IP 746/2 [IPG594]

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

Some patients with high spinal cord damage need a mechanical ventilator to help them breathe. Intramuscular diaphragm stimulation involves keyhole abdominal surgery (laparoscopy) to implant electrodes into the diaphragm. Wires from the electrodes run under the skin to a battery-operated electrical stimulation system which causes the diaphragm to contract as in normal breathing. The aim of the procedure is to strengthen the diaphragm, allowing patients to breathe without a ventilator and to improve their quality of life. Introduction

The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure (IP) overview to help members of the interventional procedures advisory committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared

This IP overview was prepared in March 2017. Procedure name

 Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

Specialist societies

 Association of British Neurologists (ABN)  Society of British Neurological Surgeons (SBNS)  British Association of Spinal Cord Injury Specialists (BASCIS) IP overview: intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries Page 1 of 24 IP 746/2 [IPG594]

 Intensive Care Society (ICS)  Faculty of Intensive Care Medicine.

Description

Indications and current treatment

Spinal cord injuries can damage the nerves that control breathing and cause respiratory failure.

Current standard care for managing chronic respiratory failure in patients with spinal cord injuries includes non-invasive forms of ventilation support (such as Bi- level positive airway pressure-[BiPAP]). In advanced stages of respiratory failure mechanical ventilation is done through a permanent tracheostomy. Phrenic nerve pacing, in which the diaphragm is stimulated to contract by electrodes placed on the phrenic nerve in the neck or thorax, is an alternative treatment for patients who have intact phrenic nerves (the nerves that contract the diaphragm).

What the procedure involves

The aim of intramuscular diaphragm stimulation is to make the diaphragm contract, strengthening it and allowing full or partial weaning from mechanical ventilation. This procedure needs intact phrenic nerve function, and avoids the need to access the phrenic nerve through the neck or thorax, as well as reducing the risk of phrenic nerve damage.

The procedure is done laparoscopically with the patient under general anaesthesia. A special probe is used to identify areas of the diaphragm where minimal electrical stimulation causes maximal diaphragm contraction (known as the 'motor points'). Two intramuscular electrodes are implanted on the abdominal surface of each hemi-diaphragm at the motor points. The electrode leads are tunnelled subcutaneously to an exit site in the chest where they are connected to an external battery-powered pulse generator. A reference electrode (anode) is also implanted and the leads tunnelled with the other electrodes. Intraoperative stimulation and voltage calibration tests are carried out to confirm adequate contraction of the diaphragm. After implantation the patient has a diaphragm conditioning programme, which involves progressive use of the system for increasing periods of time with gradual weaning from the ventilator.

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Literature review

Rapid review of literature

The medical literature was searched to identify studies and reviews relevant to intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries. The following databases were searched, covering the period from their start to 08-08-2016: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion.

The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved.

Table 1 Inclusion criteria for identification of relevant studies Characteristic Criteria Publication type Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or if the paper was a review, editorial, or laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patient Patients with ventilator-dependent chronic respiratory failure caused by high spinal cord injuries. Intervention/test Intramuscular diaphragm stimulation. Outcome Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Language Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base.

List of studies included in the IP overview

This IP overview is based on 149 patients with ventilator-dependent chronic respiratory failure caused by spinal cord injuries from 1 systematic review and 1 case report. Other studies that were considered to be relevant to the procedure and indications but were not included in the main extraction table (table 2) have been listed in appendix A.

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Table 2 Summary of key efficacy and safety findings on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

Study 1 Garara B (2016)

Details Study type Systematic review Country UK Study period Search date: January 2000-June 2015; Databases searched: the Cochrane library and PubMed; limited to English language studies and reference lists of selected papers were also reviewed. Study population n=148 patients with traumatic high cervical injuries and ventilator dependent and number (in 12 studies: 2 retrospective studies, 8 case series and 2 case reports) Age and sex Age ranged from 17 to 74 years; sex not reported Study selection Studies that reported on adult patients with traumatic high cervical injury, who were criteria ventilator-dependent, underwent intramuscular diaphragmatic stimulation and commented on safety and/or effectiveness were included. Large and more recent studies were considered if duplication of data was observed. Technique Intramuscular diaphragmatic stimulator implanted laparoscopically Follow-up Noted stated in 9 studies; varied in 3 studies (6 months in Tedde 2012 and mean 2 years in Onders 2008) Conflict of None interest/source of funding

Analysis Follow-up issues: follow-up was not stated in most studies.

