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Review Articles

Cardiac Dysfunction in Severely Burned Patients

Current Understanding of Etiology, Pathophysiology, and Treatment

Tapking, Christian*,†,‡; Popp, Daniel*,†,§; Herndon, David N.; Branski, Ludwik K.*,†,§; Hundeshagen, Gabriel; Armenta, Andrew M.||; Busch, Martin; Most, Patrick¶,#,**; Kinsky, Michael P.††

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doi: 10.1097/SHK.0000000000001465
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Abstract

INTRODUCTION

When the body is exposed to extreme environments or endures severe injury, the cardiovascular system is one of the systems most affected. Burns result in microcirculatory disruption leading to extravasation of fluid and protein in burned and non-burned tissues. While fluid resuscitation can restore initial vascular volume loss, substantial capillary leak results in massive edema, especially in large injuries. The initial acute inflammatory response with increased sympathetic activity is critical for the cardiovascular and hemodynamic compensation (1, 2). This is followed by a prolonged hyper metabolic/catecholamine response. Many factors that increase myocardial oxygen demand (e.g., increased heart rate, blood pressure and contractility, anemia) occur in burn patients. The response of the cardiovascular system to burns is manifold. This type of injury leads to decreased cardiac output and compensatory increased heart rate, peripheral resistance, (3, 4) and also a substantial loss in circulating plasma fluid volume, mainly due to increased capillary permeability (5). All of these contribute to reduced or inefficient cardiac function and patient morbidity and mortality (6). It has been over 50 years since Baxter et al. (7) first described burn-induced cardiac dysfunction. Cardiac dysfunction is known to be associated with poorer outcomes in both the adult and pediatric burn population (6).

Extensive burns lead to hypermetabolic states, inflammatory responses, and hemodynamic instability, which in turn contribute to the development of sepsis, multiorgan failure, and increased mortality rates (8). Altered sympathetic beta-adrenergic receptor function post-burn results in a suboptimal cardiac response by increasing oxygen demand and decreasing oxygen supply (9). Elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 have been shown to depress cardiac contractility (10), intracellular calcium currents and induce apoptosis of cardiomyocytes (11). In addition, plasma losses following burns can be in excess of 4 mL per kilogram of body weight per hour in burns greater than 30% of the total body surface area (TBSA) (12). This can result in intravascular hypovolemia, poor circulation, and hypoperfusion of central organs leading to myocardial ischemia and acute renal failure (13).

Factors such as inhalation injury, pulmonary edema, or subsequent acute respiratory distress syndrome with increased pulmonary resistance can cause right ventricular dysfunction due to increased pulmonary artery resistance (14). The mechanism of the burn itself, for example high voltage electrical burns, can also induce cardiac damage with causing conduction abnormalities (15).

All of these factors contribute to slowed isovolumic relaxation, impaired contractility, and decreased compliance of (mainly) the left ventricle (16). Unfortunately, dysfunction persists beyond acute hospitalization and may last for at least 2 years (6). It has been shown that even up to 12 years after burns, pediatric patients had a lower ejection fraction and impaired diastolic function compared with healthy controls (17), suggesting injury at early ages results in remodeling of cardiac tissue over time by yet unknown molecular mechanisms that remain to be characterized.

Since severe burns have a major impact on the human body, the present is a review of the current understanding of cardiac dysfunction following burns as well as the clinical strategies to diagnosing, monitoring, and treating cardiac dysfunction in both the adult and pediatric burn population.

METHODS

A comprehensive literature search of PubMed and Embase databases was performed using synonyms of the following keywords

Burns,” “Burn injury,” “Thermal injury,” “Cardiac dysfunction,” “Cardiovascular dysfunction,” “Myocardial dysfunction,” “Systolic dysfunction,” and “Diastolic dysfunction”. No language or publication date restrictions were applied. Animal and human studies have been included in our review. Articles that were found to be suitable for discussion in this review were furthermore screened for additional articles of interest.

