios sobre su efecto en la poblaci&#243;n adulta&#46;</p></span>"
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            "titulo" => "M&#233;todos"
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            "titulo" => "Resultados principales"
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            "titulo" => "Conclusiones"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; N&#250;&#241;ez-Villaveir&#225;n T&#44; S&#225;nchez M&#44; Mill&#225;n P&#44; Garc&#237;a-de-Lorenzo A&#46; Revisi&#243;n sistem&#225;tica del efecto del propranolol sobre el hipermetabolismo del quemado&#46; Med Intensiva&#46; 2015&#59;39&#58;101&#8211;113&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anabolic agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticatabolic drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Growth hormone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Beta-blockers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Metformin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">IGF-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Combinations of IGF-1 and IGFBP-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Oxandrolone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Testosterone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Drugs that attenuate the hypermetabolic response in burn patients&#46;</p>"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">FAs&#44; fatty acids&#59; FFAs&#44; free fatty acids&#59; CO&#44; cardiac output&#59; REE&#44; resting energy expenditure&#59; CHs&#44; carbohydrates&#59; i&#46;v&#46;&#44; intravenous&#59; MIP&#44; macrophage inflammatory protein&#59; n&#46;s&#46;&#44; non-significant&#59; MBP&#44; mean blood pressure&#59; PARP&#44; poly-&#40;ADP-ribose&#41; polymerase&#59; rhGH&#44; recombinant human growth hormone&#59; s&#46;c&#46;&#44; subcutaneous&#59; BBS&#44; burned body surface&#59; NGT&#44; nasogastric tube&#59; TGs&#44; triglycerides&#59; p&#46;o&#46;&#44; oral route&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Place of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study objectives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Propranolol dose and route&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Herndon et al&#46; &#40;1994&#41;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the effect of &#946;1 block upon the cardiovascular system and lipid and protein kinetics in burn patients&#8211; To show that the metabolic effects of catecholamines in burn patients are mediated by &#946;2 receptors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16 pediatric patients and adolescents &#40;&#62;40&#37; BBS&#41;&#8211; 8 receive metoprolol&#8211; 8 receive propranolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day i&#46;v&#46;&#44; every 8<span class="elsevierStyleHsp" style=""></span>h&#44; during 5 days&#46; Dose later adjusted for HR 20&#37; less than basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; No significant difference between REE of day 1 and day 5&#8211; Both drugs&#58; decrease in HR and HR-pressure product &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#8211; Propranolol reduces lipolysis&#59; metoprolol does not &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#8211; Neither propranolol nor metoprolol alter protein kinetics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Aarsland et al&#46; &#40;1996&#41;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the effect of propranolol upon peripheral lipolysis in pediatric burn patients receiving treatment with rhGH&#8211; To determine whether there are alterations in VLDL-bound triglyceride secretion rate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cross-over clinical trial in 6 children &#40;third-degree burns &#62;30&#37; BBS&#41;&#8211; 6 patients receive treatment with rhGH and with rhGH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>propranolol&#8211; 6 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 days of combined treatment with rhGH &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day s&#46;c&#46;&#41; and propranolol &#40;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day i&#46;v&#46;&#41;&#46; Dose later adjusted for HR 20&#37; less than basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; rhGH increases release of FFAs in pediatric major burn patients&#8211; Propranolol reduces release of FFAs&#44; but maintains VLDL-bound TG secretion rate &#40;greater efficiency of FFA conversion to VLDL-bound TGs and release from liver&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#8211; No significant difference in REE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Herndon et al&#46; &#40;2001&#41;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">15</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the effect of propranolol upon REE and muscle catabolism in severe burn patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 pediatric patients and adolescents &#40;&#62;40&#37; BBS&#41;&#8211; 13 receive propranolol&#8211; 12 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">After second surgery&#58; propranolol 0&#46;33<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4<span class="elsevierStyleHsp" style=""></span>h through NGT&#46; Dose later adjusted for HR 20&#37; less than basal&#46; Maintained at least 14 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol reduces REE &#40;&#8722;422<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>197<span