Study design issues: The systematic review was done according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Two authors reviewed all articles and any discrepancies were resolved by discussion with a third author. The Methodological Index for Non-Randomised Studies (MINORS) scoring system was used to evaluate the quality of non- randomised studies. Studies of greater quality were given greater weighting in the qualitative analysis. The overall quality of included studies ranged from 8/16 to 12/16. None of the studies used an unbiased assessment of the end point or provided a prospective calculation of the study size. Studies were variable in terms of demographics, technique, post-operative weaning programme and outcome data reported.

Study population issues: it is likely that some of the patients were reported more than once in different studies, although the papers do not state this explicitly.

Other issues: data on 38 patients with amyotrophic lateral sclerosis from Onders 2009 study were excluded from the analyses here and reported separately in study 5 in table 2.

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Key efficacy and safety findings Efficacy Safety Number of patients analysed: 148 patients Safety outcomes Study No of Procedure Diaphragm Weaned No of Complications design patients success conditioning from patients % (n) success ventilators* Alshekhlee 26 None Posluszny 29 with SCI 100% in 73% (16/22) 2008 2014 and 22 patients full time in Retrospective ventilator mean 10 Tedde 5 None analysis dependence. days, 2012,2012 7 patients 9% (2/22) Posluszny 29 None were part-time 2014 excluded as 14% (3/22) Onders 50 SCI Capnothorax phrenic still in 2009 and nerves not conditioning pneumothorax intact. phase (treated with aspiration, DPS wires observation or removed in chest drain): 44% (8/18) 42% (21/50) weaned patients. Superficial wound Tedde 2012, 5 with 100% 60% (3/5) infection along 2012 tetraplegia full time, 1 tunnelled wires Case series and part-time, (resolved with ventilator and 1 in antibiotics, dependence conditioning shortening and phase. terminating Alshekhlee 26 with 100% 96% (25/26) 56% (14/25) tunnelled 2008 quadriplegia 1 could not full time electrodes): 1 Case series and achieve as a 24% (6/25) Deaths ventilator result of part time (unrelated to dependence severe 20% (5/25) procedure or muscle still in device): 5 cramps. conditioning Onders 10 None 4, 12 and 24 phase. 2007 hours pacing Onders 20 DPS achieved at 2010 interacting with mean 26, 59 pre-existing and 142 cardiac days. pacemaker: 1 Onders 2009 50 patients 99% SCI patients- >50% full Onders 6* Asymptomatic with SCI and (49/50) 96% time Case series 2004,2005, small ventilator achieved 4 1 failed as DiMarco pneumothorax dependence a result of hr pacing 2005, 2006 (evacuated by a false Tidal volume chest tube positive of>6-7ml/kg drainage): 1 phrenic in 98% Delayed wound nerve infection at conduction wire test. connection Onders 2010 20 100% 100% 71% full site: 1 Case series tetraplegics achieved 4 time Right shoulder with cardiac hr pacing pain during pacemakers stimulation and (alleviated by ventilator reduced dependence current): 1 IP overview: intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries Page 5 of 24 IP 746/2 [IPG594]

Onders 2007 10 with 100% 80% (8/10) 40% (4/10) Fever: 1 Case series tetraplegia Time to full time Intermittent as a result of achieve 4 hrs 20% (2/10) aspiration of high cervical pacing was part-time food during spine median 1.9 meals (related injuries and 40% (4/10) weeks. still in to diaphragm ventilator contraction dependence conditioning phase. causing large negative Onders 2004, 6 with 83% (5/6) 50% (3/6) airway 2005, tetraplegia 1 failed as full time, 1 pressure, DiMarco as a result of a result of part-time resolved with 2005, high cervical a false and 1 still in PassyMuir DiMarco spine positive conditioning speaking valve 2006 injuries and phrenic phase. during meals): Case series ventilator nerve 1 dependence conduction test. No electrode erosions or migrations Cosendai 1 with 100% reported. 2005 cervical *Some complications may be in the same Case report spine injury and patients. ventilator dependence *The percentage of patients reported as independent of ventilator support post procedure ranged between 40% and 72%. Complete recovery was reported in 36% (8/22) patients and wires were removed (Posluszny 2014).

