Anabolic and anticatabolic agents in critical care

Abstract

Purpose of review

A complex network of hormones and other effectors characterize the hypermetabolic response in critical illness; these mediators work together to induce numerous pathophysiologic alterations. Increased incidence of infection, multiorgan failure, long-term debilitation, delays in rehabilitation, and death result from an inability to meet the prohibitively elevated protein and energy requirements, which occur during illness and can persist for several years. Pharmacologic interventions have been successfully utilized to attenuate particular aspects of the hypermetabolic response; these modalities are a component of managing critically ill patients – including those patients with severe burns. Here, we review recent advances in pharmacologically attenuating the hypermetabolic and catabolic responses.

Recent findings

Propranolol, a nonspecific β-adrenergic receptor antagonist, is one of the most widely used anticatabolic therapies. Oxandrolone, testosterone, and intensive insulin therapy represent anabolic pharmacological strategies. Promising therapies, such as metformin, glucagon-like peptide 1, peroxisome proliferator-activated receptor agonists, are currently being investigated.

Summary

Profound metabolic derangements occur in critically ill patients; this hypermetabolic response is a major contributor to adverse outcomes. Despite the pharmacological therapies currently available to counteract this devastating cascade, future studies are warranted to explore new multimodality agents that will counteract these effects while maintaining glycemic control and preventing unfavorable complications.

INTRODUCTION

Critical illness or injury results in an extensive and persistent hypermetabolic response which drives catabolism far longer than the duration of the initial insult [1]. The hallmarks of this response are supraphysiologic metabolic rates, including profoundly accelerated proteolysis, lipolysis, glycolysis, liver dysfunction, insulin resistance, and loss of total and lean body mass; fatal physiologic exhaustion occurs if this hypermetabolic response is left untreated [2–4]. Mediators of these complex responses are cytokines, acute-phase and constitutive proteins, as well as hormones. All these mediators are altered upon onset of any acute critical illness and remain abnormal for a much more prolonged period of time than previously thought [3,5].

When circulating levels of gluconeogenic hormones, glucagon, cortisol, and catecholamines are elevated in response to critical injury, inefficient liver glucose production is stimulated alongside substantially increased lipolysis, leading to futile substrate cycling [3,4]. Recent studies in critically ill and severely burned patients demonstrate significant derangements in energy-producing and mitochondrial pathways, inclusive of increased gluconeogenesis, glycogenolysis, lipolysis, and elevated glucogenic precursor circulation. Impaired insulin sensitivity and hyperglycemia result, which leads to postreceptor insulin resistance [6,7]. Lactate, the anaerobic glucose oxidation end product, is recycled to the liver to stimulate production of more glucose via gluconeogenic pathways [8]. Significant elevations in serum insulin and serum glucose remain [3], and characteristics of insulin resistance persist for at least 3 years postburn [6].

Lipid metabolism is another significantly altered metabolic pathway as a result of the hypermetabolic response. Lipolysis, characterized by the reduction of triacylglycerol into glycerol and free fatty acids (FFAs), contributes to postburn morbidity and mortality, and also organ infiltration and altered glucose metabolism [9]. FFAs specifically hamper insulin-stimulated glucose uptake [10,11] and, through inhibition of glucose transport, induce insulin resistance [12]. Increased abundance of FFAs, in the context of type 2 diabetes, is predictive not only of the incidence but also of the disease severity[13]. Modulation of plasma FFA concentrations can be the result of hypoalbuminemia or elevations in intracellular FFA turnover, despite increased lipolysis. This is part of the futile cycle involving the generation of FFA from muscle and adipose triglycerides. In general, the anabolic effect of insulin is countered by catabolic hormones causing significant lipolysis, proteolysis, and hyperglycemia [6,7]. In an attempt to fulfill unmet metabolic and energy requirements, the body inefficiently utilizes lipids and proteins after critical illness [6,7]. Additionally, as the body fails to recognize fat as a source of energy, skeletal muscle is utilized as the major obligatory fuel, resulting in substantial muscle protein catabolism [3]. Owing to the extensive depletion of net protein, consequential muscle wasting and loss of body mass occur, ostensibly contributing to reduced strength and an inability to completely rehabilitate [14]. In addition to changes in tissue loss, protein degradation also interferes with cross-leg and whole-body nitrogen balance [8,14]. Hence, protein catabolism is directly associated with elevated metabolic rate [15]. The loss of body mass affects other key processes needed for recovery: a reduction of total body mass by 10% induces immune dysfunction, wound healing is compromised with decreases of 20%, severe infections result from loss of 30%, and a 40% loss becomes fatal [16].

