Perioperative management of children with glycogen storage disease type II—Pompe disease

Pompe disease is a rare metabolic disorder caused by a deficiency of the lysosomal enzyme acid α‐glucosidase. Glycogen accumulation damages skeletal, cardiac, and smooth muscles, causing a progressive and debilitating muscle weakness and cardiomyopathy. As life expectancy has much improved since the introduction of enzyme replacement therapy an increasing number of patients are referred for surgical procedures. Due to the potential cardiopulmonary complications, these patients form a high‐risk group for the anesthesiologist.


| INTRODUCTION
Pompe disease is a metabolic myopathy or lysosomal storage disorder caused by an inheritable deficiency of the lysosomal enzyme acid aglucosidase. Glycogen accumulates progressively in the lysosomes and causes damage to myocytes. Pompe disease presents as a clinical spectrum with a predicted frequency of 1:40 000. The classic infantile form of Pompe disease (1:138 000), represents the most severe end of the spectrum with generalized hypotonia, cardiomyopathy, and respiratory insufficiency as characteristic features. Without enzyme replacement therapy (ERT), these children rarely survive beyond 1 year of age due to cardiorespiratory failure. Patients with nonclassic presentations (1:57 000) may present at any age from early infancy to late adulthood and the course may vary widely. [1][2][3] Symptoms relate to skeletal and respiratory muscle weakness and most of the patients become wheelchair bound or dependent on a respirator at some time in life. Since the diaphragm is also involved pulmonary function in supine position is mostly lower than in upright position. In these patients, the heart is rarely involved. 4 The worldwide introduction of ERT with recombinant human acid a-glucosidase in 2006 has altered life expectancy substantially, providing a therapeutic option for this previously untreatable disease. 5,6 One of the consequences is that these patients are increasingly eligible for surgical procedures, not only procedures related to the disease (insertion of a Port-a-Cath [PAC] for ERT or muscle biopsy) but also common elective surgical and diagnostic procedures. However, its implications for perioperative and anesthesia practice are largely unknown. To date, the anesthetic literature on Pompe disease is limited and knowledge is mainly based on small case series and case reports. [7][8][9][10] In children with the classic infantile form of Pompe disease, fatal perioperative cardiac complications, related to cardiomyopathy, have been described. [7][8][9] The heart is rarely affected in children with nonclassic presentations. 11 In addition, serious pulmonary complications due to respiratory muscle weakness, such as repeated (silent) aspiration and prolonged ventilation, are mentioned for both forms of Pompe disease. [12][13][14] Bulbar weakness leading to dysphagia as described in both children and adults may also contribute. According to a long-term study in children with classic infantile form of disease receiving ERT, these children suffer from facial muscle weakness, reduced pharyngeal and laryngeal sensibility, and dysphagia, making them more vulnerable for postoperative aspiration. 15,16 Enzyme replacement therapy was introduced in the Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands, already in 1999 as part of the first clinical trial performed, applying recombinant human a-glucosidase produced in milk of transgenic rabbits. 5 In this article, we provide an overview of our anesthetic experience in children with Pompe disease since the introduction of ERT in our hospital. We investigated the incidence of perioperative complications and risk factors making a separation between patients with classic and nonclassic presentations, and attempted to make a recommendation regarding the anesthetic and perioperative management of children with Pompe disease.

| MATERIALS AND METHODS
This retrospective cohort study investigated all children diagnosed and/ or treated with Pompe disease in the Erasmus MC-Sophia Children's Hospital, University Medical Centre, Rotterdam, The Netherlands, between 1999 (introduction of ERT in our hospital) and 2015. The medical charts of all Pompe patients who underwent a surgical or diagnostic procedure under anesthesia in this period were screened for general parameters, cardiac status, respiratory status, motor function tests, perioperative parameters, and adverse events. As some patients underwent more than 1 procedure, the analysis has been done on procedure level, with the patient status at the time of every procedure.
General parameters like age at diagnosis, age at time of the procedure, comorbidity, form of disease (classic infantile or nonclassic presentation), and gender were collected. Also age of starting ERT and length of treatment with ERT by the time of the first procedure were collected, as a short duration of ERT and consequently a potential high left ventricular mass index are related to severe cardiomyopathy and hypothetically a higher incidence of cardiac complications during anesthesia. 7

| General parameters
Sixty-five patients with Pompe disease were diagnosed and/or treated in the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands, between February 1999 until January 2015. During this period, 31 patients had no indication to undergo a procedure requiring anesthesia and were therefore excluded. Our final study sample consisted of 34 children who underwent 1 or more surgical or diagnostic procedures, mostly low risk (Table 1). Twenty-one  (Table 2).

| Perioperative parameters
Of the 77 procedures, 71 were performed under general anesthesia.
Six were performed with a local anesthesia technique: 5 diagnostic muscle biopsies with awake caudal anesthesia (2 of these procedures were combined with a local anesthesia for a PAC insertion) and 1 single PAC insertion under local anesthesia. One patient with nonclassic presentation of disease had a tendon release of the foot under general anesthesia, unfortunately exact intraoperative information was missing.
In both forms of Pompe disease, intravenous (IV) induction of anesthesia with propofol was most common. Three children with classic infantile type of disease (6.3%) and 1 child with nonclassic presentation (3.4%) had an induction with ketamine. For maintenance of anesthesia, IV anesthesia with propofol (dose range 3-15 mg/kg/h) was used more commonly in both forms of Pompe disease (Table 3).
Over the years we found a change in the anesthesia technique   Table 4 shows the adverse events that occurred perioperatively.

| Adverse events
One or more adverse events occurred in 13 procedures (16.8%):   We compared for both forms of disease the groups with and without perioperative complications for several relevant parameters, (such as age at start of ERT, cardiac and respiratory status, anesthesia technique used) to determine a possible risk factor for perioperative adverse events (Table 4). However, we could not demonstrate any relationship between these parameters and the occurrence of adverse events in both groups. The study sample was too small for a reliable and definite statistical analysis.

| DISCUSSION
The purpose of this study was to determine the incidence and sever- tion. 14, 17 We advocate to focus on these aspects prior to the initiation of an anesthetic procedure.
Also in healthy children, respiratory complications are the most common adverse events during general anesthesia. A study in 9297 children undergoing surgery, showed an incidence of 15% respiratory adverse events perioperatively. 20 In 10% of the children, a period of desaturation <95% was described. The incidence of perioperative desaturation for children with Pompe disease in this study is higher than in the general pediatric population, even when a different definition of desaturation is taken into account (<90% vs 95%). In our study, the period of desaturation had no further implications for treatment.
Other factors that may have contributed to a better outcome is that we focus on potential signs and symptoms of bulbar muscle weakness, respiratory difficulties, and infections which may increase the risk of aspiration. 15 Preoperative polysomnography is performed when there are doubts. In older children, spirometry in sitting and supine position is performed. All of these measures probably provide an important explanation of our relatively low percentage of complications. Also the fact that children receive a higher dose of ERT in our hospital may have contributed to a better preoperative stability. 23 We did not find a relation with anesthetic technique used

| CONCLUSIONS
The purpose of this study was to determine the incidence and