Mean delay of insertion post-injury: The mean delay in insertion of diaphragmatic wires ranged from 40 days to 9.7 years (Posluszny 2014, Onders 2007). The study (Posluszny 2014) which reported the greatest number of fully weaned patients implanted electrodes earlier (at mean delay 40 days, range 3-112 days) than other studies. Abbreviations used: DPS, diaphragm pacing stimulation; SCI, spinal cord injuries.

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Study 2 Layachi L (2015)

Details Study type Case report Country France Recruitment 2009 period Study population n=1 patient with meningitis and acute cerebral oedema leading to compressive and number spinal cord ischaemia (quadriplegia)and ventilator dependency Age and sex 15 years old, sex not reported Patient selection Not reported criteria Technique Intra-diaphragmatic phrenic nerve stimulator (NeuRXDPS, Synapse Biomedical, USA) implanted laparoscopically. Follow-up 9 months Conflict of The study was supported by the French Government and the non-profit research interest/source of association ‘ADOREPS’. funding

Analysis Other issues: details about the second patient were not extracted because this was outside the scope of this review (a phrenic nerve stimulator was implanted intrathoracically in this patient).

Key efficacy and safety findings Safety Number of patients analysed: 1 Progressive pacing failure attributed to deteriorated chest wall mechanics The patient became quadriplegic after meningitis at age 15. An intra-diaphragmatic phrenic nerve stimulator was implanted and after 9 months diaphragm pacing was considered efficient, with tidal volumes of 500 ml on average and achieving normocapnia. After a year, hypoventilation developed without obvious cause, tidal volumes fell to less than 250 ml and patient was hypercapnic. No device dysfunction was identified. Phrenic nerve conduction was normal in response to bilateral phrenic stimulation. As a result of complex endocrine disorders, the patient had gained a massive amount of weight (31 kg). Pacing failure was attributed to excessive chest wall and abdominal weight preventing diaphragm contractions to adequately inflate the rib cage. Abbreviations used:

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Efficacy

Implantation success

In a systematic review of 148 patients with traumatic high cervical spinal injuries and ventilator-dependent respiratory failure (from 12 studies), intramuscular diaphragm stimulation systems were implanted successfully in all patients except 1. This was because of a false positive pre-operative phrenic nerve conduction test in this patient1.

Mean delay of implantation post-injury

In the systematic review of 148 patients, the mean delay in inserting diaphragm pacing wires ranged from 40 days to 9.7 years. In 1 study in the systematic review (Posluszny 2014) in which devices were implanted early at a mean of 40 days, the highest percentage of patients fully weaned from a ventilator (73% [16/22]) was reported at a mean 10 days1.

Weaning from mechanical ventilation

In the systematic review of 148 patients, half of the patients (range 40% to 72%) could be weaned from ventilators after the procedure and most could use the diaphragm stimulator instead of the ventilator for several hours per day1. The largest study (Onders 2009; 50 patients) reported that more than 50% were using diaphragm pacing 24 hours per day and up to 96% were able to use pacing for 4 hours continuously. Other studies also described similar rates.

Safety

Capnothorax or pneumothorax

Capnothorax was reported in 42% (21/50) of patients with spinal cord injuries in a case series of 88 patients included in a systematic review of 148 patients. Capnothorax was managed successfully with simple aspiration, drainage or observation1.

Asymptomatic pneumothorax (which was treated by chest tube drainage) was reported in a case series of 6 patients with spinal cord injuries included in the systematic review of 148 patients1.

