Peri‐operative management of a child with ROHHAD‐NET syndrome undergoing neural crest tumour excision

Summary

A nine‐year‐old girl diagnosed with ROHHAD‐NET (rapid‐onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysfunction and neuroendocrine tumour) syndrome was scheduled for excision of a large paravertebral ganglioneuroma under general anaesthesia. Her comorbidities included hypothyroidism, diabetes insipidus and autonomic dysfunction. Intra‐ and postoperative complications included intra‐operative hypotension, long surgical time and prolonged postoperative ventilation. Complete weaning from ventilation was initially unsuccessful and she was ultimately discharged on domiciliary nasal BiPAP therapy. The peri‐operative care of children with this syndrome is challenging due to the involvement of multiple organ systems. In this report, we describe how pre‐operative optimisation, well‐planned intra‐operative management and intensive postoperative care are essential for a favourable outcome.

Introduction

First described by Ize‐Ludlow et al. in 2007, ROHHAD syndrome is rare and presents between the ages of two and seven  years [1]. The symptoms, in order of presentation and as described by the acronym, include rapid‐onset obesity, hypothalamic dysfunction, hypoventilation and autonomic dysregulation. Other less common symptoms include behavioural and developmental abnormalities and seizures. While the clinical features are phenotypically variable, alveolar hypoventilation and rapid onset of obesity associated with hyperphagia are the most common. Association of this syndrome with neuroendocrine tumours led to the addition of the suffix “NET” [2]. The anaesthetic and peri‐operative management of these children is likely to be complex due to the large number of organ systems involved and has been infrequently reported in literature [3, 4]. Here, we describe the anaesthetic management of a child with ROHHAD‐NET syndrome undergoing surgery for a large ganglioneuroma.

Report

A nine‐year‐old girl was scheduled for excision of a large paravertebral neural crest tumour. At the age of 7 years she weighed 48 kg (BMI 29.3 kg.m^‐2), after rapidly gaining 10 kg in a year, and was diagnosed with hypothyroidism, requiring 25 μg.day^‐1 of levothyroxine. A year later, she required mechanical ventilation for pneumonia in a local hospital, but could not be weaned from the ventilator and was referred to our tertiary care multispecialty hospital for further management. A tracheostomy was performed, which successfully facilitated weaning from mechanical ventilation, but a number of other derangements were found during the admission, leading to a diagnosis of ROHHAD‐NET syndrome. These findings included polydipsia and polyuria due to central diabetes insipidus; precocious puberty with increased serum prolactin but normal cortisol and adrenocorticotrophic hormone levels; autonomic dysfunction manifesting as constipation, altered diaphoresis and pain perception; retinal and subretinal haemorrhages; palpitations; hypersomnolence; and weakness of both lower limbs due to neural compression by a 3.9 × 6.5 × 9.8 cm left paravertebral ganglioneuroma extending from T8–T12 (Fig. 1). After 26 days, the child was discharged on intranasal desmopressin for central diabetes insipidus and propranolol for palpitations. Over several weeks, on a day‐care basis, the tracheostomy tube size was gradually decreased, and finally, the stoma was sealed.

Figure 1.

Sagittal reconstruction of computed tomography, showing the extent of tumour from T8–T12.

Pre‐operative evaluation for excision of the neural crest tumour showed normal power in the lower limbs bilaterally, no hoarseness of voice or difficulty in breathing and a weight of 43 kg (BMI 24.6 kg.m^‐2). There was no orthostatic hypotension. Full blood count, serum electrolytes, renal, liver and thyroid function tests and coagulation studies were within normal limits. The lateral neck radiograph did not demonstrate subglottic stenosis. Propranolol and levothyroxine were continued until the morning of surgery. The morning dose of desmopressin was omitted on the day of surgery as major fluid shifts and prolonged peri‐operative fasting were anticipated. A good rapport was established with the child and she was transferred to the operation theatre without premedication.

General anaesthesia was induced with propofol 70 mg i.v., with atracurium 22.5 mg administered for muscle relaxation. The patient’s trachea was intubated with a 5.0‐mm cuffed tracheal tube after a failed attempt with 5.5‐mm cuffed tube. Anaesthesia was maintained with isoflurane in an air–oxygen mixture. The patient’s lungs were ventilated with inspiratory pressures of 14 cmH₂O and a PEEP of 5 cmH₂O; the respiratory rate was adjusted to maintain normocarbia. Intra‐operative monitoring adjuncts included a left radial arterial line, a central venous catheter in the right internal jugular vein and an indwelling urinary catheter to assess urine output. Analgesia was achieved with morphine 10 mg i.v., paracetamol 650 mg i.v. and surgical site infiltration with 20 ml of 0.1% ropivacaine.

A left subcostal incision extending to the right subcostal region was made. The diaphragm was incised in order to access the cranial end of the tumour. There were multiple episodes of hypotension during tumour handling and resection, secondary to vascular compression. The lowest blood pressure recorded was 54/30 mmHg. These episodes resolved upon release of the retractors and no pharmacological intervention was required. The surgery lasted for 5.5 h with an estimated blood loss of 800 ml. Two litres of Ringer’s lactate were administered and the total urine output was 180 ml. No blood products were transfused. Serial intra‐operative arterial blood gas analysis did not reveal any blood gas or electrolyte abnormalities. In view of the multiple episodes of hypotension, prolonged duration of surgery and the patient’s history of difficult weaning from ventilation in the past, the patient was transferred to the intensive care unit for ongoing ventilation. There were two failed attempts at tracheal extubation on the sixth and ninth postoperative days; tracheal extubation to nasal bilevel positive airway pressure (BiPAP) was successful on postoperative day 20 following a staged weaning programme. She was discharged home on postoperative day 29 with domiciliary BiPAP therapy and gradually weaned off BiPAP support over the subsequent five months.

