The impact of contemporary treatments on the perioperative care of children with mucopolysaccharidoses: A case series and review of the literature.

Background: Patients with mucopolysaccharidosis (MPS) present significant perioperative challenges. We aimed to document the perioperative care of children with MPS undergoing anesthesia and to describe the impact of hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) on the anesthetic management of these patients. Methods: We performed a retrospective chart review of patients with MPS anesthetised for surgical or investigative procedures at the Hospital for Sick Children in Toronto between January 2000 and December 2014. Data on MPS treatment, co-morbidities, anesthetic techniques, airway management, post-operative care and perioperative complications were collected. Results: 66 children with MPS underwent 332 anesthetics for 345 procedures. The overall rate of difficult airway was 42%. Of 29 patients with MPS I (Hurler syndrome), 66% were treated with HSCT and 34% with ERT. In those treated with HSCT, 19% had difficult airways, compared with 67% in patients who received neither treatment. 90% of patients with MPS II (Hunter syndrome) had difficult airways. ERT did not improve airway difficulty in MPS I or II patients. 32% of all anesthetics were conducted without airway instrumentation. Direct laryngoscopy, was used in 26% of all anesthetics, the laryngeal mask airway in 26%, fibreoptic bronchoscope in 7%, and video laryngoscope in 5%. Conclusions: Patients with MPS I who have had HSCT are less likely to have a difficult airway compared with those not treated with HSCT. ERT in MPS I and II patients did not alter the incidence of difficult airway. A third of MPS patients underwent anesthesia for diagnostic imaging or minor interventional radiology procedures without airway instrumentation.

The purpose of this study is to document the perioperative care of children with MPS undergoing general anesthesia at our institution, and to describe the impact contemporary treatments of MPS on anesthesia management and outcomes.

Methods
Approval from the Research Ethics Board at the Hospital for Sick Children was obtained for a retrospective analysis of the records of all children diagnosed with MPS between January 2000 and December 2014. Records were reviewed to determine patient demographics, classification of MPS, treatment with HSCT or ERT, perioperative airway management and the incidence of difficult airways. A difficult airway was defined as a reported difficulty with bag mask ventilation or reported difficulty of visualising the larynx, multiple attempts at intubation, the need for intubation aids due to a failure of direct laryngoscopy, or failure to intubate the trachea by a consultant anesthetist. 18 Data retrieved are presented descriptively.

Patient demographic profiles, metabolic therapies and comorbidities
Sixty-six patients underwent 332 anesthetics for 345 surgical or diagnostic imaging procedures. All children had a confirmed diagnosis of an MPS. Patient demographics are summarised in Table 2.

Procedures performed
Of the 332 procedures performed (Table 2), 53% were done on an ambulatory basis, 41% were admitted electively and 6% were emergency procedures. The mean duration of anesthetic for all procedures was 98 minutes (median 75 minutes). The majority of anesthetics were administered for diagnostic imaging (28%) or interventional radiology (17%). Otorhinolaryngoscopic and orthopedic surgery comprised 12% and 8% respectively. (Table 3)
Sixty-seven percent (n = 222) of the anesthetics were maintained with inhalational agents (sevoflurane, isoflurane, desflurane or halothane with or without nitrous oxide) and 33% (n = 109) were maintained with intravenous anesthesia agents, mainly propofol.
Thirty-nine percent (n = 129) of patients did not receive perioperative fluid therapy, 45% (n = 151) received normal saline or Hartmann's solution and 11% (n = 35) received a dextrose containing solution. One patient required blood transfusion.

Airway management
Airway management and incidence of difficult airway is presented in Table 4. The overall rate of difficult airway was 42% (n = 42), and the overall failed intubation rate was 2% (n = 3). 32% of procedures were completed without airway instrumentation (face mask, nasal prongs or regional only). In these cases, patients remained spontaneously ventilating, and anesthesia was maintained with total intravenous anesthesia (propofol) or inhalational agent via face mask. The majority of these anesthetics were for diagnostic imaging or brief interventional radiology procedures.
Of the 29 patients with MPS I (Hurler's syndrome), 16 were treated with HSCT and 7 with ERT, 3 received both ERT and HSCT, and 3 remained untreated. In those treated with HSCT, 19% had difficult airways, compared with 67% in patients who received neither HSCT nor ERT, representing a 72% reduction in airway difficulty. There was no difference in the difficult airway rate in untreated MPS I patients (67%) versus MPS I patients who received ERT (71%). None of the MPS I patients who received both treatments (ERT prior to HSCT) had difficult airways. In 70% of MPS I children, ERT was commenced over 5 years of age, whereas HSCT occurred under 18 months of age in 89% of cases.
Ninety percent of patients with MPS II (Hunter's syndrome) had difficult airways. ERT was not associated with improvement in airway difficulty (100% vs 80%).