ETIOLOGY OF MYOCARDIAL DYSFUNCTION (GENERAL AND SPECIFIC TO BURNS)

Myocardial ischemia and microvascular dysfunction

Myocardial ischemia occurs due to myocardial ischemia or microvascular dysfunction when myocardial oxygen demand exceeds that of its supply (18). Factors that increase myocardial oxygen demand include myocardial mass, heart rate, blood pressure (afterload), and contractility. Additionally, factors that decrease cardiac oxygen supply are tachycardia, hypoxemia, anemia, hypovolemia, and a decrease in coronary artery patency as well as perfusion pressure (diastolic pressure minus left ventricular end-diastolic pressure) (18). Many of these factors occur in severely burned patients. Most of the Starling forces (hydrostatic pressure in the capillary, hydrostatic pressure in the interstitium, oncotic pressure in the capillary, and oncotic pressure in the interstitium) are altered in burn patients and lead to fluid filtration and relative hypovolemia (19). Increased capillary permeability is usually a later occurrence leading to severe hypovolemia and decreased cardiac output (5). To maintain blood perfusion to vital organs and tissue, the release of catecholamines leads to compensatory increases in cardiac chronotropy (heart rate), inotropy (contractility), bathmotropy (excitability), dromotropy (conduction velocity), as well as systemic vascular resistance (3). The increase in cardiovascular workload and oxygen demand in combination with a hypovolemic state can lead to hypoperfusion of the myocardium and relative myocardial ischemia (8).

Hypermetabolism

The hypermetabolic response to burns is defined by an increase in blood pressure and heart rate, increases in catabolism, body temperature, energy expenditure, muscle wasting, and the release of acute phase reactants (20). A releasing cascade of catecholamines, glucocorticoids, glucagon, and dopamine precedes this response (21). The first phase of the response lasts approximately 2 days and is characterized by decreased cardiac output, oxygen consumption, metabolic rate, and hyperglycemia (22). The second phase reaches a peak 5 days post-burn and results in a continuous rise in catecholamines, cortisol, and other stress mediators, which can persist up to 24 months after the initial burns (21). The response increases concurrently with increasing burn size (23). Even rather small injuries with 15% to 20% TBSA burned can raise metabolism up to 118% to 210% of basal metabolic rate (24). In children, heart rates and cardiac output can reach up to 150% and 180% of their predicted values, respectively (6). The body's response to burns can be detrimental to cardiac tissue and function and could contribute to cardiac cachexia. Therapeutic interventions are aimed at blunting this hypermetabolic response (25). However, the molecular foundation and detrimental changes of the hypermetabolic state at the cardiac epigenome, transcriptome, and proteome have not been characterized yet and may lead to a better understanding of the underlying pathophysiology.

Myocardial depressants

In a state of hypermetabolic shock, numerous myocardial depressants may be circulating throughout the bloodstream. Interleukins 1β and 6, TNF-α and other acute phase reactants, depress cardiac contractility, intracellular calcium currents, and induce apoptosis of cardiomyocytes (11). Certain peptides, like myocardial depressant factor (MDP), are thought to materialize. However, specific characteristics have not been identified in many cases. MDP is likely released from an ischemic pancreas as a result from splanchnic vasoconstriction and pancreatic anoxia in the body's effort to maintain sufficient perfusion to more vital organs (26). One of the functions of MDP is suppressing myocardial contractility (26). Shires et al. identified depolarization of cellular membranes as the main acute change in hemorrhagic shock (27). Baxter et al. (7) reported the presence of a serum myocardial depressant factor of burn shock as early as 1966. Severe burns predispose patients to external infection with pathogen-associated molecular proteins, such as lipopolysaccharide (LPS), which causes further proliferation of interleukins. Moreover, LPS itself has been shown to produce a negative ionotropic effect in rats (28). It remains unknown, which molecular pathways and signaling cascades may bring about detrimental actions of inflammatory cardiac microenvironment in response to burns.