Anabolic and anticatabolic treatment options

Elevations in circulating glucagon, cortisol, and catecholamines perpetuate the extensive alterations in metabolic rate, physiology, and growth observed following critical illness or severe injury. Over the past several decades, the utility of pharmacologic agents to increase anabolism has been studied, including recombinant human growth hormone (rhGH), insulin, the combination of insulin-like growth factor 1 (IGF-1) with IGF-binding protein-3 (IGFBP-3), testosterone, and oxandrolone. A catecholamine surge is a hallmark of critical illness, the effects of which can be circumvented with the administration of propranolol, a nonselective β-adrenergic receptor antagonist. The administration of anabolic or anticatabolic therapies to the critically ill has led to significant decreases in protein catabolism when given in addition to the current standards of care.

Recombinant human growth hormone and insulin-like growth factor 1

Significant improvements in cardiac function, bone mineral content, lean body mass, height velocities, and weight gain result from rhGH administration 0.2 mg/kg via daily intramuscular injection to severely burned children [17,18]. The hepatic acute-phase response is favorably influenced by rhGH as indicated by the increase in serum IGF-1 concentrations in the serum [4,19]. Furthermore, muscle protein kinetics improved, muscle growth is maintained [17,20], time to donor site healing reduces by 1.5 days [21], and cardiac output and resting energy expenditure is decreased [22]. IGF mediates these beneficial effects of rhGH. Relative to healthy controls, serum IGFBP-3 and IGF-1 increased 100% in patients receiving rhGH [21]. However, these findings did not translate well into critically ill adult patients. The results from a prospective, multicenter, double-blind, randomized, placebo-controlled trial of 0.10±0.02 mg/kg body weight rhGH administered to 285 critically ill nonburned patients demonstrated that these relatively high rhGH doses were associated with greater morbidity and mortality [21–23] and hyperglycemia and insulin resistance [21,22]. Further examination of the short-term compared with the long-term administration of rhGH in severely burned children revealed that there was no increased risk of mortality in this patient population [22].

Taking into consideration that the effects of growth hormone are mediated by IGF-1, the infusion of equimolar doses of recombinant human IGF-1 and IGFBP-3 effectively improved protein metabolism without inducing hypoglycemia, such as seen with rhGH administration in catabolic pediatric study participants and adults [21,24,25]. The combination of recombinant human IGF-1 (rhIGF-1) and IGFBP-3 diminishes muscle catabolism and concurrently improves gut mucosal integrity in severely burned children [21,25]. The attenuation of the type 1 and type 2 hepatic acute-phase responses improves ratios of circulating constitutive proteins that modify the hypercatabolic usage of body proteins [25,26]. The administration of IGF-1 alone as an independent therapy should be cautioned against as studies by Langouche and van den Berghe [27] showed that in nonburned, critical care patients, IGF-1 alone lacks efficacy.

Insulin

Insulin remains one of the most extensively studied therapeutic agents, leading to the discovery of novel uses for this hormone. Apart from decreasing blood glucose via mediation of peripheral glucose uptake into adipose tissue and skeletal muscle, or suppressing hepatic gluconeogenesis, insulin also increases DNA replication and protein synthesis via modulating amino acid uptake, increasing fatty acid synthesis, and decreasing proteolysis [28]. Owing to the latter property, insulin is particularly attractive as an antihyperglycemia therapy in severely burned patients in light of the findings that muscle protein synthesis increases, donor site healing accelerates, and lean body mass loss and the acute-phase response each decrease when insulin is administered during acute hospitalization [29–31]. The European multicenter trial Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis found that when administered to patients with severe infections and sepsis, insulin administration did not affect mortality; however, severe hypoglycemia was four-fold higher with intensive insulin as opposed to conventional therapy [32]. Another large multicenter study reported a dramatic increase in serious hypoglycemic episodes with the use of a continuous hyperinsulinemic–euglycemic clamp throughout ICU stay [33]. The gap in knowledge that remains is to determine the ideal target glucose range, although clinical trials to determine ideal glucose levels for ICU and burned patients are underway. Suggestions for reduction of glucose levels to 140 mg/dl or less [34] or to less than 150 mg/dl [35] have been made. For severely burned patients, reductions to 140 mg/dl resulted in decreased morbidity and mortality, whereas attenuation of the hypermetabolic response was seen with blood glucose levels 130 mg/dl or less [36].

Although maintaining a continuous hyperinsulinemic–euglycemic clamp in burn patients is particularly difficult because of the necessity for continuous enteral feeding to maintain euglycemia, the occasional halt in enteral feeding because of daily dressing changes or weekly operations may disrupt gastrointestinal motility and increase the incidence of hypoglycemia [8].