class="elsevierStyleHsp" style=""></span>kcal&#47;day after 2 weeks &#91;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93;&#41; and lean mass catabolism in pediatric severe burn patients &#40;net muscle protein balance 82&#37; greater than basal &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; versus 27&#37; less in control group &#40;n&#46;s&#46;&#41;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Hart et al&#46; &#40;2002&#41;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether combination treatment with GH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>propranolol exerts additive effects upon the reduction of burn-induced catabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56 pediatric patients and adolescents &#40;&#62;40&#37; BBS&#41;&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#58; rhGH&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#58; propranolol&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#58; rhGH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>propranolol&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#58; controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol 0&#46;33<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4<span class="elsevierStyleHsp" style=""></span>h p&#46;o&#46; Dose later adjusted for HR 20&#8211;25&#37; less than basal&#46; Maintained at least 10 daysrhGH 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day s&#46;c&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Propranolol&#58; accelerates protein synthesis in early hypercatabolic period in pediatric major burn patients&#44; and reduces REE &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#8211; rhGH exerts no additive effect upon muscle protein accretion or REE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Morio et al&#46; &#40;2002&#41;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To quantify components of the splanchnic metabolism of FAs and VLDL-TGs in order to understand the mechanisms underlying fatty liver development in severe burn patients&#8211; To determine whether propranolol can reduce the accumulation of FAs in the liver&#44; over the short and long term&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 adult and pediatric patients &#40;BBS&#62;55&#37;&#41;&#8211; All 8 receive propranolol i&#46;v&#46; in the first study and serve as their own controls&#8211; 4&#58; propranolol 3 weeks&#8211; 4&#58; controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol i&#46;v&#46; &#40;bolus&#58; 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg and then perfusion 0&#46;04<span class="elsevierStyleHsp" style=""></span>&#956;mol&#47;kg&#47;min&#41;Propranolol p&#46;o&#46; 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day every 4<span class="elsevierStyleHsp" style=""></span>h during 3 weeks&#46; Dose later adjusted for HR 25&#37; less than basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Liver fat is stored in burn patients with diet rich in CHs&#44; due to low FA oxidation rate and secretion in form of VLDL-TGs&#8211; Propranolol&#58; reduces availability of FAs and liver storage of TGs &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;&#8211; The effect of propranolol persists after 3 weeks of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Herndon et al&#46; &#40;2003&#41;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the effect of propranolol upon protein metabolism of pediatric burn patients&#8211; To define the genetic and phenotypic events associated to beta-adrenergic block&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">37 pediatric patients and adolescents &#40;BBS &#62;40&#37;&#41;&#8211; 14 receive propranolol&#8211; 23 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">After second surgery&#44; propranolol 0&#46;3&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4&#8211;6<span class="elsevierStyleHsp" style=""></span>h through NGT&#46; Dose later adjusted for HR 10&#8211;15&#37; less than basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Balance between protein synthesis and protein catabolism&#58; &#8722;14&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;9<span class="elsevierStyleHsp" style=""></span>nmol&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>ml in controls&#59; &#43;69&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>34&#46;9<span class="elsevierStyleHsp" style=""></span>nmol&#47;min&#47;100<span class="elsevierStyleHsp" style=""></span>ml in propranolol group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#41;&#8211; Increase of 9 genes implicated in muscle metabolism and decrease of 5 genes implicated in gluconeogenesis and insulin resistance in the propranolol group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Barrow et al&#46; &#40;2006&#41;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether propranolol can be beneficial in pediatric major burn patients by attenuating peripheral lipolysis&#44; portal blood flow and hepatomegalia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98 pediatric patients and adolescents &#40;BBS&#62;40&#37;&#41;&#8211; 44 receive propranolol&#8211; 54 receive placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">After second surgery&#44; propranolol 0&#46;3&#8211;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4&#8211;6<span class="elsevierStyleHsp" style=""></span>h through NGT adjusted for HR 12&#8211;15&#37; less than basal&#46; Maintained until healing of 95&#37; of the surface&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Propranolol