a b s t r a c t

Patients with Duchenne muscular dystrophy are living longer and are increasingly seen in Emergency Depart- ments. Though the most common cause of death remains progressive respiratory failure, increased life expectan- cies have unmasked the significance of progressive myocardial dysfunction, now associated with nearly 40% of mortalities in the DMD population. cardiac complications such as arrhythmias and cardiomyopathy are becom- ing ever more widely recognized. Emergency physicians may encounter DMD patients with untreated, undiag- nosed or worsening of known heart disease. This review will initially familiarize the emergency physician with the pathophysiology and lifetime trajectory of care for these patients before describing specific emergency de- partment evaluation and treatment.

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1. Introduction to Duchenne muscular dystrophy in the emergency department

Longitudinal, multidisciplinary care has improved over time for many patients with complex and rare medical conditions. As a result of these successes emergency physicians are now challenged to deliver an unprecedented degree of disease specific care. Duchenne muscular dystrophy (DMD) represents an example of this construct. Patients with DMD are living longer and are increasingly seen in Emergency De- partments [1,2].

This review will initially familiarize the emergency physician with the pathophysiology and lifetime trajectory of care for these patients before describing specific emergency department evaluation and treat- ment. Phases of DMD care that are important for all emergency physicians to consider are worsening Respiratory insufficiency and symptomatic heart failure. A brief review of each phase is followed with suggested history, physical and diagnostic studies assessing the likelihood that heart failure is contributing to the presenting symptoms.

1. Background

Muscular dystrophy refers to a group of Genetic disorders which cause primary myopathies, and often lead to progressive muscle loss

* Corresponding author at: Department of Emergency Medicine, University of Virginia, PO Box 800699, Charlottesville, VA 22908, United States of America.

E-mail address: [email protected] (W.A. Woods).

and increased weakness over time [3]. Of these, Duchenne muscular dystrophy is the most common and most studied. Historically most chil- dren with DMD died from respiratory insufficiency. Treatment with chronic steroids [4] and non-invasive ventilation [5] have substantially increased the median survival of boys with DMD by nearly a decade, with most now living to their late 20’s. Current multidisciplinary recom- mendations typically recognize the different functional status of pa- tients ranging from ‘ambulatory stage’ to ‘early non-ambulatory’ to ‘late non-ambulatory stages’ [6,7]. Progressive weakness, acute infec- tion, progressive kyphoscoliosis and swallowing dysfunction may im- pact acute respiratory support needs. Though the most common cause of death remains progressive respiratory failure, increased life expec- tancies have unmasked the significance of progressive myocardial dys- function, now associated with nearly 40% of mortalities in the DMD population [8]. Cardiac complications such as arrhythmias and cardio- myopathy are becoming ever more widely recognized. As expected, car- diac involvement will vary by type of MD and by age of presentation [9]. Emergency physicians may encounter DMD patients with untreated, undiagnosed or worsening of known heart disease.

1. Respiratory insufficiency

Patients with DMD uniformly experience chronic, progressive respi- ratory failure. forced vital capacity may plateau then deteriorate as patients enter the non-ambulatory phase of disease [10]. FVC may be limited by neuromuscular weakness, scoliosis and/or increased

https://doi.org/10.1016/j.ajem.2022.07.056

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body mass index. As cough strength decreases, patients are at risk of at- electasis, mucous plugging and/or infectious complications. Further de- terioration may be caused by swallowing difficulty with subsequent aspiration [11]. As patients progress into the late non-ambulatory phase they may initially experience nighttime hypoventilation that can progress through the day. Lifetime respiratory support starts with compliance with recommended the vaccine schedule and early moni- toring and then progresses to cough management, lung volume recruit- ment techniques, and nighttime respiratory support which continues on to full time ventilatory support with or without tracheostomy.

1. Dystrophin-associated cardiomyopathy

While onset of non-invasive ventilator support may be initiated at an average age of 18 years of age, onset of clinical cardiomyopathy is identified at an average age of 14.9 years [12]. The unique fibrosis and infiltrative changes have prompted the term ‘dystrophin-associated car- diomyopathy’ [9] to differentiate from the more common dilated car- diomyopathy. Fibrosis and infiltration can occur within the conducting system leading to predictable electrocardiographic changes [13]. Atrial arrhythmias are most commonly noted, especially as the ejection frac- tion falls below 35% [14].