Infection

Superficial wound infection along tunnelled wires (which resolved with oral antibiotics, shortening and terminating tunnelled electrodes) was reported postoperatively in 1 patient with spinal cord injuries postoperatively in a case series of 88 patients included in the systematic review1. Delayed wound infection at the superficial wire connection site was reported in 1 patient in the case series of 6 patients included in the systematic review1. IP overview: intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries Page 8 of 24 IP 746/2 [IPG594]

Interaction with pre-existing devices

The diaphragmatic pacing stimulator interacting with a pre-existing cardiac pacemaker was reported in 1 patient in the case series of 20 patients included in the systematic review1.

Pain

Right shoulder pain during maximum stimulation of a single electrode (which was relieved by reducing the current) was reported in 1 patient in the case series of 6 patients included in the systematic review1.

Fever

Fever symptoms redeveloped in 1 patient (which were common before injury but absent during mechanical ventilation) in the case series of 6 patients included in the systematic review1.

Aspiration of food

Intermittent aspiration of food was reported in 1 patient in the case series of 6 patients included in the systematic review. This was thought to be related to the large negative airway pressure generated during contraction of the diaphragm. It was stopped by using a 1-way valve, designed for patients with a tracheostomy tube, during meals1.

Progressive pacing failure

Progressive pacing failure was reported in 1 quadriplegic patient who was successfully weaned off mechanical ventilation with an intra-diaphragm phrenic stimulator. After a year hypoventilation developed without obvious cause. The patient had gained a massive amount of weight as a result of endocrine disorders. Pacing failure was because of excessive chest wall and abdominal weight preventing diaphragm contractions to adequately inflate the rib cage2.

Validity and generalisability of the studies

 Phrenic nerve stimulation, which involves direct stimulation of the phrenic nerve, is out of the scope of this guidance. Only intramuscular diaphragm stimulation using an abdominal laparoscopic approach is considered in this guidance.  Only 1 device is currently available for this procedure.  There are no studies comparing phrenic nerve stimulation and intramuscular diaphragm stimulation.

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 Most of the studies are small, non-randomised cohort studies in which methodological details are not clearly described. Most studies seem to have only short-term follow-up of patients.

Existing assessments of this procedure

There were no published assessments from other organisations identified at the time of the literature search.

Related NICE guidance

Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed.

Interventional procedures  Extracorporeal carbon dioxide removal for acute respiratory failure. NICE interventional procedure guidance 564 (2016). Available from https://www.nice.org.uk/guidance/IPG564  Extracorporeal membrane oxygenation for severe acute respiratory failure in adults. NICE interventional procedure guidance 391 (2011). Available from https://www.nice.org.uk/guidance/IPG391

Specialist advisers’ opinions

Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and is not intended to represent the view of the society. The advice provided by Specialist Advisers, in the form of the completed questionnaires, is normally published in full on the NICE website during public consultation, except in circumstances but not limited to, where comments are considered voluminous, or publication would be unlawful or inappropriate. Three Specialist Advisor Questionnaires for intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries were submitted and can be found on the NICE website. Patient commentators’ opinions

NICE’s Public Involvement Programme was unable to gather patient commentary for this procedure.

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Company engagement

A structured information request was sent to 1 company who manufacture a potentially relevant device for use in this procedure. NICE did not receive a submission. Issues for consideration by IPAC

 Ongoing studies  NCT02556125: Diaphragm pacing after spinal cord injury; observational case series; n=40; completion date: December 2017; status: recruiting participants.  NCT02354651: Response to diaphragmatic pacing in subjects with Pompe disease; observational cohort study; n=12; completion date: February 2017; status: recruiting participants.  NCT01815554: Follow up study of diaphragm pacing for patients with high tetraplegia; observational study; n=60; completion date: June 2016; status: enrolling participants by invitation only.