prevents or attenuates the increase in weight and liver size in pediatric major burn patients &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#8211; Propranolol reduces the expression of genes related to lipid metabolism in adipose tissue&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Jeschke et al&#46; &#40;2007&#41;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">29</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine the effect of propranolol upon infections&#44; sepsis and inflammation in severe burn patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">245 pediatric patients and adolescents &#40;BBS &#62;40&#37;&#41;&#8211; 102 receive propranolol&#8211; 143 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol 0&#46;5&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;6<span class="elsevierStyleHsp" style=""></span>h enteral route started after 7 days&#46; Intent-to-treat&#58; all administered for at least 3 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; No significant difference between groups in terms of mortality &#40;6&#37; controls&#44; 5&#37; treated&#41;&#44; incidence of infections &#40;30&#37; controls&#44; 21&#37; propranolol&#41; or sepsis &#40;10&#37; controls&#44; 7&#37; propranolol&#41;&#8211; Propranolol&#58; decrease in REE&#44; TNF-&#945; and IL-1&#946; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Jeschke et al&#46; &#40;2008&#41;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether combined treatment with rhGH<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>propranolol improves hypermetabolism&#44; the hepatic acute phase response&#44; and the inflammatory response in severe burn patients&#44; without adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 pediatric patients and adolescents &#40;BBS &#62;40&#37;&#41;&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#58; propranolol<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>rhGH&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#58; controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment started on day 7&#8211;10 of admission with rhGH &#40;0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day s&#46;c&#46;&#41; and propranolol &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;4<span class="elsevierStyleHsp" style=""></span>h&#44; adjusted for HR 10&#8211;15&#37; less than basal&#41;&#46; Treatment maintained for 25 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; REE &#8722;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#37; of predicted value in treated versus 35&#60;<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>20&#37; in controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;Treated group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#58;&#8211; Decrease in C-reactive protein&#44; cortisone&#44; GPT&#44; GOT&#44; FFAs&#44; IL-6&#44; IL-8 and MIP-1&#8211; Increase in IGF-I&#44; IGFBP-3&#44; GH&#44; prealbumin and IL-7&#8211; Without side effects of rhGH alone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Mohammadi et al&#46; &#40;2009&#41;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">39</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shiraz Burn Research Center &#40;Iran&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether propranolol shortens healing time in burn patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">79 patients &#40;16&#8211;60 years&#59; 20&#8211;50&#37; BBS&#41;&#8211; 37 receive propranolol&#8211; 42 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatment started on day 4 of admission with propranolol 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day every 4<span class="elsevierStyleHsp" style=""></span>h enteral route&#44; adjusting for HR 20&#37; less than basal &#40;maximum 1&#46;98<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treated group&#58;&#8211; Shorter superficial burn epithelization time &#40;16&#46;13<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;4 versus 21&#46;52<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;94 days&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41;&#8211; Shorter graft bed preparation time in deep burns &#40;28&#46;23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;43 versus 33&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;17 days&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41; and greater reduction of size of burn area for grafting &#40;treated&#58; mean BBS 31&#46;42&#37; &#8211; require grafting 13&#46;75&#37;&#59; controls&#58; mean BBS 33&#46;61&#37; &#8211; require grafting 18&#46;72&#37; &#91;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#93;&#41;&#8211; Shorter stay &#40;24&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;11 versus 30&#46;95<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;44 days&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#8211; No significant difference in mortality or sepsis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Williams et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">27</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine the propranolol dose that reduces HR by 15&#37; with respect to HR upon admission and improves cardiac function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">340 pediatric patients and adolescents &#40;&#62;30&#37; BBS&#41;&#8211; 125 with propranolol &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80 BBS 30&#8211;60&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33 