Introduction

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by failure of automatic control of breathing [1]. CCHS is typically diagnosed in infancy and persists as a lifelong disorder as there is no known cure. The disease-defining gene mutation for CCHS involves the paired-like homeobox 2B (PHOX2B) gene, which is involved in neural crest cell migration and autonomic nervous system development [1,2,3]. Affected patients most commonly have a polyalanine repeat expansion mutation (PARM), with longer expansions generally associated with a more severe phenotype. Less than 10% of patients have nonpolyalanine repeat mutation (NPARM), which is also usually found in patients with more severe manifestations of the disease [1, 4]

CCHS is characterized by severe hypoventilation during sleep that may extend to wakefulness. Affected patients can become hypoxemic and hypercarbic because they lack the necessary ventilatory responses to overcome these challenges [1, 5]. Therefore, patients with CCHS must rely on lifelong ventilatory support either during sleep only or 24 h per day to maintain adequate ventilation [1, 6,7,8]. Ventilatory support modalities include positive pressure ventilation (PPV) via tracheostomy, noninvasive positive pressure ventilation (NPPV), negative pressure ventilators, and diaphragm pacing (DP) [1, 7,8,9,10,11,12,13,14]. DP, in particular, allows patients requiring full-time ventilator support more independence during the day, while those who are ventilator-dependent only during sleep have the potential for decannulation of their tracheostomy [14, 15]

Several case reports have shown that patients with CCHS are particularly sensitive to neurodepressant medications [16,17,18]. Mahfouz et al. described an asymptomatic 6-year-old child who could not be extubated following general anesthesia for a dental procedure who was subsequently diagnosed with CCHS. In this case, the child was noted to breathe comfortably without overt respiratory distress despite pCO2 of 112 mmHg [16]. Recently, we reported a case of a 52-year-old woman with history of prolonged recovery from anesthesia and an elevated serum bicarbonate of 45 meql/L who shared the same PHOX2B gene mutation as her child [18]. These cases suggest risk for vulnerability during the perioperative period. However, aside from case reports, there are limited published data on the management and outcomes of patients with CCHS undergoing general anesthesia [19,20,21,22].

The objective of this study was to describe the perioperative outcomes of patients with CCHS undergoing a diaphragm pacer-related procedure under general anesthesia. We chose this procedure to reduce confounders. Because it is an elective procedure, patients must be at their optimal healthy baseline at the time of surgery.

Methods

We conducted a historical cohort study of all patients with CCHS who underwent a primary implantation of bilateral phrenic nerve electrodes for diaphragm pacing at the Children’s Hospital Los Angeles (CHLA) between January 2000 and May 2016. Patients with genetically confirmed diagnosis of CCHS were included. Charts were reviewed for demographics, PHOX2B genotype, usual need for ventilatory support, type of ventilatory support, associated medical conditions, type and dosage of anesthesia medications administered, and the pre-, intra-, and postoperative course of each procedure. Descriptive statistics were used to describe the study population.

The study was approved by the Children’s Hospital Los Angeles Institutional Review Board.

Results

Patient characteristics

Of the 19 patients who underwent primary phrenic nerve pacer implantations, 11 were female (58%). The mean age at surgery was 8.6 ± 5.8 years (range 3–23 years) with a mean BMI of 18.6 ± 4.9 kg/m2. One patient was obese based on cutoffs by the World Health Organization of BMI of ≥ 30 kg/m2. PHOX2B gene mutation was confirmed in all patients. Nine patients had 20/25 polyalanine repeat expansion mutation (PARM), 2 patients had 20/26 PARM, seven had a 20/27 PARM, and one had a novel point p.P82L mutation. Seven patients had autonomic nervous system dysfunction (ANS) manifestations in their history such as Hirschsprung’s disease, gastroesophageal reflux disease, cardiac pacemaker dependence for bradyarrhythmia, and strabismus. Four patients had feeding gastrostomies. Other associated conditions are listed in Table 1. Six patients had more than 1 associated ANS dysfunction and/or medical condition.

Table 1 Comorbidities for patients undergoing primary diaphragm pacer implantation
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Each stage of anesthesia is described along with their related outcomes.

