Interventional procedure overview of phrenic nerve pacing for congenital central hypoventilation syndrome
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Evidence summary
Population and studies description
This interventional procedure overview is based on 1,562 people who had the procedure from 4 case series (Ali 2008; Diep 2015; Nicholson 2015; Tsolakis 2022) and 1 analysis of the ABD database (Headley 2023). This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 5 studies as the key evidence in table 2 and table 3, and lists other relevant studies in table 5.
Of the 4 case series included in the key evidence, 2 case series (Diep 2015; Nicholson 2015) were done in the US, 1 case series (Ali 2008) in Canada, and 1 case series (Tsolakis 2022) in Sweden. All 4 case series included people with CCHS, with a total of 63 people (31 male and 32 female). The reported age was mean 4 years (Ali 2008), median 5.7 years (Nicholson 2015) and mean 9 years (Diep 2015; Tsolakis 2022). The follow-up or observational duration was from mean 3 to 10 years across 3 studies and potentially around 30 years for 1 study. In 3 case series (Diep 2015; Nicholson 2015; Tsolakis 2022) with 59 people, PHOX2B mutations were confirmed in 50 people.
The analysis of the ABD database (Headley 2023) included people with different indications (including CCHS) and potentially from multiple countries, but the exact number of people with CCHS was not reported. But, it reviewed the data collected for over 38 years and included 1,522 people who had the Avery device implanted. Also, it particularly reported revision data and detailed the reasons for revisions (safety data). Table 2 presents the study details.
Procedure technique
Of the 4 case series, 3 case series described the procedure technique but varied in detail, while 1 case series (Tsolakis 2022) only mentioned the cervical approach to implantation. When reported, the common device used was the Avery diaphragm pacing system.
To assess the PN integrity, the nerve was stimulated transcutaneously and the response of the diaphragm was monitored using fluoroscopy (Ali 2008). The PN pacers were then implanted either by an open thoracotomy or a thoracoscopic technique. Two case series (Nicholson 2015; Diep 2015) published in 2015 mainly used a thoracoscopic approach to implant the PN pacers, while another (Ali 2008) reported the common approach being thoracic placement of the PN pacers. One probable explanation for the different techniques used was that the thoracoscopic approach (VATS) became a breakthrough method during the late 1990s and early 2000s. The procedure was usually done bilaterally and the mean operative time was 3.3 hours (Nicholson 2015).
After the procedure, pacing was attempted at week 1 (Ali 2008). The median time to initiation of pacing was 2.6 months (Nicholson 2015) with a mean of 2.8 months (Diep 2015). Diaphragmatic conditioning took a mean of 2.7 months (Nicholson 2015) to 6.6 months (Diep 2015).
The review of the ABD database (Headley 2023) generally described the procedure technique with a cervical or thoracic approach. The authors stated that positive identification of the PN was achieved with a disposable nerve stimulator that revealed diaphragm movement. The cervical technique remained the most minimally invasive technique and could be done under local anaesthesia. But, there was a greater area of accessible PN in the chest for the placement of the electrode, so more thoracic surgeons have been practicing thoracic placement (using either the open thoracostomy or the less invasive VATS technique) as opposed to cervical. Also, thoracic placement of the electrodes was more common in paediatric cases.
Efficacy
Daily pacing duration and decannulation of tracheostomy
Daily pacing duration was reported in all 5 studies and the proportion of people who were paced during sleep, or for 7 hours and above, ranged from 65% to 100%. When reported, successful tracheostomy decannulation was present in 64% of people or above.
In the Diep (2015) study of 18 people with CCHS who were ventilator-dependent only during sleep, 15 people had PPV by tracheostomy, 1 person had PPV by endotracheal tube and 2 people had PPV by nasal mask at baseline. At a mean of 6.6 months after pacing initiation (about 10 months after implantation), 89% (16/18) of people achieved full nighttime PNP. Of the 15 people with tracheostomy before PNP, 73% (11/15) of people were decannulated successfully at a mean follow up of 12.2 months after implantation. At about 10 years after implantation, 72% (13/18) of people were successfully ventilated by PNP without tracheostomy (1 person paced for 7 years without tracheostomy and then returned to using non-invasive PPV because of obesity), 22% (4/18) of people used PNP with tracheostomy and 6% (1/18) of people had only non-invasive PPV. The authors found that obstacles to decannulation included obesity, severe upper airway obstruction, seizures and developmental delay, as well as social reasons.