BBS 60&#8211;80&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12 BBS &#62;80&#37;&#41;&#8211; 215 controls &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>139 BBS 30&#8211;60&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>58 BBS 60&#8211;80&#37;&#59; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18 BBS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>80&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">From 24 to 72<span class="elsevierStyleHsp" style=""></span>h until end of admission&#44; propranolol every 6<span class="elsevierStyleHsp" style=""></span>h via enteral route&#46; Start with 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; Dose later adjusted for HR 15&#8211;20&#37; less than basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Propranolol at dose of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day reduces HR 15&#37; with respect to basal&#46; The dose must increase to 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day the first 10 days in order to maintain the effect &#40;4&#8211;6<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day in the BBS 60&#8211;80&#37; group&#41;&#8211; Effective plasma concentration in pediatric burn patients within 30<span class="elsevierStyleHsp" style=""></span>min &#40;50<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#41;&#46; Half-life&#58; 4<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Kobayashi &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether propranolol reduces M2b monocytes in peripheral blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; First part&#58; 22 pediatric patients &#40;BBS&#62;30&#37;&#41; and 6 healthy volunteers&#8211; Second part&#58; randomization to two groups of 15 patients &#40;8 receive propranolol and 7 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day enteral route during 7&#8211;17 days&#44; starting 2&#8211;5 days after injury&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; M2b&#58; predominate in non-treated pediatric burn patients&#8211; Patients with propranolol&#58; no predominance of M2b &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Olah et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the activation of PARP in burn patients and the effect of propranolol upon such activation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; First part&#58; 16 vastus lateralis muscle biopsies in different burn stages versus 3 cleft palate&#47;lip biopsies in controls&#8211; Second part&#58; 21 patients &#40;0&#8211;17 years&#44; BBS&#62;40&#37;&#41;&#8211; 9 receive propranolol&#8211; 12 do not receive propranolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day enteral route from admission and during 10<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Burn patients showed activation of PARP&#8211; Propranolol&#58; suppresses activation of PARP in the muscle biopsies of the patients &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Herndon et al&#46; &#40;2012&#41;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To determine whether the long-term administration of propranolol improves cardiac function&#44; REE and body composition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">179 pediatric patients and adolescents &#40;BBS&#62;30&#37;&#41;&#8211; 90 receive propranolol&#8211; 89 controls&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol started 3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2 days after admission&#44; at dose required to reduce HR 15&#37; &#40;mean dose 4<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day p&#46;o&#46;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; Low mortality in both groups &#40;5 controls&#44; 4 treated&#41;&#44; without significant differences&#46; All deaths due to sepsis&#8211; Propranolol&#58; few adverse effects &#40;0 hypotension&#44; 2 bradycardia&#44; 1 hypoglycemia&#44; 1 cardiac arrhythmia&#44; 2 respiratory problems&#41;&#8211; Propranolol reduces HR and cardiac work&#46; The drug reduces central body mass and trunk fat&#44; improves lean body mass and bone mineral density &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#8211;0&#46;02&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Porro et al&#46; &#40;2013&#41;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">42</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Shriners Burns Institute &#40;USA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; To assess the effect of aerobic and resistance exercise during 12 weeks together with propranolol treatment in pediatric major burn patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 pediatric patients and adolescents &#40;7&#8211;18 years&#44; BBS<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30&#37;&#41;&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#58; propranolol<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>exercise&#8211; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#58; only exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Propranolol adjusting to reduce HR by 15&#8211;20&#37; versus basal &#40;4&#8211;8<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day p&#46;o&#46;&#41;&#46; Start in first 48<span class="elsevierStyleHsp" style=""></span>h of admission and maintained until end of physical training &#40;within 6 months after injury&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211; 50&#37; increase in muscle strength after training in all children&#8211; Increase in peak O<span