Discussion

Rapid‐onset obesity is the cardinal feature of ROHHAD syndrome [1]. It closely resembles congenital central hypoventilation syndrome, but can be distinguished by later age of onset, sudden dramatic weight gain and the absence of POHX2B genotypic sequencing [5]. No genetic or causal basis has been established for ROHHAD syndrome so far. Other differential diagnoses for ROHHAD syndrome include Prader Willi syndrome, Beckwith–Wiedemann syndrome, obstructive sleep apnoea (OSA) and Pickwickian syndrome. The first two can be diagnosed by genetic testing, OSA by polysomnography and Pickwickian syndrome can be differentiated based on the age of onset and phenotypic features [5]. The diagnosis of ROHHAD syndrome is primarily based on clinical features, which in our patient appeared around the age of seven years and included rapid‐onset weight gain, hypothyroidism, difficulty in weaning from ventilation possibly due to hypoventilation, central diabetes insipidus, hyperprolactinemia, precocious puberty, autonomic dysfunction, hypersomnolence and neuroendocrine tumour.

Patients living with obesity have a higher risk of difficult airway management. Our patient was overweight with a BMI of 24.6 kg.m^‐2 at the time of surgery [6]. We did not have any difficulty in mask ventilation or with visualisation of the larynx. The only airway issue encountered was that a cuffed tracheal tube smaller than the one calculated by the standard paediatric formula [(age/4) + 3.5] could be introduced [7], potentially suggesting tracheal narrowing due to previous prolonged intubation and tracheostomy.

Hypoventilation has been reported in 75% of patients with ROHHAD‐NET syndrome, mostly in the form of OSA but also as respiratory distress in some cases [8]. In the early stages of the syndrome, there may be alveolar hypoventilation with shallow breathing during sleep. As the disease progresses, hypoventilation becomes apparent even when awake, necessitating assistance with breathing in order to prevent life‐threatening hypoxemia or hypercapnia. Other components of hypoventilation include central sleep apnoea, an abnormal ventilatory response to carbon dioxide and cyanotic episodes. Our patient had a history of respiratory distress necessitating mechanical ventilation followed by difficult weaning. She also required prolonged ventilation postoperatively and could not be weaned completely, with non‐invasive nasal BiPAP to be continued at home. If tracheal extubation is planned for the end of the surgery, the anaesthesia technique could be modified to prevent hypoventilation by using non‐opioid analgesics and regional analgesia. Use of volatile agents with low blood gas solubility is recommended to hasten recovery and reduce the risk of postoperative airway obstruction. Non‐invasive ventilation following tracheal extubation is a reasonable and safe approach in children who continue to demonstrate hypoventilation.

Hypothalamic dysfunction presenting with rapid‐onset obesity, hyperprolactinemia, central hypothyroidism, disordered water balance, failure of response to growth hormone stimulation, corticotropin deficiency and delayed or precocious puberty may be found in children with ROHHAD syndrome [9]. Our patient had most of these features and required pre‐operative optimisation with levothyroxine and desmopressin. Even though her pre‐operative serum sodium concentration was normal, the intra‐operative sodium values were mildly elevated. Thus, it is essential to monitor serum electrolytes and fluid intake and output peri‐operatively. Patients on steroid replacement therapy must receive peri‐operative supplementation.

Autonomic dysfunction may manifest as altered pain perception, gastrointestinal dysmotility, thermal dysregulation (with hypothermia or hyperthermia), brady‐tachyarrhythmias or ophthalmological abnormality [1]. The thermal dysregulation seen in these children makes it imperative to monitor and maintain core temperature to avoid extremes of temperature and their related adverse consequences. Of particular concern to anaesthetists is gastro‐oesophageal reflux which may necessitate rapid sequence induction and intubation. Similarly, high arrhythmogenicity combined with autonomic dysfunction makes hypotension and hypertension more likely, mandating invasive blood pressure monitoring, especially in major surgeries. The underlying autonomic dysfunction may have contributed to the intra‐operative hypotension in this patient.

Apart from the pre‐operative investigations related to the organ systems involved, liver function tests should be evaluated in view of the association of this syndrome with non‐alcoholic fatty liver disease. Our patient also had hepatitis a few months prior to surgery; however, her pre‐operative liver function test results were within normal limits.

Ganglioneuromas originate from neural crest cells which include sympathetic ganglia and cells of the adrenal medulla. Due to their close proximity to the neural tube, these tumours have the ability to secrete various vasoactive peptides. In rare cases, such tumours may co‐exist with disorders such as neurofibromatosis, Beckwith–Wiedemann syndrome or Di‐George syndrome [10]. Excision of neural crest tumours requires meticulous surgical dissection. Haemodynamic fluctuations and blood loss during surgery should be anticipated and invasive blood pressure monitoring should be used.

Postoperative analgesia was provided by an intravenous fentanyl infusion in addition to regular paracetamol and diclofenac. We did not use epidural analgesia because of the neural origin of the tumour and the recent history of bilateral lower limb weakness. Ultrasound‐guided bilateral subcostal transverse abdominis plane block with ropivacaine and clonidine could have been used as an alternative to epidural analgesia.

In summary, patients with ROHHAD syndrome require thorough pre‐operative evaluation and optimisation, individualised anaesthetic management based on the organ systems involved and continued care in the postoperative period in order to achieve the best possible outcome.