A patient with chronically compensated heart failure often comes to medical attention during times of intercurrent illness with relative hy- povolemia from decreased intake or increased insensible fluid losses. The challenge for the emergency physician is to suspect and identify heart failure in addition to the primary illness that served as a tipping point for cardiac symptoms. When the emergency physician does sus- pect heart failure, the history, physical and diagnostic evaluation should be directed towards assessing the functional class and determining the perfusion and filling pressure status while keeping in mind the tenuous respiratory status of this population.

Symptoms of heart failure in adolescents without neuromuscular disease commonly include fatigue, exercise intolerance and gastrointes- tinal symptoms. It may be less common to note palpitations, chest pain, peripheral edema or ascites than is commonly noted in adults [15]. The challenge of identifying heart failure in those patients with muscular dystrophy are further complicated where the patient is a wheelchair user. Symptoms may not be evident in those with significant myocardial dysfunction in those in the ‘non-ambulatory’ stage of disease incapable of performing provocative activities such as walking [10].

Classification of patients into their perfusion and filling pressure sta- tus provides an insight into their current hemodynamic status. Perfu- sion may be assessed as either ‘warm’ or ‘cold’ [15]. Those considered ‘cold,’ or having poor perfusion, may demonstrate weakened pulses, hy- potension, tachycardia, cool extremities, irritability or decreased level of consciousness. Filling pressure can be assessed as either ‘wet’ or ‘dry.’ [15]. Those considered ‘wet’ may have tachypnea, hepatomegaly or edema. The ideal state of perfusion and filling pressure is ‘warm and dry,’ while the most concerning is ‘cold and wet.’

1. Emergency department evaluation

Current recommendations for emergency department care focus on early goal setting with patients and families while addressing concerns over lack of familiarity of EM providers with nuances of care for patients with MD [7,16]. Diagnostic evaluation may reveal respiratory symptoms due to slowly increasing fatigue from nighttime hypoventilation, acute respiratory insufficiency, new or worsening heart failure, pneumotho- rax from positive pressure ventilation, infections, Adrenal insufficiency or gastric ulcers due to chronic steroid use, as well as long bone fracture during patient transfer due to decreased mobility.

The following describes the use of history, physical examination and diagnostic studies to assess the risk of heart failure as a component of a patient’s acute presentation.

1. History

Emergency physicians must consider how a patient may describe their symptoms and what that description may suggest when taking a history in a patient with a progressive neuromuscular condition. It is also important to note that approximately 20% of patients with DMD have significant developmental delays (IQ < 70) which may preclude their ability to provide a meaningful history [17], forcing emergency physicians to rely entirely on care providers’ accounts. Providers’ ac- counts will be invaluable as they should be viewed as experts in nuances of care of these patients with complex issues who receive a substantial portion of their care at home. Additionally, the patient’s home neuro- muscular team will often have valuable, detailed information. Historical features to consider in muscular dystrophy include the following:

Fatigue: Fatigue may be associated with worsening heart failure. Further questioning may be required to clarify the patient’s meaning of the term ‘fatigue,’ especially if in the non-ambulatory phase of their illness. Fatigue may also be related to hypoventilation, inadequate sleep or a psychologic manifestation of their chronic disease.

Dyspnea: The words used to describe dyspnea may vary between patients, especially those in the late non-ambulatory stage. Complaints at this stage may be subtle or patients may present with the franticness of air hunger. Any suggestion or complaint of dyspnea must be explored fully as this is typically due to a concerning etiology.

Abdominal pain and back pain: Patients with DMD are at increased risk of vertebral Compression fractures, gastric ulcers, adrenal insufficiency and renal colic which may also present with Abdominal or back pain.

Medication compliance: Medications and compliance with prescribed medications must be reviewed as patients are often taking corticosteroids and cardio-active medications.

• 1. Physical examination

In addition to a physical examination focused on the presenting complaint, an examination of the cardiovascular system is warranted in all patients with muscular dystrophy presenting to the ED to identify findings present in decompensated heart failure. The physical examina- tion may be complicated as these patients are often overweight, have doughy skin or have lower extremity contractures.

