Pediatric Anesthesia ISSN 1155-5645
ORIGINAL ARTICLE
Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures Leal G. Segura1, Jessica D. Lorenz2, Toby N. Weingarten1, Federica Scavonetto1, Katarina Bojanic3, Duygu Selcen4 & Juraj Sprung1 1 2 3 4
Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA Medical Center Anesthesiologists, Des Moines, IA, USA Department of Pediatric and Neonatology, University Hospital Merkur, Zagreb, Croatia Department of Neurology, Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN, USA
Keywords Becker muscular dystrophy; Duchenne muscular dystrophy; hyperkalemia; hypermetabolism due to defect in mitochondria; rhabdomyolysis; succinylcholine Correspondence Juraj Sprung, MD, PhD, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA Email:
[email protected] Section Editor: Barbara Brandom Accepted 13 July 2013 doi:10.1111/pan.12248
Summary Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are associated with life-threatening perioperative complications, including rhabdomyolysis, hyperkalemia, and hyperthermia. Current recommendations contraindicate use of succinylcholine and volatile anesthetics; however, the latter recommendation remains controversial. Objective: To review the perioperative outcomes of patients with DMD and BMD. Methods: We reviewed records of patients with DMD or BMD who underwent anesthetic management at our institution from January 1990 through December 2011. Results: We identified 47 patients (DMD, 37; BMD, 10) who underwent 117 anesthetic exposures (DMD, 101; BMD, 16). Volatile anesthetic agents were used 66 times (DMD, 59; BMD, 7). One patient with undiagnosed BMD received succinylcholine and developed acute rhabdomyolysis and hyperkalemic cardiac arrest. All other major complications were attributed to the procedure (i.e., large bleeding), to preexisting comorbidities (i.e., respiratory failure, cardiac disease), or to both. Conclusions: Use of succinylcholine in children with dystrophinopathy is contraindicated. These patients have significant comorbidities and are frequently undergoing extensive operations; complications related to these factors can develop, as evidenced by our series. These complications may occur with use of volatile and nonvolatile anesthetics. However, because most of our patients were older than 8 years at the time of surgery, our observation cannot be generalized to younger dystrophin-deficient children.
Introduction Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are rare, X-linked, inherited dystrophinopathies (1 per 3000–3600 male newborns) caused by recessive mutations in the dystrophin gene on the short arm of chromosome X (Xp21). Dystrophin is a large protein, found on the cytoplasmic surface of skeletal muscle cell membranes (Figure 1a); it regulates the integrity of the sarcolemma, the membrane enclosing the striated muscle fibers (1,2). Mutations that result in a © 2013 John Wiley & Sons Ltd Pediatric Anesthesia 23 (2013) 855–864
partially functional dystrophin protein (BMD) or the total absence of dystrophin (DMD) lead to the breakdown of sarcolemma, resulting in myofibril atrophy, necrosis, and fibrosis (Figure 1b–d) (2). These patients have progressive muscle weakness and cardiomyopathy (3). Weakness becomes apparent by age 2 or 3 years, and virtually all patients are symptomatic by age 5. Respiratory muscles are similarly affected, and diaphragmatic weakness leads to recurrent pneumonias and respiratory failure. By age 30, 90% of DMD and BMD patients have cardiac involvement (4). Patients with DMD typically die 855
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(a)
(b)
(c)
(d)
Figure 1 (a) Dystrophin rod domain immunostain from a control (healthy) muscle shows a normal sarcolemmal immunostaining pattern (original magnification 940). (b) Dystrophin immunostain from a Duchenne muscular dystrophy (DMD) specimen shows the complete absence of sarcolemmal staining in muscle fibers, except for three dystrophin-positive (revertant) fibers, which is characteristic of DMD (original magnification 940). (c,d) Sections from a DMD muscle
specimen (Gomori trichrome, original magnification 940). Note the clusters of regenerating fibers with more basophilic, larger nuclei, and prominent nucleoli (panel c), necrotic fibers with pale cytoplasm and indistinct nucleus (panel d), and hypercontracted fibers and significant increase in endomysial and perimysial connective tissue (panels c and d).