Mechanism of injury (electrical)

Cardiac dysfunction can also occur due to the mechanism of the burn itself. Electrical injuries are rare and account for approximately 5% of all burn center admission in the United States (29) and 20% in low-income countries (30). In electrical burns, the heart can be negatively affected in two ways, direct necrosis of the myocardium and the induction of arrhythmias (31). Electricity can result in focal or diffuse injury to the heart and often causes contraction band necrosis with involvement the myocardium, nodal tissue, conduction pathways and coronary arteries (32). The degree of myocardial injury depends on the voltage, the duration of contact with the source, the pathway through the body and the type of current, however even low currents have been known to cause arrhythmias (32). High voltage injury (> 20,000 volts) is more likely to result in complete cardiac arrest requiring immediate defibrillation, while lower voltage injury may cause only minor arrhythmias that spontaneously return to normal sinus rhythm (33). However, in a retrospective review of 145 patients with electrical injuries (88% low voltage and 12% high voltage), only 3% of the patients experienced cardiac issues such as atrial fibrillation, with a higher frequency of arrhythmias occurring in patients that had high voltage injuries (34). Even continuous electrocardiography (ECG) monitoring of high-risk patients after electrical injury did not show late arrhythmias (15).

Rare case reports of survivors of lightning injuries showed clinical signs of acute myocardial infarction and ischemia with presence of elevated cardiac muscle creatinine kinase isoenzyme and corresponding pathological patterns seen on ECG (35, 36). In a previously healthy pediatric patient who fell victim to a lightning strike, focal myocardial necrosis, myocardial degeneration, and signs of early fibroblastic restructuring were seen on autopsy, findings that are usually related to myocardial infarction and severe anoxia (37).

Myocardial dysfunction

Left ventricular ejection fraction (ratio of stroke volume and left ventricular end-diastolic volume) is a standard parameter for left ventricular systolic function. It is an indicator for the contractile function of the heart, with reduced ejection fraction indicating myocardial depression. Diastolic dysfunction is a reduction in the ability of the left ventricle to relax during the filling phase of the heart (i.e., compliance or stiffness), which causes increased filling pressures, and is referred to as heart failure with preserved ejection fraction (HFpEF). Both can be assessed reliably via transthoracic echocardiography (38). However, it is important to note that both HFrRF and HFpEF entail reduced cardiac output due to a decline in stroke volume (39).

Systolic and diastolic left ventricular function have been identified as predictors for the development of chronic heart failure in non-burn patients (40, 41). However, it is currently unknown to what extent the reduction of cardiac function (i.e., depressed cardiac output) during the acute phase of burns plays in long-term cardiac sequelae.

In patients with septic shock, Rudiger and Singer concluded that functional rather than structural changes are responsible for temporary reduced CO after burns. This is due to the fact that myocardial cell death is rarely seen and only minimal in post-mortem human studies (42). A rat model of burn followed by resuscitation showed prompt myocardial damage as early as 1 h after burn evidenced as cardiomyocyte edema, granular degeneration, and focal hemorrhage (43).

It also has been shown that burn patients with greater than 15% TBSA had elevated cardiac Troponin I levels as early as 3 h postinjury (44). These findings and the elevation of various other cardiac specific biomarkers as mentioned below suggest structural damage early after burns caused also by nonelectrical burns (45). In addition to burn-induced myocardial damage, burn patients are prone to develop sepsis throughout their acute hospital stay which can exacerbate myocardial dysfunction. This “double hit” was reported in an experimental rat model of burn followed by sepsis, where inflammatory response and cardiac injury were both increased (46, 47).