Difficult airway management
A total of 28 patients with difficult airways underwent 142 anaesthetics ( Table 5). 29% of these patients underwent anesthesia without airway instrumentation (face mask or nasal prongs). The laryngeal mask airway (LMA) was utilised in 23% of their anesthetics and the remaining 47% of cases were intubated. In this group of patients with difficult airways, direct laryngoscopy was used only 8% of the time. Direct laryngoscopy with assistance occurred in 13% of cases. Assisted direct laryngoscopy included the use of backward, upward and rightward pressure on the larynx, a bougie and/or the two-person technique where one experienced anesthetist performs laryngoscopy and manipulates the larynx externally to achieve the best possible view whilst another passes the endotracheal tube through the vocal cords. The fibreoptic bronchoscope was used 15% of the time. 27% of fibreoptic intubations occurred using the LMA as a conduit for the bronchoscope.
Videolaryngoscopy was used 11% of the time. Videolaryngoscopy was introduced to our institution in 2006. Of note, its use increased proportionately more in the latter years of this study, with 68% of its use being since 2009. Conversely, the number of fibreoptic intubations have declined overtime, with only 32% of fibreoptic intubations occurring after 2009 in this case series.

Postoperative care and perioperative complications
Post-operatively, 45% (n = 150) of children were discharged on the day of surgery, 47% (n = 157) were managed on a general ward, and 8% (n = 25) were managed in a pediatric intensive care unit. The average length of hospital stay was 14 days; however, this was influenced heavily by the cohort of MPS I (Hurler syndrome) patients who were inpatients during their HSCT. Excluding the children with MPS I, the average length of hospital stay was 5 days.
The most frequent intraoperative complications related to the challenging airways so common amongst children with MPS. Of significance, two cases developed laryngospasm (0.6%) and 5 cases whose airways were not instrumented had obstructive breathing (1.5%). Aspiration occurred in one child. Only 2 children received regional anaesthesia without general anaesthesia (spinal anesthetic combined with ilioinguinal block in one and caudal anesthetic in the other). In another case, caudal anesthesia failed and general anaesthesia was induced.
In the postoperative period, complications were similarly minimal with only four children developing airways obstruction requiring intervention in the post anesthetic recovery unit (1.2%). Of note, the most serious morbidity and mortality were as a result of complications HSCT, with two patients developing graft versus host disease. Four children died whilst still inpatients from complications secondary to HSCT (21% of all patients receiving HSCT).

Discussion And Review Of Mps
Patients with MPS have a 25% overall reported rate of difficult airway, and up to 54% and 71% in patients with Hurler's and Hunter's syndromes, respectively. 9 HSCT and ERT appear to slow the progression of MPS, although the benefits of HSCT in patients over 18 months of age are reported to be minimal. 19- 21 We report a 72% reduction of difficult airway in patients with Hurler's syndrome treated with HSCT. Compared to HSCT, ERT did not improve airway difficulty in any of the MPS types, however the impact of ERT administered in infancy remains unknown. Regardless of airway difficulty, almost a third of MPS patients were managed without airway instrumentation, suggesting that spontaneous ventilation in these patients can be safely used whether with inhalational agents or total intravenous anesthesia for non-invasive or minimally invasive procedures.
Where intubation of the difficult airway is required, videolaryngoscopy appears to be succeeding fibreoptic intubations as the first option in securing the airway.
This study has many important limitations. Firstly, it is a retrospective review of data over many years. The reported results are therefore reliant on the accuracy of documentation for example of airway management. However, although documentation of airway management in normal airways may be incomplete, we have found that where difficult airways were encountered, documentation is often very detailed. As MPS as a whole is a relatively uncommon disease, this study is limited by the small numbers of patients available for inclusion. This makes statistical comparisons difficult and less clinically meaningful. Galsulfase (Naglazyme) for MPS VI (Maroteaux-Lamy). 23 Recombinant ERT is administered as a weekly infusion, and has proved to be safe, with minor allergic responses to the infusion being the main side effects. It is indicated as the primary treatment in attenuated MPS I (Scheie syndrome), MPS II (Hunter) and MPS VI (Maroteaux-Lamy), or as an adjuvant to HSCT where it has been shown that administration prior to and after HSCT can improve engraftment. 21,24 Clinical improvement after the use of ERT in MPS I has been demonstrated with a 5.6% increase in pulmonary function, improved left ventricular function (although valve disease remains unchanged), increased functional exercise capacity and activities of daily living.
It is suggested that earlier commencement of ERT further improve outcomes. ERT does not cross the blood brain barrier and therefore does not improve neurological outcomes. 21

Current focus of research includes ERT for MPS III (Sanfilippo) and MPS IV (Morquio) as
well as the potential of intrathecal administration of these drugs to improve neurological outcomes.