by age 30 of cardiac or pulmonary failure, whereas patients with BMD have a longer life expectancy (3). Patients with sex-linked dystrophinopathies may have life-threatening perioperative complications. Triggering agents can induce skeletal muscle tissue breakdown (termed rhabdomyolysis), during which intracellular content is released into the bloodstream, resulting in hyperkalemia, increased serum creatine kinase, and myoglobinuria. The muscle relaxant succinylcholine can induce rhabdomyolysis and hyperkalemic cardiac arrest (1,5), as well as hyperthermic reactions resembling malignant hyperthermia (MH) (5–12). In addition, because volatile anesthetics per se have been implicated in causing rhabdomyolysis (13–16), their use is discouraged (17). However, this recommendation remains controversial (1,5,12). In an editorial, Hopkins (1) commented that ‘if the potent inhalation anesthetics are a major factor, it is surprising that so few cases have been reported’. Other experts have suggested a conservative approach (to use only nontriggering anesthetic agents) because the current literature is insufficient for making definitive statements regarding the safety of volatile anesthetics (12,18). Although some European centers exclusively use nontriggering anesthetics in dystrophin-deficient
patients (19), volatile agents are often used at our institution, which provided us with the opportunity to review the anesthetic management strategies and outcomes in these patients. In addition, we reviewed the relevant literature to gain greater insight into the nature of complications associated with dystrophinopathies.
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Methods This study was approved by the Mayo Clinic Institutional Review Board. The study was performed according to the World Medical Association Declaration of Helsinki. Consistent with Minnesota Statute 144.335 Subd. 3a. (d), we included only patients who provided written authorization for use of their medical records for research (historically, >95% of Mayo Clinic patients) (20). Patient identification We searched the institutional medical record database from January 1, 1990, through December 31, 2011, to identify patients with DMD or BMD. Diagnosis of DMD or BMD required confirmation by genetic evaluation, results from muscle biopsy, or a clinical diagnosis and note by a staff neurologist. We reviewed the medical © 2013 John Wiley & Sons Ltd Pediatric Anesthesia 23 (2013) 855–864
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records to further identify patients with documentation of an anesthetic administered during the study period. Data abstraction Patient characteristics were abstracted from the medical records. In addition to demographic information, we gathered information about the natural clinical course of disease, specifically with regard to pulmonary involvement (21) (as noted by a staff pulmonologist, including results of pulmonary function tests), respiratory insufficiency (e.g., preexisting tracheostomy, respiratory weakness, ventilator, or oxygen dependency), and cardiac involvement (4,22) (cardiomyopathy was determined from echocardiograms and/or cardiologist reports). We noted the type of anesthesia used (general vs. monitored anesthesia care), types of procedures performed, difficulties encountered during anesthetic induction (e.g., difficult airway, defined as trachea intubation with a fiberoptic bronchoscope, or if the medical records noted difficulty), and specific agents used for anesthetic induction and maintenance, with emphasis on volatile vs. nonvolatile agents. We recorded adverse intraoperative events such as cardiac dysrhythmias (including ‘extreme’ tachycardia, defined as heart rate >99th percentile for age (23)) cardiac arrest, hemodynamic instability (defined as need for major inotropic support such as with infusion of phenylephrine, dopamine, epinephrine, etc), and indicators of cardiovascular decompensation (from anesthesiologist or cardiologist notes). Signs of hypermetabolism were defined as hypercarbia (endtidal carbon dioxide >15 mm Hg from baseline mean measurements during the first 30 min after the airway was secured), hyperthermia (core temperature ≥38°C; administration of dantrolene), hyperkalemia (serum potassium >5.5 mM), and rhabdomyolysis (elevated serum and urine myoglobin levels or serum creatine kinase levels). The postoperative course was reviewed for notes or signs of hemodynamic instability, cardiac decompensation, pulmonary complications (including requirement for prolonged intubation or reintubation), other complications (e.g., infections, thrombosis, intensive care unit admissions), and duration of hospital stay. Because previous reports focused on volatile anesthetics and their possible link to complications such as rhabdomyolysis, our data were stratified by volatile vs. nonvolatile anesthetic technique. Only descriptive statistics were used. Literature search The literature search was conducted on Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL from inception through January 2013. All three databases use © 2013 John Wiley & Sons Ltd Pediatric Anesthesia 23 (2013) 855–864