Preoperative considerations

Mode of ventilation

At the time of diaphragm pacer implantation, 17 patients were receiving ventilatory support during sleep only, while the remaining two patients received 24-h ventilatory support. Of the 17 patients receiving sleep-only ventilatory support, 14 were using PPV via tracheostomy, and 3 by NPPV via mask. One of the 3 patients ventilated noninvasively still had tracheostomy that was capped 24 h/day. Both patients on 24-h ventilatory support used PPV via tracheostomy as their primary mode of ventilatory assistance. The two patients, who did not have a tracheostomy in place at the time of diaphragm pacer implantation, were on NPPV prior to the operation.

Preoperatively, two patients received premedication in the form of midazolam.

Events

One of the two patients given preoperative sedation was not placed on mechanical ventilatory assistance and experienced profound sedation and hypoventilation with oxygen saturation down to 78% (Table 2). Hand bag-to-trach ventilatory support was instituted, and she was subsequently placed on her home ventilator until she went to the operating room. No long-term sequelae were apparent.

Table 2 Perioperative events for patients undergoing primary diaphragm pacer implantation
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Intraoperative considerations

Anesthesia

All 19 patients were intubated endotracheally and received general anesthesia for the surgery. We found a variation in anesthetic management based on individual anesthesiologist’s preference. Six patients (32%) with tracheostomy were induced via inhalation route alone, eleven (58%) combined inhalation via tracheostomy and an IV route, and two (11%) intravenously with propofol only. To facilitate endotracheal intubation, seven patients received a neuromuscular blocker in the form of vecuronium or rocuronium (5) or succinylcholine (2). These medications were allowed to wear off during the procedure to enable testing of the diaphragm pacer system intraoperatively. The other 12 patients were intubated by deepening the anesthetic plane using a combination of sevoflurane, propofol, and fentanyl. Anesthesia was maintained with sevoflurane in 16/19 patients and total intravenous anesthesia in three. This included propofol and remifentanil infusions in 2 and propofol, dexmedetomidine, and remifentanil infusion in one. Fifteen patients received intraoperative fentanyl and four patients received morphine towards the end of their procedure.

Diaphragm pacers were implanted thoracoscopically as protocol in our center [23, 24]. The surgery required one lung ventilation whereby the ipsilateral lung is deflated for the surgical placement of the phrenic nerve electrodes. The mean surgery duration was 3.1 ± 0.5 h (range 2.4–4.1 h).

Events

Out of the 19 operations, intraoperative events were noted in 10 (53%). Two patients had intraoperative bradycardia (11%). One of the patients had brief bradycardia to less than 30 bpm that responded to IV atropine. In addition, this patient received chest compressions for the low heart rate but did not have asystole or hypotension. The other patient had bradycardia to 34 bpm, relieved with IV atropine without the requirement for cardiopulmonary resuscitation. One patient was noted to be hypotensive that occurred within 5 min of anesthesia induction but resolved with placement in Trendelenburg position and intramuscular atropine. Five patients had hypoxemia with the lowest SpO2 of 50% and 2 patients had bronchospasm (Table 2).

Postoperative considerations

All patients continued to receive positive pressure ventilation postoperatively. Seventeen patients were extubated to tracheostomy in the OR. The duration of intubation was 4.0 ± 0.6 h (range 3.2–5.3 h). The two remaining patients, who were previously on NPPV via mask, went to the PICU intubated and were extubated to NPPV on postoperative day 1. The patient on NPPV by mask at home but had tracheostomy capped full time was transitioned to a portable ventilator. Mean time for transition to portable ventilator was 3.0 ± 2.2 days (range 1–9 days), and mean hospital stay was 5.0 ± 2.1 days (range 3–12 days).

Events

Postoperative events were noted in 15 diaphragm implantation procedures (79%). One patient experienced a 2-min generalized tonic–clonic seizure on postoperative day two (5%), attributed to hypoventilation with rising CO2 over course of few hours up to 85 mmHg on end-tidal CO2 monitoring. Seizure resolved with lorazepam during which the patient was hand-bagged with normalization of gas exchange. Twelve patients were found to have atelectasis (63%), with five treated with antibiotics for pneumonia. Four patients had pneumothoraces related to the surgery and had chest tubes for up to 5 days. Four patients had recorded episodes of tachycardia. Other noted postoperative events included fever (2), urinary retention (3), nausea and vomiting (2), and mild lactic acidosis in one patient (Table 2). Eight of the 12 patients (67%) who developed atelectasis were transitioned to their home ventilator/NPPV within 3 days of surgery and only 1 of the 12 patients was transitioned to home ventilator after 1 week of surgery. Three of these 12 patients were hospitalized for ≥ 7 days.