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References

1. Garara B, Wood A, Marcus H J, Tsang K, Wilson M H, and Khan M (2016). Intramuscular diaphragmatic stimulation for patients with traumatic high cervical injuries and ventilator dependent respiratory failure: A systematic review of safety and effectiveness. Injury 47(3), 539-544 2. Layachi L, Georges M, Gonzalez-Bermejo J, Brun AL, Similowski T, and Morelot-Panzini C (2015). Diaphragm pacing failure secondary to deteriorated chest wall mechanics: When a good diaphragm does not suffice to take a good breath in. Respiratory Medicine Case Reports. 15 (pp 20-23), and 2015 Date of Publication, December 01

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Appendix A: Additional papers on intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

The following table outlines the studies that are considered potentially relevant to the IP overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies.

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Article Number of Direction of Reasons for non- patients/follow-up conclusions inclusion in table 2 Alegret Monroig N, Retrospective case General anesthesia was Anaesthetic Serra P et al (2016). series required for abdominal management for Diaphragmatic pacing N=16 patients (5 laparoscopy; we used different indications stimulation: Anesthetic pediatric) with DP intravenous 87% versus including spinal cord management at institut indication due to spinal inhalatory induction injuries. guttmann. cord injuries, 63%; 13% and total Journal of amyotrophic lateral intravenous anesthesia Neurosurgical sclerosis, 25%; or other (TIVA) 50% versus Anesthesiology (28 (2)) neurological diseases, balanced 50% for S6-S7. 12%. maintenance anesthesia. Succinylcholine was administered to 31% of the patients for orotracheal intubation. Anesthetic deepening was needed during the surgery for pneumoperitoneum tolerance in 50% of cases in the balanced anesthesia group and in 25% of the cases in the TIVA group. Registered complications were: 31% mechanical ventilation difficulty during laparoscopy, pneumotorax 12.5%, and autonomic dysreflexia 6%. Adler D, Gonzalez- Case Series Olfaction was very poor Intrathoracic phrenic Bermejo J, Duguet A, N=10 tetraplegics with during positive pressure nerve stimulation in 9 Demoule A, Le Pimpec- cervical spinal cord mechanical ventilation patients and only 1 Barthes , F , Hurbault A, injuries treated with (University of intra-diaphragmatic Morelot-Panzini C, and diaphragm pacing (DP). Pennsylvania Smell pacing. Similowski T (2009) Identification Test, Diaphragm pacing mean+/-SD 17.1+/-6.4, restores olfaction in anosmia or severe tetraplegia. European microsmia). It improved Respiratory Journal during DP (35.2+/-1.9, 34(2), 365-70 normosmia or mild microsmia; p<0.0001) and Satisfaction with Life Scale was 18.5+/- 4.2. 9 patients stated that DP had improved their quality of life. This was driven by better mobility (ranked first), improved self-image and relationships with others (ranked second), improved olfaction and better feeling of security (both ranked third).

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Alshekhlee A, Onders Case series Procedural success Included in systematic RP, Syed TU et al. N=26 patients with 100%. 25 patients review (Garara 2016) (2008) Phrenic nerve quadriplegia as a result (96%) achieved added to table 2. conduction studies in of motor vehicle diaphragm conditioning. spinal cord injury: accident (n =13), sport Median time to achieve Applications for injury (n = 12), 4 hours, 12 hours and diaphragmatic pacing. meningitis (n =1). 24 hours of continuous Muscle & Nerve 38: pacing: 26, 59 and 142 1546-1552. Technique: laparoscopic days. 1 patient could implantation of not initiate the diaphragm pacing diaphragm conditioning system with phase because of intramuscular electrodes severe muscle cramps. Follow-up: not stated 56% (14/25) of patients use the system 24 hours per day. 24% (6/25) of patients use the system part-time. 20% (5/25) of patients are still in the diaphragm conditioning phase. No safety outcomes were reported. DiMarco AF, Onders Case report Five weeks after a Included in systematic RP, Ignagni A et al. N=1 patient with successful procedure, review (Garara 2016) (2006) Inspiratory tetraplegia (spinal cord the patient was able to added to table 2. muscle pacing in spinal injury at C3 from motor use the system This patient is also cord injury: case report vehicle accident) who continuously for 8 hours reported in the 3 studies and clinical had a diaphragm pacing and after 8 weeks, for below (Onders and Di commentary. Journal of stimulation system 24 hours. Marco). Spinal Cord Medicine implanted. No safety outcomes 29: 95-108. Technique: laparoscopic were reported. implantation of diaphragm pacing system with intramuscular electrodes Follow-up: not stated. Le Pimpec-Barthes , F , Literature review Reviewing all available Review. Legras A, Arame A, literature shows that DP Pricopi C, Boucherie J is an effective method C, Badia A, and Panzini to wean selected C M (2016) Diaphragm patients’ dependent on pacing: The state of the ventilator and improve art. Journal of Thoracic their daily life. Other Disease 8(pp S376- potential indications will S386), have to be evaluated by randomised control trials.