Heart rate: Patients with DMD typically demonstrate a resting sinus tachycardia attributed to Autonomic dysfunction [18,19] as it is almost universally present prior to echocardiographic evidence of myocardial dysfunction. Interval worsening, however, could be a sign of progressive myocardial dysfunction and should be thoroughly evaluated [20]. Patients or their families often know baseline vital signs and should be used as a resource in this situation.

Blood pressure: Blood pressure may be much lower in those patients with MD, especially those complying with early, aggressive therapy. Early prophylactic neurohormonal blockade therapy is becoming in- creasing common in this patient population as data demonstrates its ef- ficacy in slowing the rate of myocardial dysfunction and improving long-term survival [21].

Respiratory rate: Respiratory effectiveness diminishes throughout the course of illness due to muscular weakness as well as mechanical features such as kyphoscoliosis. Baseline respiratory rate is often higher at the end of the second decade of life in those with DMD [22].

Extremities and abdomen: It is important for the emergency physi- cian to remember that hepatomegaly may be the only manifestation of Right heart failure–especially in young children. Bedside ultrasound can be used to confirm the physical examination when trying to identify the breadth of the liver edge. While unusual, patients may present with peripheral edema, ascites or anasarca.

• 1. Diagnostic studies

The role and limitations of common diagnostic studies include the following:

Fig. 1. Typical electrocardiogram for a boy with Duchenne Muscular Dystrophy demonstrating normal left ventricular voltages without strain pattern, but large R waves in the early precordial leads without other evidence of Right ventricular hypertrophy or right QRS axis deviation.

Serum electrolytes: Due to chronically diminished muscle mass, serum Creatinine levels are substantially lower than typical age matched patients. In a study assessing renal function in patients with DMD, serum creatinine levels below 0.2 mg/dL were most common while no patient had a level above 0.3 mg/dL in a report of 20 adolescents and young adults [23]. As such, a teenager with DMD and serum creatinine values >0.5 mg/dL should be considered as having severe renal failure. An elevated serum bicarbonate may be noted, suggestive of chronic respiratory insufficiency or nighttime hypoventilation.

Pulse oximetry: In patients with neuromuscular disease hypercarbia

may precede hypoxia so normal oxygen saturation values are not reli- ably reassuring.

Blood gas analysis: Significant CO2 retention is always concerning, but a near normal value of serum CO2 does not exclude a respiratory source for new symptoms [24]. It would be prudent to consider blood gas analysis prior to providing supplemental oxygen to assess the degree of CO2 retention and to consider how supplemental oxygen may impact respiratory drive.

Liver function studies: Liver function studies may be valuable but should be interpreted in comparison to their baseline values as these patients often have stable baseline elevations due to muscle inflamma- tion. Any significant acute elevation in serum liver function studies must be considered as a possible manifestation of heart failure. As is common in young children, passive hepatic congestion from cardiac dysfunction may cause dramatic elevations of AST and ALT levels. Also potentially clouding the picture, gallbladder wall thickening may be visualized on ultrasound in cases of significant venous congestion.

B-type Natriuretic Peptide : Serum BNP or N-terminal pro-B- type naturetic peptide (NT-proBNP) is commonly obtained during the diagnostic evaluation in the muscular dystrophy patient presenting for acute care if there is any consideration of cardiac dysfunction. While the role of an isolated measurement of BNP is debated in the ambulatory evaluation of these patients, an increase (a doubling or up to a log in- crease) from baseline BNP may be the only diagnostic clue to the emer- gency physician when considering worsening heart failure in the MD patient [25-28]. While this may be the most sensitive early diagnostic test available in the ED, the positive and negative predictive value of an isolated result for acute worsening heart failure in DMD are unknown.

Troponin: serum troponin level is of limited value in the diagnostic value of worsening heart failure in patients including those with muscu- lar dystrophy. A series by Spurney et al. lists several cases where tropo- nins were elevated in the absence of acute ischemic disease [29].