Discussion

Our study showed that a significant proportion of patients with CCHS have anesthetic complications pre-, intra-, and/or post primary diaphragm pacer implantation surgery under general anesthesia. To our knowledge, there are limited data that describe an optimal anesthetic approach for managing these patients.

Cardiovascular presentations of CCHS include alterations in autonomic function including decreased heart rate variability, bradycardia, and transient asystole [24,25,26,27,28]. Woo et al. described bouts of bradycardia and tachycardia that can occur in CCHS patients, unrelated to central hypoventilation [24]. This autonomic instability may be correlated with the intraoperative bradycardia that was seen in a subset of our patients.

During the thoracoscopic placement of the phrenic nerve electrodes, the lungs are deflated sequentially, putting patients at risk for atelectasis and pneumonia. We found atelectasis in 2/3 of our cohort with 24% requiring treatment for pneumonia. Ballard et al. found atelectasis in 3 of 14 patients (21%) undergoing diaphragm pacers implantation surgery [19]. Our findings highlight the significance of airway clearance and ventilatory support to mitigate these complications. In our center, we optimize airway clearance therapies with bronchodilator and chest physiotherapy in the post-op period to minimize this risk. In those with large tracheostomy stoma, the tracheostomy tube is upsized or cuffed tracheostomy tube is temporarily used in the immediate post-op period to improve ventilation.

During the surgery, anesthesiologists need to be aware that neuromuscular blocking agents should not be used because the diaphragm pacer system is tested several times intraoperatively. When using these agents to facilitate intubation, the agents should be short acting or allowed to wear off by the time testing is performed. One patient had profound hypoventilation after premedication highlighting the importance of ensuring that all patients with CCHS receive adequate assisted ventilation and gas exchange monitoring if receiving premedication since they lack subjective and objective responses to hypoxia or hypercapnia. Therefore, these patients will not demonstrate respiratory distress, tachypnea, or retractions in response to hypercarbia or hypoxemia. Hence, it is imperative that healthcare team involved in their perioperative care must be aware of the importance of close monitoring and ventilatory support during this vulnerable period. The importance of vigilant monitoring and need for mechanical ventilation extends to the post-op period when patients are receiving sedating, pain, or other CNS depressant medications. In patients with CCHS, the most common problem is inadequate ventilation whether they are awake or asleep; therefore, when problems arise (i.e., seizures, lethargy), the first step should be to provide optimal ventilatory support. At the authors’ center, patients are stabilized with hyperventilation and supplemental oxygen until the source of the problem can be identified. Because of CCHS, the etiology of any such problem is likely to be hypoventilation until proven otherwise and a brief period of hyperventilation will not be harmful, but may be lifesaving. Our approach in caring for patients with CCHS undergoing phrenic nerve electrode implantation surgery for diaphragm pacing is summarized in Table 3.

Table 3 Approach to patients undergoing phrenic nerve electrode implantation surgery for diaphragm pacing
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Our study has some limitations in that being retrospective, some data points are not available and not all events that occurred may have been captured. Furthermore, the numbers are too small to run a subgroup analysis to determine the relationship of the occurrence of events and the PHOX2B genotype.

Given that patients with CCHS undergoing primary diaphragm pacer implantation surgery are at their optimal healthy baseline, we chose to study this group to examine their perioperative outcomes as related to anesthesia to reduce confounders. We propose that our findings on the outcomes from the effect of anesthesia may occur in any patient with CCHS receiving sedation and anesthesia for any surgeries or procedures. Our study showed that all patients experienced at least one anesthetic complication before, during, or after a diaphragm pacer implantation surgery. We speculate that these complications were caused or exacerbated by absent ventilatory responses or autonomic dysfunction. Therefore, it is vital that the healthcare team is cognizant of the increased risks in patients with CCHS, the crucial role of appropriate monitoring to prevent hypoxia and/or hypoventilation, and the delivery of adequate ventilatory support in the pre-, intra-, and postoperative periods.