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Niazi AU, Mocon A, Case report Describes anaesthetic Varadi RG, Chan VW, N=1 patient with central management during and Okrainec A (2011) alveolar hypoventilation implantation. Ondine's curse: syndrome (CAHS) anesthesia for underwent laparoscopic laparoscopic DPS implantation. implantation of a diaphragm pacing stimulation system. Canadian Journal of Anaesthesia 58(11), 1034-8. Onders RP, Elmo MJ, Case series Procedural success: Included in systematic and Ignagni AR. (2007) N=10: patients with 100%.8 patients have review (Garara 2016) Diaphragm pacing tetraplegia who were achieved 4 hours of added to table 2. stimulation system for injured at 18 years of continuous use. 4 tetraplegia in individuals age or younger. patients use the system injured during childhood continuously full-time, 1 or adolescence. Journal Technique: laparoscopic use part time and 4 are of Spinal Cord Medicine implantation of still in conditioning 30: Suppl-9. diaphragm pacing phase. All patients who system with completed conditioning intramuscular electrodes phase were able to Follow-up: not stated. obtain tidal volumes above expected basal rate by 44%. All patients were satisfied and stated they would recommend it to others. There were no perioperative complications and patients were discharged day after.

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Onders RP, DiMarco Case series Procedural success: Included in systematic AF, Ignagni AR et al. N=6 consecutive 83% (5/6). 1 patient review (Garara 2016) (2005) The learning patients with tetraplegia required two operations added to table 2. curve for investigational (high cervical injuries) to achieve placement of Results from 3 surgery: lessons who had a diaphragm a functioning system.1 publications reporting learned from pacing stimulation patient had a failed on the same patients laparoscopic diaphragm system implanted. procedure as a result of are presented here and pacing for chronic a false-positive phrenic some complications ventilator dependence. Technique: laparoscopic nerve conduction study. implantation of may be in the same Surgical Endoscopy 19: 3 patients use the patient. 633-637. diaphragm pacing system with system continuously DiMarco AF, Onders intramuscular electrodes full-time, 1 uses part RP, Ignagni A et al. time and 1 was still in

(2005) Phrenic nerve conditioning phase. pacing via Follow-up: not stated Tidal volumes after intramuscular conditioning increased diaphragm electrodes in to 110-1240ml. 1 tetraplegic subjects. patient had a delayed Chest 127: 671-678. asymptomatic small Onders RP, DiMarco pneumothorax, 1 had AF, Ignagni AR et al. wound infection, 1 (2004) Mapping the developed right should phrenic nerve motor pain during stimulation, point: the key to a 1 had fever and 1 had successful laparoscopic intermittent aspiration of diaphragm pacing food. All complications system in the first were managed. human series. Surgery 136: 819-826