class="elsevierStyleInf">2</span> consumption greater in patients with propranolol &#40;36&#37; versus 22&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Physiopathology and particularities of burn patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Effects of propranolol in burn patients or animal burn models&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Primary mediators of hypermetabolic response&#58; catecholamines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-selective &#946;-adrenergic receptor block&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Hyperdynamic circulation and increased cardiac output&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Decreases heart rate and cardiac work&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Increased basal energy expenditure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduces supraphysiological thermogenesis and resting energy expenditure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Increased muscle protein catabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Favors recycling of intracellular free amino acids in muscleStimulates the expression of genes implicated in muscle metabolism and reduces the activation of genes implicated in gluconeogenesis&#44; with reduction of net catabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Increased peripheral lipolysisFat accumulation in liver&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduces peripheral lipolysisIncreases efficiency of liver free fatty acid secretionReduces mesenteric blood flow&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Need for healing of burns and graft donor zones&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increased fractional protein synthesis in woundIncreased efficacy in use of amino acids from wound catabolism for synthesizing new proteinsIncreased protein accumulation and free amino acid concentrations in the woundImproved healing and epithelization&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">In sepsis&#44; increased monocytosis with suppression of inflammatory response of monocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction of monocytosis induced by sepsis in burns&#44; increase in percentage of inflammatory monocytes&#44; granulocytosis and production of TNF-&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Predominance of type M2 monocytes&#44; with lesser antibacterial capacity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Increase in type M1 monocytes&#44; with possibly greater resistance to certain infections &#40;<span class="elsevierStyleItalic">S&#46; aureus</span>&#44; <span class="elsevierStyleItalic">E&#46; faecalis</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:51 [
            0 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Energy expenditure of major burns"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46; Long"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:6 [
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                        "volumen" => "19"
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                        "paginaFinal" => "906"
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            1 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nutrition and metabolism following thermal injury"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46;W&#46; Wilmore"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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Article information

ISSN: 21735727
Original language: English

DOI:10.1016/j.medine.2015.02.003

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2023 August	80	19	99
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2023 June	95	25	120
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2023 March	153	34	187
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2022 December	119	51	170
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2022 October	170	104	274
2022 September	142	85	227
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2021 December	138	121	259
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2021 September	105	63	168
2021 August	106	105	211
2021 July	101	82	183
2021 June	77	70	147
2021 May	82	79	161
2021 April	194	163	357
2021 March	146	84	230
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2021 January	123	70	193
2020 December	128	85	213
2020 November	118	84	202
2020 October	95	96	191
2020 September	110	86	196
2020 August	94	37	131
2020 July	109	39	148
2020 June	103	39	142
2020 May	94	31	125
2020 April	106	27	133
2020 March	99	24	123
2020 February	183	36	219
2020 January	104	55	159
2019 December	90	34	124
2019 November	196	36	232
2019 October	229	37	266
2019 September	124	34	158
2019 August	142	31	173
2019 July	82	33	115
2019 June	108	21	129
2019 May	86	43	129
2019 April	91	15	106
2019 March	112	34	146
2019 February	110	41	151
2019 January	72	29	101
2018 December	159	60	219
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2018 October	87	33	120
2018 September	58	8	66
2018 August	51	14	65
2018 July	45	9	54
2018 June	51	10	61
2018 May	34	5	39
2018 April	55	11	66
2018 March	56	12	68
2018 February	43	11	54
2018 January	41	9	50
2017 December	49	11	60
2017 November	44	10	54
2017 October	47	9	56
2017 September	48	9	57
2017 August	31	14	45
2017 July	55	18	73
2017 June	60	13	73
2017 May	70	16	86
2017 April	67	17	84
2017 March	53	26	79
2017 February	140	14	154
2017 January	58	9	67
2016 December	71	14	85
2016 November	123	17	140
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