Systemic and pulmonary vascular resistance (SVR and PVR) increase after burns, resulting in increased afterload of the left and right hearts. At cost of higher myocardial oxygen consumption, the left ventricle maintains stroke volume and CO through adrenergic stimulation, whereas the right ventricle has only minimal ability to compensate. Isolated heart studies showed a reduction of contractility after burns resulting in reduced myocardial function due to direct impairment of the myocardium (16, 48). In an experimental animal study, Sugi et al. (49) have shown that a 40% TBSA burn or inhalation injury alone caused reduced contractility. However, this was not seen with carbon monoxide poisoning alone (49).

Studies that investigated resuscitation and cardiac function support prompt and adequate fluid therapy to reduce myocardial dysfunction in burn patients. In an animal burn model without a resuscitation protocol, Cioffi et al. (50) found persistent myocardial depression after burns. To the contrary to most other studies, they also found that immediate adequate resuscitation could fully restore cardiac contraction and compliance. Other studies showed that massive burns over 45% TBSA can cause intrinsic contractile and compliance dysfunction despite early and aggressive volume replacement (16). An animal model with extensive scald burns in sheep showed reduction of 15% CO despite intensive resuscitation (51), suggesting that hypovolemia is only one factor amongst others contributing to myocardial defects early postburn.

MOLECULAR CHANGES

Cytokines

Burns initiate an intense inflammatory reaction including the release of inflammatory mediators. The acute inflammatory response can be both beneficial in the acute phase and detrimental in the long term; overall, though, the inflammatory response leads to myocardial fibrosis and remodeling leading to a dilated cardiomyopathy type picture (52). The inflammatory sequelae consisting of increasing levels of cytokines, free radicals, intracellular calcium as well as activation of the complement cascade may contribute to the clinical picture of cardiac dysfunction (53–55). Although not being specifically isolated, cytokines including TNF-α, Interleukin 1-beta (IL-1β), gut-derived factors from plasma and mesenteric lymphatics, and other neuro-humoral mediators have been shown to reduce contractility and relaxation properties of the heart (56–58).

TNF-α is a cytokine that can be detected in the human body in several cardiac-related diseases/conditions (e.g., congestive heart failure or septic cardiomyopathy), and has been linked to cardiac dysfunction (59) as well as multiple organ dysfunction following burns (60). It is partly released by cardiomyocytes and increased levels can be found following severe burns (61, 62). With increasing levels, TNF-α was shown to depress cardiac contractility and induce programmed cell death (apoptosis) of cardiomyocytes (63). This leads to an overall cardiac depression and decreased ejection fraction and left ventricular contractility (Fig. 1).

Fig. 1
Fig. 1:
Pathomechanisms and current options to treat the hypermetabolic, hyperinflammatory response, and in particular cardiac dysfunction after a major burn.

Many studies have focused on the effect of TNF-α on cardiac function (64). Several recent studies showed synergistic effects between TNF-α and IL-1β (65, 66). In animal models, IL-1β injection following burns led to cardiac depression (67). However, the co-administration of IL-1β, TNF-α and Interleukin 6 resulted in the maximal cardiac dysfunction compared with single administration (10, 68). Maass et al. (10) reported that the increase of IL-1β and TNF-α levels that occurs over the first 24 h after burns was paralleled by a progressive increase in cardiac abnormalities.

Catecholamines

Elevated sympathetic activity can be seen following burns, but is also present after major trauma, cold exposure, infection, shock, or other stresses. Stress may result in the development of cardiovascular abnormalities such as ischemic heart disease, myocardial infarction, or heart failure, depending on the individual predisposition (69). Catecholamines, which are released in large quantities after burns during the course of the stress reaction, maintain the increased metabolic rate and myocardial oxygen demand, which can contribute to ischemia of the myocardium (25). Sustained release of large amounts of catecholamines can be detrimental to cardiomyocytes (70). High levels of catecholamines with the constant activation of beta-adrenergic receptors cause focal degeneration and hypertrophy of the myocardium (71). Kulp et al. (72) have previously shown prolonged elevation of catecholamine levels associated with increases of resting heart rates, cardiac work, and energy expenditures in pediatric burn survivors for more than 3 years after burns. The chronic down-regulation of beta-adrenergic receptors might contribute to the inability to increase heart rate and meet oxygen demand during exercise in the long term (72). Catecholamine levels following burns can increase up to 10-fold, which can promote cardiac stress, leading to severe morbidity and mortality (73). An early work by Minifee et al. (70) in 1989 showed that severely burned patients have largely elevated catecholamine levels, but do not show high cardiac output as it would be expected from healthy patients with sympathetic stimulation. These findings suggest ongoing myocardial suppression in those patients (70).