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Onders RP, Elmo M, Case series Procedural success: Included in systematic Khansarinia S et al. N=88 patients with 99% (87/88). 1 SCI review (Garara 2016) (2009) Complete ventilator-dependent patient had a failed added to table 2. worldwide operative SCI (n = 50) and procedure as a result of Ten SCI patients were experience in respiratory- a false-positive phrenic injured as children and laparoscopic diaphragm compromised ALS (n nerve conduction study. were reported in pacing: results and =38). There was no Onders et al (2007). difference in spinal cord Technique: laparoscopic perioperative mortality It is likely that at least injured patients and even in ALS patients amyotrophic lateral implantation of 16 more SCI patients diaphragm pacing with forced vital are also reported in the sclerosis patients. capacity (FVC) below Journal of Surgical system with above studies. intramuscular electrodes 50% predicted. There However, the paper Endoscopy. 23:1433- was no cardiac 1440. Time from SCI to does not state this involvement from explicitly. implantation ranged diaphragm pacing even from 3 months to 27 when analyzed in 10 years. patients who had pre- Follow-up: 2 years existing cardiac (mean: SCI) pacemakers. No infections occurred even with simultaneous gastrostomy tube placements for ALS patients. In the SCI patients 96% were able to use DPS to provide ventilation replacing their mechanical ventilators and in the ALS studies patients have been able to delay the need for mechanical ventilation up to 24 months. Onders R P, Prospective study Diaphragmatic wires Included in systematic Khansarinia S, Weiser (multicentre) were successfully review (Garara 2016) T, Chin C, Hungness E, N=20 patients with SCI placed in all. Only1 SCI added to table 2. Soper N, Dehoyos A, (tetraplegics) and patient had a failed Cole T, and Ducko C internal cardiac procedure as a result of (2010) Multicenter pacemakers (level of a false-positive phrenic analysis of diaphragm injury not stated). nerve conduction study. pacing in tetraplegics 76% were using the with cardiac Time from SCI to system 24 hours, and pacemakers: positive implantation ranged up to 96% were able to implications for from 6 months to 24 use for 4 hours ventilator weaning in years. continuously. Safety intensive care units. Follow-up: not stated issues reported include Surgery 148(4), 893-7; capnothorax and discussion 897-8. pneumothorax

postoperatively in 42% cases. All were treated successfully. 2 cases of postoperative infection was treated with antibiotics.

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Perez IA, Kun S et al General article (2016). PATIENT EDUCATION, INFORMATION SERIES. Diaphragm Pacing by Phrenic Nerve Stimulation. American journal of respiratory and critical care medicine (193) 8 P13-P14 15. Posluszny JA, Jr , Retrospective analysis 22 patients were Included in systematic Onders R, Kerwin AJ, (multicentre study) successfully implanted. review (Garara 2016) Weinstein MS et al N=29 traumatic SCI Time from SCI to added to table 2. (2014). Multicenter patients who underwent implantation mean 40 review of diaphragm laparoscopic diaphragm days (range 3 to 112 pacing in spinal cord pacing implantation days). 72% (16/22) injury: successful not (injury type- motor were completely free of only in weaning from accident 7, diving 6, ventilator support in an ventilators but also in falls 4, gunshot wounds average of 10.2 days. 2 bridging to independent 4, athletic injuries 3, had delayed weans of respiration. The Journal bicycle collision 2, 180 days, 3 had partial of Trauma and Acute heavy object failing on weans at times during Care Surgery 76(2), spine 2, motor cycle the day and 1 patient 303-9; discussion 309- collision 1. went to long term acute 10. care and had life 7 patients were prolonging measures excluded as phrenic withdrawn. 36% (8/22) nerves were not intact. had complete recovery Follow-up: not stated. of respiration and wires were removed. Tedde M L, Onders R Case series Diaphragmatic Included in systematic P, et al (2012) Electric (prospective) pacemaker placement review (Garara 2016) ventilation: indications N=5 tetraplegic patients was successful in all. 3 added to table 2. for and technical underwent laparoscopic patients could breathe aspects of diaphragm diaphragm pacing using DPS alone for pacing stimulation implantation (4 more than 24 hours, 1 surgical implantation. electrodes implanted could use for more than Jornal Brasileiro De two on each side to 6 hours and could not Pneumologia: stimulate branches of do so at all. The initial Publicacao Oficial Da phrenic nerve). results have been Sociedade Brasileira promising. Two patients De Pneumologia E Time from SCI to presented with Tisilogia 38(5), 566-72. implantation ranged capnothorax during the from 6 months to 14 perioperative period, years. which resolved. Follow-up: 6 months.