Anaesthetic considerations in the Mucopolysaccharidoses
Children with MPS should be managed by a multidisciplinary team with experience in the care of this patient group, and ideally in a hospital with pediatric intensive care facilities. 25 The risks of anesthesia must be carefully considered along with the anticipated benefits of the scheduled procedure and discussed with the child's family. 26 As demonstrated in our case series, patients with MPS who have received early treatment are less likely to present the same clinical challenges as those who remain untreated or received late treatment. They will have reduced risk and perioperative care requirements.
The success of modern treatment options means that many children with MPS will now reach adulthood and present new challenges to a group of clinicians previously unfamiliar with this condition. This will present new challenges and risks, and continued guidance will be required from those with experience in the care of children with MPS.
A preoperative assessment should include evaluation of the child's cardiac and respiratory systems. Respiratory tract infections should be fully treated prior to anesthesia. Evidence of sleep apnoea should be sought including a review of sleep study results if available.
The airway review should also include consideration of the cervical spine. The airway management plan must always anticipate a difficult airway, and an experienced anesthesiologist with appropriate equipment should be available.
Where appropriate, preoperative investigations may include full blood count and electrolytes, chest and cervical spine X-rays, electrocardiogram and echocardiography. and should cervical myelopathy be suspected then it is best evaluated with magnetic resonance imaging. [26][27][28][29][30][31] It is useful to review previous anesthetic records, but progression of any airway and clinical findings is to be expected and the view at direct laryngoscopy may be significantly less favourable with increasing age. As we have found in our study, airway difficulty is significantly reduced in children with MPS I treated with stem cell transplantation. 16,17 Sedative premedication should be used in these children judiciously. An anti-sialogogue may be useful to reduce secretions that may compromise airway management.
Intravenous cannulation may be difficult due their coarse skin and tissue deposits.
The incidence of airway difficulties has been found to be 25%, with failure to intubate in 8% of children with mucopolysaccharidoses. In Hurler syndrome this is even higher, at 54% and 23% respectively. 9 Our study demonstrated a 42% difficult airway rate with a 2% failed intubation rate in a tertiary referral centre staffed by pediatric anesthesiologists familiar MPS. Airway difficulties are due to a combination of factors including airway tissue deposition of glycosaminoglycans, a short, potentially unstable neck, poor joint mobility including the cervical spine and temporomandibular joints, macroglossia and micrognathia. Untreated, and sometimes despite treatment, all of these factors are expected to worsen with age.
Facemasks may not fit appropriately due to their abnormal facial features, and children with MPS often develop airway obstruction on induction. Obstruction may not be relieved by oropharyngeal airways, which may push the enlarged epiglottis downwards causing laryngeal obstruction. Nasopharyngeal airways are difficult to pass due to nasal tissue deposits. Some clinicians have advised forward traction of the tongue. Neck manipulation should be minimised, and where there is known atlanto-axial subluxation as occurs in Morquio syndrome (MPS IV), manual inline immobilisation should be employed. 26,29,32 The laryngeal mask airway has been found to be useful, and may be life-saving, [33][34] however, tissue infiltration in the upper airway can make satisfactory placement difficult. 36 The endotracheal tube size required may be smaller than expected for age, and a range of sizes should be available. 37 The McCoy blade can be useful where an enlarged epiglottis is obstructing the view. Fibre-optic intubation may be useful where cervical spine instability exists or the view at laryngoscopy is poor. 38,39 As we have observed, video laryngoscopy is increasingly used in the airway management of MPS patients. 40 The equipment and staff able to perform emergency tracheostomy should be available. 41,42 Post-obstructive pulmonary oedema has been described in patients with advanced disease. Pre-existing supraglottic obstruction may be compounded by an exacerbation of pre-existing glottic obstruction following tracheal extubation and this may contribute to the development of negative pressure pulmonary oedema. Of note pulmonary oedema can occur some hours after the obstructive event. 43 The timing of extubation should be carefully considered to ensure the patient is fully awake and dexamethasone given prior to extubation may reduce complications.
Postoperative care should take place in a monitored environment (high dependency or intensive care) and humidified oxygen and early physiotherapy are helpful. A multimodal approach to analgesia should occur. Regional anaesthesia may be challenging, but where practical, is a useful adjunct. 44. 45 As the treatment options for this unique group of conditions evolves so will their medical needs. Similarly, as anaesthetic techniques, equipment and safety practices improve so will their perioperative requirements.

Conclusions
In summary, we present a case series of our experience with MPS patients over a 15-year period and review the current medical management of MPS and the challenges posed to anaesthetists caring for these patients. Our findings confirm previous reports of reduced airway difficulty in the MPS population treated with HSCT, although in our series, ERT did not make a difference in the incidence of difficult airway. Patients with MPS I who received HSCT were found to be less likely to have a difficult airway compared with those not treated with HSCT. We report an overall difficult airway rate of 42%, and observed that video laryngoscopy is increasingly used to secure the airway in this population. Despite

Consent for publication: Not applicable.
Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests:
The authors declare that they have no competing interests.
Funding: No funding was required for this study.
Author contributions: GS conceived of the study, formed the study proposal and ethics application, collected and analysed data, and drafted the manuscript. CP prepared the study proposal and ethics application, collected data, drafted and reviewed the manuscript. GW prepared the study proposal and ethics application, collected and analysed data, and drafted and reviewed the manuscript. All authors read and approved the final manuscript.    Fibreoptic bronchoscope 22 15 Video laryngoscope 15 11 Laryngeal mask airway 32 23 Nasal prongs 22 15 Face mask 20 14