EARLY VERSUS LATE OCCURRENCE

Burns is a unique form of trauma in that the perioperative period lasts weeks, months or longer, especially with large %TBSA burns that require multiple operations. Comprehensive longitudinal assessment of systolic and diastolic function, during this prolonged period, has not been undertaken. The early burn resuscitation phase, especially in severe burns, is followed by hypermetabolism and catabolism, which can last over a year. Left ventricular diastolic dysfunction has a poor prognosis, despite the presence of “normal” systolic heart function (74). Initial development of diastolic dysfunction is an independent predictor for the development of heart failure, increased mortality, and reduced cardiorespiratory capacity (75). Chronic diastolic dysfunction results in increased sympathetic activity, neuro-inflammatory responses (e.g., renin angiotensin aldosterone system) (76), and pro-inflammatory cytokines and metabolic derangements due to reduced cardiac output. Burn-induced hypermetabolism has been described previously (21) and includes insulin resistance, fatty liver infiltration, muscle loss, poor growth, and overall phenotype similar to cachexia (25).

Duke et al. (77) reported that burns in the childhood may be a predictor for the development of cardiovascular issues later in life. More recently, Hundeshagen et al. (17) showed that severe burns in children have a prolonged impact on cardiac structure and function. Cardiac abnormalities are evident in late adolescence and early adulthood in these patients. Specifically, severe burns in children are associated with myocardial fibrosis, systolic, and diastolic dysfunction and reduced exercise tolerance compared with contemporary controls (17).

CURRENT CLINICAL STRATEGIES

Diagnosis and monitoring

According to the New York Heart Association (NYHA) classification, which is a score from I to IV, heart failure is rated based on whether the patient has symptoms at rest and/or exertion. For example, patients with; Class I, are asymptomatic at rest and during exertion; Class II are asymptomatic at rest, but physical activity is limited; Class III have marked limitation with physical activity; and Class IV are symptomatic at rest and unable to carry out normal activity e.g., climbing a flight of stairs. This method has been widely used to determine progression as well as to define intervention for clinical trials (78). Besides clinical observation, several laboratory parameters and (non-) invasive tools are useful for evaluating cardiorespiratory health.

Biochemical markers

Myocardial cells have been shown to be damaged after burns (4). Most biomarkers of myocardial damage, which were primarily developed for the diagnosis and prognosis of acute myocardial infarction, include cardiac troponin I or T, cardiac myosin light chain 1, or creatine kinase (CK).

While biochemical markers such as CK are not specific to cardiac injuries, cardiac troponin I and T are specific to cardiac muscle. Chen et al. (79) showed that troponin I is detectable during the first 2 days post-burn and again from day 5 onward. Peak values were found between day 7 and 13 post-burn and seem to be associated with early burn wound infection (79). In burn patients, increases in serum troponin I have been found only in patients with large burns greater than 20% TBSA. However, in those large burns, no correlation could be found between troponin levels and total burn size, third-degree burn size, age or delay in resuscitation (44).

However, to date there are no studies that show a relationship between elevated troponin I levels and the extent of myocardial dysfunction. Therefore, in burn patients, troponin I or troponin T can only be used as a non-specific marker for cardiac injury with the former showing a much stronger dependency on kidney function alterations. Inflammatory response initiated by infection leads to the release of mediators such as tumor necrosis factor alpha, interleukins, and others, which can disrupt cell membranes and likely contribute to myocardial injury (80). Horton (44) reported that severe thermal injury is associated with a mild elevation of serum troponin I, but did not correlate with overt cardiac morbidity or mortality.