Testosterone, ketoconazole, and oxandrolone

Despite the profound improvements anabolic agents have on improving lean body mass, physical activity is imperative to developing strength [37]. Burn patients have significant reductions in testosterone such that severely burned men have similar concentrations of serum testosterone to women [38]. Exogenous testosterone administration for 2 weeks resulted in a two-fold reduction in muscle protein breakdown and improved net muscle balance and protein synthesis efficiency [38]. Similarly, the antifungal imidazole ketoconazole reduces steroid synthesis by blocking P450-dependent enzyme systems [39,40]. However, in burned children, although cortisol levels were reduced to a normal range for up to 60 days after injury, ketoconazole administration did not impact inflammation, hormone secretion (IGF-1, rhGH, and IGFBP-3), hypermetabolism, organ function, or net protein balance/synthesis [41].

Administration of the testosterone analog oxandrolone leads to increased muscle protein catabolism via improved protein synthesis efficiency [42], better donor site wound healing times, and reduced weight loss [43]. Length of hospital stay resulted from the administration of 10 mg of oxandrolone every 12 h in a prospective randomized study [44]. In a large single-center, prospective, double-blinded, randomized trial, 0.1 mg/kg of oxandrolone administered every 12 h, in an age-independent manner, reduced length of hospital stay, maintained lean body mass, and improved hepatic protein synthesis [45,46]. Compliance with long-term administration of oxandrolone is good because of the oral, and not injected, route of administration. The effects of burn-associated hypermetabolism on body tissues are significantly reduced, leading to significant increases in total body mass, lean body mass, and bone mineral content throughout the 1-year administration period [47]; resting energy expenditure and the rate pressure product were reduced [48], whereas lung function improved [49■] with the 1-year administration of oxandrolone. In a 5-year follow-up study, the improvements in bone mineral content with oxandrolone were found to persist for up to 5 years postburn – despite cessation of oxandrolone treatment 1 year after injury [48]. Children treated with oxandrolone gained greater height percentiles as well. The combination of exercise with oxandrolone was even more effective, leading to greatest efficacy in children between the ages of 7 and 18 years, with significant increases in lean body mass and muscle strength. Duration of administration of oxandrolone directly impacts the outcomes; patients receiving oxandrolone for up to 2 years postburn had significantly greater increases in bone mineral content, bone mineral density, and height velocities compared with control patients. Interestingly, when compared with patients treated with oxandrolone for up to 1 year, those patients in the cohort receiving oxandrolone for 2 years had significantly improved bone mineral density and content [50■■]. Thus, despite the elusive benefits of steroid hormones such as testosterone or ketoconazole, oxandrolone is superior in terms of improving outcomes in severely injured patients.

Propranolol

Propranolol has shown great promise in terms of reversing the effects of injury. Propranolol administration to severely burned patients reduced resting energy expenditure, marked tachycardia, and thermogenesis [4,51,52]. With a reduction in heart rate of 20%, cardiac work decreased significantly [51,52]. Propranolol prevents peripheral lipolysis by blocking the activation of the β-2-adrenergic receptor by catecholamines, which are elevated to supraphysiologic levels postburn [4,51,53,54]. At the same time, a significant decrease in fatty infiltration of the liver occurs with propranolol administration [55]. Decreased skeletal muscle wasting and improvements in lean body mass were found with propranolol administration [51]. Despite the numerous benefits, the mechanisms underlying propranolol administration have yet to be fully elucidated. The efficacy of propranolol may be a result of increased protein synthesis taking place in an environment that promotes reduction in peripheral lipolysis and persistent protein breakdown [56]. Glucose levels, typically elevated in severely burned patients, can be normalized with propranolol administered 4 mg/kg body weight/q24, significantly reducing the amount of insulin needed [52]. Taken together, propranolol is a promising treatment to counteract postburn insulin resistance. The advantages attributed to postburn propranolol administration persist beyond the acute hospitalization period. In patients receiving propranolol for 1 year following burn injury, significant reductions in the percentage of predicted resting energy expenditure and in the percentage of the predicted heart rate were found [57]. Additionally, central mass and central fat accumulation were significantly reduced. Long-term administration of propranolol also improved the accretion of lean body mass and prevented bone loss over the course of 1 year.