In the Nicholson (2015) study of 18 people with CCHS, 15 people had tracheostomies and 3 people used BiPAP during sleep at baseline. At a mean of 5.3 months after implantation, 65% (11/17) of people who had primary placement of PN pacer achieved the daily pacing goal (PNP only used during sleep without assistance when awake, or 12 to 14 hours of pacing daily maximum). Of the 11 people with primary implantation, 64% (7/11) of people had successful tracheostomy decannulation at a mean of 12.5 months after implantation. For the 1 person who had a revision of an original operation, during a follow up of 20 months, this person achieved the daily pacing goal and subsequently had their tracheostomy decannulated.
In the Ali (2008) study of 6 people with CCAHS, 3 people had asphyxia, 2 had apnoea and 1 person was unable to wean from ventilation at baseline. After several months of diaphragmatic conditioning, all people were paced during the day (3 people with daily pacing of 8 to 10 hours and 3 people with daily pacing of 10 to 12 hours) but were mechanically ventilated at night because the authors preferred to limit the period of pacing to 12 hours to minimise the risk of PN damage.
In the Tsolakis (2022) study of 23 people with CCHS, 18 people were on non-invasive ventilation and 5 had a tracheostomy before implantation. After implantation, 87% (20/23) of people successfully transitioned to PNP (complete change to sleep-assisted, non-MV) and 13% (3/23) of people continued with non-invasive ventilation. All 5 people were decannulated within 6 months after implantation. Some people used PNP for 30 years without needing replacement electrodes or receivers (exact data not reported).
In the analysis of the ABD database, Headley (2023) reported that, of the 111 people who responded to the survey, 57% of respondents reported they were paced for 7 to 12 hours daily (primarily while sleeping), 14% reported 13 to 15 hours daily, 13% reported 16 to 20 hours daily, and 16% used the pacer at all times. The authors also found that 5 people spent 40 years pacing (3 active people and 2 deceased people in the database), and 41 people spent over 30 years pacing (33 active people and 8 deceased people). The survey results also showed that 76% of respondents had a tracheostomy before implantation, and of these people, around 33% chose to have them removed following implantation.
Return to productivity
Ali (2008) reported that all 6 people led an active life, attended school or worked full time during a 10-year period. Some were even involved in intramural team sports.
Implant longevity
Implant longevity was shown by years in between revision surgeries and presented in 2 studies. Headley (2023) who reviewed the ABD database of 1,522 patients found that the mean longevity was 6.5 years (SD 6.2) for both cervical and thoracic approaches. When comparing the 2 approaches, there was no statistically significant difference in device longevity (cervically implanted device: mean 6.4 years, SD 6.8; thoracically implanted device: mean 6.4 years, SD 5.7; p=0.9382). In Ali (2008), the mean time to failure of a receiver was 8.1 years and the mean time to change of a wire was 8.8 years.
Safety
Revision
Revision or device replacement was reported in 3 studies. Headley (2023) reported that, of the 854 people implanted with the current version of the receiver (I-110), 20% (172/854) needed revision surgeries. For the electrodes, 17% (66/380) of cervical cases needed at least 1 revision of the electrode compared with 18% (95/518) of thoracic cases. Data showed that in people initially implanted cervically, 45% of electrode revisions involved moving the electrode placement to the chest compared with 10% of people whose implants were moved from the chest to the neck. The authors also reported the revision rationale for people with cervical implantation as follows:
no report or no problem found: 18%
surgical placement of implants: 14%
intermittent (loss of stimulation): 14%
insultation damage: 12%
damage to wire: 9%
calcification of anode: 8%
accidental damage (sports): 6%
accidental damage (medical treatment): 5%
infection after surgery: 5%
twiddler (people who play or nervously fidget with their subcutaneously placed receivers): 4%
patient growth: 5%
Ali (2008) reported that, of the 6 people with CCAHS, equipment replacement happened in 5 people, including receiver replacement (n=4, 2 people on 1 side and 2 people on both sides) and wire or electrode changes (n=4; 2 people on the right side and 2 people on the left side). More than 1 replacement of the receiver or wire on the same side was found in 2 people (Ali 2008).