Brain natriuretic peptide (BNP, also B-Type natriuretic peptide) plays an important role in cardiac homeostasis (81). It is released when the heart chambers are under increased volume or pressure and it serves as a marker for acute and chronic heart failure (82). Lindahl et al. (83) found in their study, that BNP levels in burn patients show a “peak pattern,” where BNP increases constantly until a peak is reached around 1 week after burn in most patients, and declines until post burn day 14. BNP levels correlated with injury severity in the first 2 weeks post-burn. Whereas maximum BNP levels correlated with resuscitation volume within the first 24 h and even more interestingly correlated with length of stay and mortality (83).

On the contrary, de Leeuw et al. (84) have shown that burn patients with higher BNP levels during the resuscitative phase paradoxically received less fluid. While the authors concluded that this could be due to these patients having less capillary leakage resulting in more intravascular fluid and therefore needing less volume infused, it is currently not a well-understood phenomenon. These authors also found that higher BNP levels in combination with low proteinuria levels are negatively associated with injury severity (SOFA scores) and mortality (84).

Invasive (pulmonary artery catheter, transpulmonary thermodilution)

One approach for the monitoring of the severely injured patients in the intensive care unit is via a pulmonary artery catheter (PAC). Continuous observation of the central venous pressure, cardiac output (CO) or cardiac index (CI), systemic vascular resistance index (SVRI), pulmonary capillary occlusion pressure, and oxygen delivery and consumption may be measured using a PAC. While the PAC can be used to assess hemodynamics, its invasive nature reduces its clinical utility (85). Specifically, placement of a PAC into the right heart is an invasive procedure, associated with a high incidence of cardiopulmonary complications (86). A large cohort study of Medicare beneficiaries showed that the overall rates of using PAC are decreasing. Furthermore, improved outcomes compared with other monitoring devices were not shown (87). It was furthermore shown that the use of PAC can increase anticipated adverse events but did not affect mortality or length of hospital stay in patient with congestive heart failure (88, 89).

Transpulmonary thermodilutation (TPTD) is a less invasive alternative for measuring hemodynamic parameters such as CO, CI, and SVRI. Additionally, extravascular lung water index and global end-diastolic volume allow for independent parameters of excess fluid content and preload, respectively, in critically ill patients. Beat-to-beat pulse wave contour provides continuous cardiac output and SVRI determination (PiCCO, Pulsion Medical Systems, Munich, Germany). TPTD has been validated and widely used in different patient populations (e.g., trauma, cardiorespiratory diseases, and burns) (90, 91). Branski et al. (90), using the PiCCO system, reported evidence that hyperdynamic circulation persists throughout the entire intensive care hospital stay following severe burns. The PiCCO system is our standard of care, in pediatrics and adults after severe burns, for monitoring hemodynamics.

Although both of these techniques can provide additional information, they are not standard of care and were not shown to significantly improve patient outcomes.

Noninvasive (electrocardiography/chest radiography/magnetic resonance imaging)

ECG is a noninvasive and the least costly method to assess potential cardiac injury. In a study with 260 people aged 75 to 92, Olesen and Andersen (92) showed that ECG in combination with BNP could be helpful as a first step for detecting left ventricular systolic dysfunction. Specifically, five changes in the ECG: Q-waves (93), atrial fibrillation (94), pace rhythm (95), QRS duration > 120 ms (96), and new onset of a left bundle branch block (97) were associated with impaired left venticular function (92). ECG, however, could be normal despite severe injury, which reduces its specificity in cardiac injury. Continuous ECG monitoring of less extensive burns has not been reported as beneficial. However, the European Resuscitation Council Guidelines for Resuscitation 2010 stated that survivors of electrical injuries of any voltage should have continuous ECG monitoring for the first 24 h, if they experienced a loss of consciousness (98) (reviewers #1 and #2).