Chest radiograph: The chest x-ray can be useful, although difficult to interpret, in assessing acute symptoms in the patient with muscular dystrophy. The presence of kyphoscoliosis or respiratory muscular weakness may make interpretation more challenging since cardiomy- opathy may be inaccurately suggested in the case of kyphoscoliosis or hypoventilation. Hypoventilation may predispose to atelectasis which may be difficult to distinguish from an infectious infiltrate.

Electrocardiogram: While an ECG is important in the evaluation of

any patient with concern for worsening heart failure, a comparison ECG is vital. Care providers should have a copy of prior tracings. Each type of MD patient may have a unique ECG pattern, thus findings may not be specific in assessing the time sensitive nature of the complaint. The classic ECG finding of DMD includes tall R waves with an increased RS ratio in the Right precordial leads with deep, narrow Q waves in I, aVL, V5 and V6 [13]. A new Left bundle branch block was present in 8 of 13 mechanically ventilated DMD patients with acute heart failure [30]. Those with other types of muscular diseases may present with conduc- tion delays and arrhythmias rather than heart failure [9]. Thus, any find- ings suggestive of conduction delay and/or ischemia in a patient with any type of muscular dystrophy should be further evaluated. Note Fig. 1 for an exemplar ECG.

transthoracic echocardiogram: The role of bedside transthoracic echocardiogram by the emergency physician is not clear in identifying

differential diagnoses that may sha”>acute heart failure in patients with muscular dystrophy. Adults with DMD and scoliosis can have challenging acoustic windows [31]. Differ- ent types of muscular dystrophy may have different types of cardio- myopathies. DMD causes an infiltrative process with a decrease in contractility while other forms of muscular dystrophy may cause a more dilated cardiomyopathy [13]. Early cardiology consultation and echocardiography are recommended in an attempt to identify the presence and degree of myocardial dysfunction in these challenging patients [6].

• 1. Differential diagnoses that may share findings of heart failure

Respiratory insufficiency: Patients can have either an acute deterio- ration or more chronic deterioration in Respiratory function. Home use of respiratory support is common in patients as illness progresses. Inad- equate home respiratory support (either duration or intensity of device settings) may lead patients to present with indistinct complaints such as ‘fatigue,’ dyspnea, sleep difficulties (awakenings, hypersomnolence, nightmares) or headaches. Sleeplessness due to insufficient ventilation may be the origin of some of the Nonspecific complaints [7,32].

Worsening of psychiatric illness: Depression is common in patients with DMD, often worsening during events of worsening functional status [33,34]. While worsening depression or anxiety are diagnoses of exclusion, wheelchair bound patients experiencing worsening depression or anxiety may offer indistinct complaints such as ‘fatigue.’ Sepsis versus hypovolemia: Sepsis may be difficult to identify in DMD patients who often have a baseline resting tachycardia and pharmacologically induced hypotension. For patients in the late non- ambulatory phase, goal systolic blood pressures of 80-90 mmHg is com- mon. Additionally, patients with relatively stable cardiac disease may

have worsening failure during episodes of an acute febrile illness.

Arterial vascular events: The risk for stroke is considered elevated in patients with DMD [35] while myocardial infarction has not been demonstrated to be more common.

Venous thromboembolic disease: While the literature notes intermittent references to potential risk of pulmonary embolism in wheelchair bound patients in the late non-ambulatory phase of their illness, there is no convincing reporting of hypercoaguability and/or elevated venous thromboembolic risks in these patients. Additionally, baseline D-dimer levels in patients with muscular dystrophy are unknown.

Adrenal insufficiency: DMD patients on long term glucocorticoid therapy are at risk of acquired secondary adrenal insufficiency. Acute symptoms include dehydration, hypotension, hypoglycemia and/or al- tered mental status, while chronic symptoms can be more general and include fatigue, nausea, vomiting, or abdominal pain [36,37]. Adrenal crisis may be precipitated by infection, surgery or trauma [38]. Acquired secondary adrenal crisis may occur in the absence of hypoglycemia or hyperkalemia.