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a controlled vocabulary to describe articles, and the term ‘muscular dystrophy/ies’ is common to all. We used keywords and controlled vocabulary for the associations with anesthesia as follows: ‘preoperative care’, ‘intraoperative complications’, ‘postoperative complications’, ‘expand anesthetic agents/adverse effects’, ‘expand anesthesia/adverse effects’, ‘hyperkalemia’, ‘rhabdomyolysis’, ‘heart arrest’, ‘cardiac arrest’, ‘ventilation support’, and ‘hyperthermia’. The search was limited to human studies with available English-language abstracts. In addition, we reviewed references cited in the identified articles for any additional reports that were not captured by our main search. Results During the study timeframe, 47 patients (DMD, 37; BMD, 10) were identified; they underwent 117 procedures with anesthetics (DMD, 101; BMD, 16). All patients but one were male; the female patient had Turner syndrome (XO karyotype). Patient characteristics are shown in Table 1. The majority of anesthetic exposures (n = 79 [67.5%]) occurred in patients at least 8 years old. Compared with patients with BMD, patients with DMD had more comorbid conditions and higher rates of cardiomyopathy and severe restrictive lung disease. The majority of patients underwent orthopedic procedures, including major spine surgeries (n = 45 [38.5%]) and diagnostic muscle biopsies (n = 19 [16.2%]). Table 2 summarizes surgical, anesthetic, and other intraoperative factors. Volatile anesthetics were used in 66 cases (DMD, 59; BMD, 7). Several patients (5/51 exposed to nonvolatile agents; 10/66 exposed to volatile agents) developed markers of hypermetabolism (e.g., hypercapnia, metabolic acidosis, hyperthermia). However, in each case, hypermetabolism could be attributed to causes unrelated to dystrophinopathy. Cases complicated by metabolic acidosis had undergone major operations characterized by labile hemodynamics (e.g., spine surgery, abdominal exploration in septic patients, heart surgery), and in one patient, it was a consequence of cardiac arrest after succinylcholine exposure. Furthermore, postoperative fever was recorded in 16 patients (31%) who received volatile agents and 5 (15%) who received nonvolatile agents; however, in all instances, fever was linked to an ongoing infection. Nondepolarizing muscle relaxants were used during 56 procedures, with no indication of prolonged paralysis (24). Major perioperative complications occurred in seven patients, four of whom were receiving a volatile anesthetic (Table 3). One patient, a 19-year-old with undiagnosed BMD, received succinylcholine and developed acute rhabdomyolysis with hyperkalemic cardiac arrest. 857
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Table 1 Patient characteristics
Characteristic
Table 2 Surgical, anesthetic, and intraoperative characteristics
Duchenne muscular dystrophy (n = 37)a
Becker muscular dystrophy (n = 10)a
Intravenous Anesthetics (n = 51)a
Volatile Anesthetics (n = 66)a
14 10 7 6 5 3 2 0 4
14 15 12 8 12 3 0 1 1
43 8
66 0
8 6 30 7 3
0 12 46 8 2
– – – – 46
7 39 19 1 27
40 1 11 1 0 22 16 0 5d
21 0 1 11 2 34 10 1 10e
8 0 0 4g 15 4 1 (0–10)
15 1 1 7h 31 3 3.5 (0–11)
CK, creatine kinase. Values are number or median (interquartile range). b One female patient had Turner syndrome. c Underwent 34 procedures. d Underwent 2 procedures. e Underwent 39 procedures. f Underwent 1 procedure. g Only two patients had available laboratory test results.
Type of surgery or procedure Orthopedic Otolaryngologic or oral Muscle biopsy General Spine fusion Cardiovascular Bone marrow biopsy Radiologic Gastrointestinal Type of anesthesia General Monitored care Airway management Spontaneous airwayb Mask anesthesia or laryngeal mask airway Endotracheal tube Preexisting tracheostomy Difficult tracheal intubationc Inhalational agents Halothane Isoflurane Sevoflurane Desflurane Nitrous oxide Intravenous agents Propofol Etomidate Ketamine Thiopental Succinylcholine Nondepolarizing muscle relaxants Intraoperative DETCO2 >15 mmHg Intraoperative temperature ≥38°C Intraoperative metabolic acidosis Intraoperative dysrhythmiaf Extreme tachycardiac Trigeminy Asystole Need for inotrope infusion Intensive care unit admission Perioperative complications Duration of hospital stay, days
Subsequent muscle biopsy confirmed BMD, and the neurology report indicated that despite being considered ‘healthy’, the patient subsequently stated that he experienced ‘weakness throughout [his] life’. Of note, another patient undergoing heart transplantation received succinylcholine uneventfully; however, no measures of serum creatine kinase or serum or urine myoglobin were obtained. A 13-year-old boy with DMD (Table 3, patient 3) had a prolonged spine surgery with an intravenous propofol infusion (200 µgkg 1min 1 for the first 6 h; 100 µgkg 1min 1 for the last 4 h) and had
DETCO2, change in endtidal CO2 concentration. a Values are number or median (interquartile range). b During monitored anesthesia care. c See Methods for definition. d Metabolic acidosis (base deficit ≥ 5 mEql 1; PaCO2