Novel agents

In severely injured patients, metformin, a member of the biguanide family, has recently emerged as an alternative therapy for the management of hyperglycemia [58]. Metformin counteracts the major metabolic processes that drive injury-induced hyperglycemia via preventing gluconeogenesis and impaired peripheral insulin sensitivity [59]. In addition, metformin is not typically associated with inducing hypoglycemic events associated with the administration of exogenous insulin [60■■]. A small, randomized study showed the reduction of glucose concentrations and of endogenous glucose production alongside faster glucose clearance with metformin treatment [58]. Metformin increased the muscle protein fractional synthetic rate and improved net muscle protein balance as well [59]. In a recent phase II randomized control trial, metformin administered to adult burn patients demonstrated safety and efficacy and appears to be an alternative to insulin [60■■]. As a replacement for insulin to control blood glucose, metformin is a promising alternative that has proven efficacy for counteracting hyperglycemia and muscle protein wasting in critically injured patients. Despite therapeutic potential and numerous benefits, metformin is associated with lactic acidosis [61]. Metformin-associated lactic acidosis can be avoided by not administering to patients with a potential risk for impaired lactate elimination (such as occurs with renal or hepatic failure) or tissue hypoxia. Caution should be used when administering metformin to subacute burn patients.

Other agents are being trialed as antihyperglycemia agents in severely burned patients, including glucagon-like peptide 1 (GLP-1) and the peroxisome proliferator-activated receptor gamma agonists such as the thiazolidinedione pioglitazone. Cree et al. [62] demonstrated in a prospective, double-blind, placebo-controlled randomized trial that the peroxisome proliferator-activated receptor alpha agonist fenofibrate significantly improved mitochondrial glucose oxidation, increased insulin sensitivity, and reduced plasma glucose. Improved insulin receptor signaling was found in muscle with fenofibrate treatment via greater tyrosine phosphorylation of the insulin receptor 1 after hyperinsulinemic– euglycemic clamp compared with placebo patients [62]. Similarly, exogenous administration of GLP-1 decreases blood glucose by counteracting glucagon, stimulating insulin, and suppressing gastric emptying, which are not associated with hypoglycemia. In a recent study, Deane and colleagues investigated seven mechanically ventilated critically ill patients with no known history of diabetes, and showed that acute exogenous GLP-1 infusion significantly attenuated the glycemic response to enteral nutrition. These results suggest that GLP-1 and/or its analogues may have potential in the management of hyperglycemia in critically ill patients [63,64].

CONCLUSION

Critical illness induces profound metabolic derangements, which are associated with persistent changes that underlie adverse outcome in this patient population. Oxandrolone and propranolol have been shown to have great promise in improving long-term outcomes and reducing catabolism individually. Additionally, other pharmacological treatments have proven successful in attenuating the hypermetabolic response, including IGF and growth hormone (Table 1, Fig. 1). Although maintaining blood glucose levels at 130 mg/dl with intensive insulin therapy reduces mortality and morbidity in critically ill patients, associated hypoglycemic events have led to the investigation of alternative strategies such as metformin and fenofibrate. Nevertheless, additional investigations are warranted in critically ill patients to determine ideal glucose ranges, the safety and efficacy of new therapies, and whether the coadministration of these therapies could yield greater improvements.

Table 1.

Summary of the main effects of various pharmacologic interventions to alter the hypermetabolic response to burn injury

Drug	Inflammatory response	Stress hormones	Body composition	Net protein balance	Insulin resistance/glucose metabolism	Cardiac work
rhGH	Improved	No difference	Improved	No difference	Hyperglycemia	No difference
IGF-1	Improved	No difference	Improved	Improved	Improved	No difference
Oxandrolone	Improved	No difference	Improved	Improved	No difference	No difference
Insulin	Improved	No difference	Improved	Improved	Improved	No difference
Fenofibrate	No difference	No difference	No difference	No difference	Improved	No difference
GLP-1	Unknown	Unknown	Unknown	Unknown	Improved (indirect)	Unknown
Metformin	Improved	Unknown	Unknown	Improved	Improved	Unknown
Propranolol	Improved	Improved	Improved	Improved	Improved	Improved
Ketoconazole	Unknown	Improved	Unknown	Unknown	Unknown	Unknown
rhGH + propranolol	Improved	Improved	Improved	Improved	Improved	Improved
Oxandrolone + propranolol	Improved (preliminary)	Improved (preliminary)	Improved (preliminary)	Improved (preliminary)	Improved (preliminary)	Improved (preliminary)

GLP-1, glucagon-like peptide 1; IGF-1, insulin-like growth factor 1; rhGH, recombinant human growth hormone. Adapted from[20,24–26,42,45,51,53,54,61,63]and previously published in[21].

FIGURE 1.

Pathophysiological alterations in multiple organs after burn trauma.

KEY POINTS.

• A complex network of hormones and other effectors characterize the hypermetabolic response in critical illness, resulting in myriad pathophysiological alterations.

• Presently, propranolol and oxandrolone represent the most efficacious anticatabolic therapies.

• Novel pharmacological approaches have emerged to counteract hypermetabolism and catabolism in burn and critically ill patients, including metformin, GLP-1, and fenofibrate.