Fat embolism syndrome: Fat embolism after trauma, including Minor injury, is becoming increasingly recognized in the presence of hypoxia, confusion and/or petechial rash that may initiate rapidly progressing respiratory failure. Reviews have demonstrated cases where fractures were both not identified or identified only after respira- tory and/or neurological symptoms [39,40]. Fractures in these reviews are sometimes dramatic, yet may not have been identified on initial evaluation. The chest computed tomography finding most commonly described is patchy ground-glass opacities with interlobular septal thickening.

1. Emergency department management

Emergency physicians should consider hospitalization for all pa- tients with muscular dystrophy who present to the emergency depart- ment with potentially MD related issues, unless the provider is very confident the patient has a benign, self-limited condition. While

patients with muscular dystrophy have higher ED utilization rates than patients without Pre-existing conditions [2], families are often very comfortable providing substantial care at home thus are less likely to present for low acuity concerns. Emergency physicians should con- sider early consultation to a patient’s neuromuscular team to assist with nuanced guidance and should consider partnering with families for respiratory equipment that patients may consider most effective and comfortable. Caregivers should also know appropriate dosing for stress dose steroids in cases where adrenal crises may be contributing to the current presentation. In these instances, early dosing with stress dose steroids is indicated.

The emergency department treatment recommendations for patients with heart failure in muscular dystrophy do not differ from those in heart failure from other causes [41]. Continuous cardiac moni- toring, including admission for the same, is indicated if there is any suspicion of arrhythmia. Because these patients may not articulate symptoms specific to an arrhythmia, emergency physicians should have a low threshold for admission for monitoring or, at least, consulta- tion with the patient’s specialist.

Escalating non-invasive respiratory support will rarely worsen car- diorespiratory status. Considering the interdependence between lung volume and Pulmonary vascular resistance (PVR), inflating the lungs to functional residual capacity minimizes PVR. Thus, increasing levels of non-invasive respiratory support in the hypoventilating MD patient may offload the right ventricle and improve left ventricular filling. Fur- ther, minimizing respiratory effort significantly reduces left ventricular afterload [42].

Additional therapy follows usual guidelines based upon the perfu- sion and filling pressure status. In the ‘warm’ patient a trial of intrave- nous fluids may be warranted–especially if the clinician considers the acute situation to be due to a relative decrease of intravascular volume due to an intercurrent illness. Pulmonary edema is rare in patients with DMD as diastolic dysfunction is uncommon [13,43], though diure- sis and afterload reduction are options in the patient considered to be ‘wet.’ Afterload reduction in the ED might take the form of milrinone or the continuation of outpatient medications after specialty consulta- tion. Nitrates are not typically indicated in those with heart failure from a childhood etiology. Patients with inadequate perfusion may re- quire rescue with vasoactive infusions, typically epinephrine.

Resuscitation with intubation may be warranted in extreme cases. The risks of intubation of patients with muscular dystrophy range from immediate deterioration to longer term issues of difficulty to wean from ventilatory support. Risks of deterioration during intubation attempts are well documented–especially for those with underlying cardiac dysfunction. Thus, the following principles apply: a priming dose of intravenous fluids should be considered if there is any suspicion that filling pressure is acutely decreased. Epinephrine boluses or infu- sions are always prudent to have immediately available during intuba- tion attempts. Non-depolarizing Neuromuscular blockers are indicated in patients with muscular dystrophy to prevent acute episodes of hyperkalemia [44].

1. Summary

Duchenne muscular dystrophy represents an example of a disease where the clinical evaluation, knowledge of the disease, and thus care in the emergency department is evolving as the long term treatment for condition improves. This review assembles the existing literature and recommendations in a way that describes the nuance and the strategies for considering the presentation, evaluation and disposition of patients with DMD in the ED and also identifies gaps in current un- derstanding. Ideally, principles discussed here will can be applied to pa- tients with Duchenne muscular dystrophy as well as patients with other Rare conditions involving neuromuscular and/or cardiovascular presen- tations.

Source of support: none.

CRediT authorship contribution statement

William A. Woods: Writing – review & editing, Writing – original draft, Conceptualization. William G. Harmon: Writing – review & editing, Writing – original draft. Lauren W. Webb: Writing – review & editing, Writing – original draft, Conceptualization. Grant G. Robinson: Writing – review & editing, Writing – original draft. Michael A. McCulloch: Writing – review & editing, Conceptualization.

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