While the emergence of high-resolution imaging techniques has evolved over the last decades, chest x-ray remains a common tool to assess progression of acute and chronic cardiopulmonary conditions (99). For example, chest x-ray determination using the cardio-thoracic ratio is predictive of risk of progression in the NYHA class, hospitalization, and the outcome in patients with impaired left ventricular function (100). Chest x-ray, as a widely available technique of low cost and low risk, can be a first approach for the evaluation of cardiac dimensions (99). Most often, in burn patients, chest x-rays are used to evaluate positioning of heart catheters and for primary pulmonary diagnoses, e.g., inhalation injury, pulmonary edema, and pneumonia (101).

Cardiac magnetic resonance imaging (MRI) provides unique image resolution for evaluating cardiac structure, myocardial perfusion, and myocardial viability (102). Cardiac MRI could even be the gold standard for the evaluation of left and right ventricular volumes as well as ejection fractions (103). However, providing a clinical direction in a severely burned patient using MRI is limited due to several logistical and cost issues, especially in the highly acute phase. Therefore, today MRI is mainly used for research purposes rather than in the daily clinical work.

Echocardiography

When distinguishing between cardiac and non-cardiac causes of hemodynamic instability in critically ill patients, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are excellent tools (104). The effectiveness and reliability of echocardiography as a noninvasive method to guide resuscitation efforts and assess cardiac function in critically ill burn patients, has been evaluated in several studies (105, 106). Echocardiography (either TTE or TEE) rapidly provides multiple parameters including atrial and ventricular size, wall thickness, left ventricular systolic function, e.g., ejection fraction, diastolic indices, e.g., early and late peak mitral flow (E and A waves, respectively) as well as other structural abnormalities, e.g., valve competency, shunts, and effusions (Table 1) (107). Guidelines from the American College of Cardiology as well as the European Society of Cardiology state that echocardiography is the single most useful test for the diagnosis of heart failure by obtaining structural abnormalities or systolic and diastolic dysfunction (108). Bobbia et al. (109) recently proposed an automated, TTE-based tool in a porcine hemorrhagic shock model to accurately measure cardiac output. There have been few complete studies examining echocardiography in burn patients. Howard et al. (110) reported that 62% of pediatric patients with severe burns showed evidence of systolic dysfunction during their ICU stay and this was associated with nearly a two-fold increase in hospital stay compared with burn patients without systolic dysfunction. O’Halloran et al. (111) reported that even moderate burns can result in increased left ventricular end systolic diameter 3 months after injury, supporting evidence for either an increase in afterload or reduced contractility. Echocardiography is also advantageous to follow patients over prolonged periods of time. Hundeshagen et al. (17) measured cardiac function and structure and exercise tolerance in young adults who sustained severe burns, 5 to 15 years prior, during their early childhood. Data showed a persistence of systolic and diastolic dysfunction as well as evidence of myocardial fibrosis. Exercise tolerance was reduced in patients with systolic and diastolic function (17). Positive effects of exercise programs on cardiorespiratory fitness were also reported in other studies (112).

Table 1
Table 1:
Parameters of cardiac function in echocardiography (reference values for middle aged men)

MANAGEMENT OF BURN-INDUCED MYOCARDIAL DYSFUNCTION

Current and future therapeutic approaches

Approaches to pharmacologically address the negative sequelae of hypermetabolism, and hypercatabolism along with the surge in catecholamines continue to be studied (113). The use of anabolic and anticatabolic agents show promise in improving the long-term outcome of burn survivors (114) (Fig. 1).