In the Nicholson (2015) study of 18 people with CCHS, 1 person who had the procedure before the study period returned to the hospital twice during the study period for a replacement of the receiver portion of the pacing apparatus. This repair needed only a small abdominal incision, and the portion of the device contained within the thorax was not disturbed.
PN damage
PN damage was presented in 2 studies. Ali (2008) reported that, of the 6 people with CCAHS, axonal damage to the left PN was seen in 1 person who had been pacing for 13 years. There were no PN damages found in other people during a mean pacing of 10 years. Headley (2023) found that, of the 3,478 implants, PN injury caused by surgical manipulation of the nerve was found in 6 cases over 38 years (less than 0.2%). In 5 of the 6 cases the nerve function recovered.
Respiratory complications
Atelectasis was described in the Nicholson (2015) study. Of the 18 people with CCHS, 3 people had persistent atelectasis after PN pacer implantation, with 1 progressing to pneumonia.
Infectious complications
In the Ali (2008) study of 6 people with CCAHS, 1 person had both infectious complications and equipment failure. This person also had a subcutaneous pocket infection 1 month after surgery and subsequently developed an empyema on the same side 3 years later. Their electrode was eventually replaced in the neck. They developed unwanted secondary brachial plexus twinges, for which revision was again done (Ali 2008).
Tonic clonic seizure
Seizure was presented in the Nicholson (2015) study. Of the 18 people with CCHS, 1 person with no medical history of seizure disorder experienced a 2-minute generalised tonic clonic seizure 2 days after implantation, likely secondary to hypercarbia, with pCO2 transiently measured in the 90s mmHg. After aggressive suctioning, pCO2 was maintained in the 40s mmHg with no further seizure activity.
Anecdotal and theoretical adverse events
Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other adverse events for this procedure that they had heard about (anecdotal) which were not reported in the literature. They were also asked if they thought there were other adverse events that might possibly occur, even if they had never happened (theoretical).
They listed the following anecdotal or theoretical adverse events: those expected for an implantable neurostimulation device, repeated surgical intervention, risk of general anaesthetic, and post operative risks.
Six professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.
Validity and generalisability
All 5 studies were retrospective. Four case series included small samples (6 to 21 people with CCHS), with 2 case series (Nicholson 2015; Diep 2015) reporting outcomes at mean 3 and 10 years after implantation, and 1 study by Ali (2008) reporting results at mean 10 years after pacing. Loss to follow up was 6% (Diep 2015) to 22% (Nicholson 2015). Tsolakis (2022) reported 30-year pacing in some people. Also, 12 international referrals could not be followed up, so the dropout rate was 52%.
For the review of the ABD database, Headley (2023) included a large sample with mixed indications, but the exact number of people with CCHS was unknown. This review mainly focused on the revision aspect, so there was a lack of other outcomes of interest reported.
When reported, only 1 paper's authors had conflicts of interest (Headley 2023) and 1 reported no conflict of interest (Tsolakis 2022).
Although the daily pacing duration was reported in all studies, the outcomes reported varied. The review of the ABD database provided the revision data, reported the implant longevity and detailed the reasons for revision. But, as the procedure technology and the devices used are evolving, this would potentially affect the safety and efficacy profiles of the procedure, in particular the device longevity. As noted by Ali (2008) and Headley (2023), as the device gets more and more refined, it lasts longer.
Overall, the evidence shows that the proportion of people who were paced during sleep, or for 7 hours and above, ranged from 65% to 100%. The key factors that prevented successful PNP without tracheostomy (decannulation of tracheostomy) were obesity and (severe) upper airway obstruction (Diep 2015). Two people who had cardiac pacemakers placed for syncope or bradycardia on Holter monitoring were included in the Nicholson (2015) study, but no particular concerns were highlighted. To avoid interference with a PN pacer, the use of bipolar cardiac pacing electrode was preferred (Weese-Mayer 2010; Trang 2020).
Implant longevity was measured by years in between revision surgeries, with the mean longevity being 6.5 years. The data on revision mainly came from a review of the ABD database, showing that the rate of revision surgeries for the I-110 receiver (current version) was 20%. Other complications, such as PN damage, were rare.
Nevertheless, the evidence is limited and there is a lack of evidence on survival, reduction in respiratory complications, and quality of life. But, it is noted that CCHS is a rare genetic condition which would limit evidence generation, and to date, no ongoing trials have been identified.
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