A primary cardiac disturbance, following burns, can be linked to hyper-stimulation of the beta-adrenergic receptors (115). Early studies in severely burned children have shown that beta-adrenergic blockade for 5 days reduces cardiac work, e.g., less tachycardia without affecting the resting energy expenditure (70, 116, 117). Herndon et al. showed that 12-month administration of propranolol, a non-selective β-receptor antagonist, dosed at 4 mg/kg/d significantly reduces cardiac work and resting energy expenditure (118). Furthermore, secondary effects such as bone and muscle loss and insulin resistance appear to be attenuated (119). Propranolol mitigates the actions of plasma catecholamines and reduces the hyperdynamic and hypermetabolic response in severely burned patients (120). Furthermore, the use of β-receptor antagonists after severe burns decreases levels of interleukin-6 and other cytokines, suggesting a pleiotropic nature for these agents, e.g., anti-inflammatory response (121).

Severe burns often lead to insulin resistance. Hyperglycemia critically worsens mortality in burn patients (122). Besides promoting normoglycemia and wound healing, tight control of glucose using insulin infusions can prevent muscle loss and decrease inflammatory cytokine expression and apoptosis in cardiomyocytes (123). On the other hand, burn patients are at increased risk of hypoglycemic events since enteral feeding is often interrupted due to frequent surgeries and dressing changes (20).

Oxandrolone is an oral, synthetic testosterone and has been used in both adult and pediatric burn patients. It was shown that oxandrolone is safe and improves protein kinetics, when administered to severely burned children during the acute stay (124). Furthermore, length of hospital stay is shorter when compared with a control group and controlled for TBSA and age (125). In a follow-up study, Porro et al. reported that severely burned children treated for 12 months with oxandrolone demonstrated improvements in height, bone mineral content, cardiac work, and muscle strength compared with the patients who received placebo (126, 127). Additionally, cardiac output, stroke volume, heart rate, as well as the rate pressure product were significantly lower in the oxandrolone group compared with the control group.

As shown by the work of Tracey et al, one potential therapeutic target to control excessive production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 is the “Cholinergic anti-inflammatory pathway” (128, 129). Acetylcholine, the primary parasympathetic neurotransmitter, inhibits proinflammatory cytokine release from macrophages, (130) and previous work has demonstrated that stimulation of the vagus nerve can prevent damage of cytokine release in models of sepsis, hemorrhagic shock, and myocardial ischemia (130, 131).

Various agonists can dock to the nicotinic cholinergic receptor alpha, expressed by various types of cytokine-secreting cells such as macrophages (132).

Nicotine was shown to be even more potent in inhibiting the production of pro-inflammatory cytokines than acetylcholine. In particular, the nicotinic acetylcholine receptor α-7 subunit was identified as to play an essential role (132, 133).

CONCLUSIONS

In this review, we summarize the etiology as well as the diagnostic and therapeutic options of cardiac dysfunction following severe burns.

Burns frequently result in cardiac depression and dysfunction. Cardiac dysfunction after burns is multifactorial including presence of inhalation injury, inflammatory response, and hypoxia and others. High-voltage electrical burns are especially known to affect the heart. For the continuous hemodynamic monitoring, transpulmonary thermodilution can provide parameters that reflect cardiovascular and resuscitation status. Noninvasive echocardiography provides real-time evaluation of the cardiac structure and function during the acute stay at the intensive care unit as well as in follow-up visits.

The use of biochemical markers could be helpful for the diagnosis of acute cardiac events in burn patients and potentially be used to assess effectiveness of resuscitation. However, these parameters should always be used together with other tools.

Several pharmacologic approaches such as the use of propranolol, insulin or oxandrolone show promise in treating severe burns, not only for recovery of lean body mass and metabolism in general, but also for the cardiac outcome. These agents could lead to a better outcome and rehabilitation, especially in severely burned children.

A comprehensive understanding by all team-members on how burns impair cardiac function as well as how to best stratify burn patients with cardiac dysfunction could lead to better treatment modalities for this specific patient population.

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Keywords:

Burns; cardiac dysfunction; cardiovascular system; diagnosis; pathophysiology

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