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Tedde ML, Filho PV et Case series Diaphragmatic Included in systematic al (2012). (prospective) pacemaker placement review (Garara 2016) Diaphragmatic pacing N=5 tetraplegic patients was successful in all. 3 added to table 2. stimulation in spinal underwent laparoscopic patients could breathe This is a multiple cord injury: Anesthetic diaphragm pacing using DPS alone for publication of the same and perioperative implantation (4 more than 24 hours, 1 study above. management. Clinics electrodes implanted could use for more than (67) 11 1265-1269. two on each side to 6 hours and could not stimulate branches of do so at all. The initial phrenic nerve). results have been promising. Two patients Time from SCI to presented with implantation ranged capnothorax during the from 6 months to 14 perioperative period, years. which resolved. Follow-up: 6 months

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Appendix B: Related NICE guidance for intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

Guidance Recommendations Interventional Extracorporeal carbon dioxide removal for acute respiratory procedures failure. NICE interventional procedure guidance 564 (2016) 1 Recommendations 1.1 Current evidence on the safety of extracorporeal carbon dioxide removal (ECCO2R) for acute respiratory failure shows several serious but well-recognised complications. Evidence on its efficacy is limited in quality and quantity. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

1.2 Clinicians wishing to do ECCO2R should:  Inform the clinical governance leads in their trusts.  Ensure that patients (if possible) and their families or carers understand the uncertainty about the procedure's efficacy and the risk of complications and provide them with clear written information. In addition, the use of NICE's information for the public is recommended.  Audit and review clinical outcomes of all patients having ECCO2R (see section 1.4 and section 7.1). 1.3 Only patients with potentially reversible acute respiratory failure or those being considered for lung transplantation should be selected for this procedure. ECCO2R should only be used by specialist intensive care teams trained in its use. 1.4 NICE encourages clinicians to enter patients into ongoing trials such as the protective ventilation with veno-venous lung assist in respiratory failure (REST) trial, and to collaborate in data collection initiatives such as the Extracorporeal Life Support Organization register. Data collected should include information on patient selection criteria, thresholds for intervention, the type of ECCO2R technique being used and clinical outcomes. NICE may update the guidance on publication of further evidence.

Extracorporeal membrane oxygenation for severe acute respiratory failure in adults. NICE interventional procedure guidance 391 (2011) IP overview: intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries Page 21 of 24 IP 746/2 [IPG594]

1 Guidance This document replaces previous guidance on extracorporeal membrane oxygenation in adults (interventional procedure guidance 39). 1.1 Evidence on the safety of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adults is adequate but shows that there is a risk of serious side effects. Evidence on its efficacy is inadequate to draw firm conclusions: data from the recent CESAR (Conventional ventilation or extracorporeal membrane oxygenation for severe adult respiratory failure) trial were difficult to interpret because different management strategies were applied among many different hospitals in the control group and a single centre was used for the ECMO treatment group. Therefore this procedure should only be used with special arrangements for clinical governance, consent and research. 1.2 Clinicians wishing to undertake ECMO for severe acute respiratory failure in adults should take the following actions.  Inform the clinical governance leads in their Trusts.  Whenever possible, ensure that patients and their carers understand the uncertainty about the procedure's efficacy and its risks and provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended (available from www.nice.org.uk/IPG391/publicinfo). 1.3 Extracorporeal membrane oxygenation for severe acute respiratory failure in adults should only be carried out by clinical teams with specific training and expertise in the procedure. 1.4 Clinicians are encouraged to submit data on all adults undergoing ECMO for severe acute respiratory failure to the international Extracorporeal Life Support Organization register (www.elso.med.umich.edu). 1.5 NICE encourages further research into the use of innovative technologies for the management of severe acute respiratory failure, and may review this guidance on publication of further evidence.

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Appendix C: Literature search for intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries

Databases Date Version/files searched

Cochrane Database of Systematic 24/05/2017 Issue 5 of 12, May 2017 Reviews – CDSR (Cochrane Library)

Cochrane Central Database of 24/05/2017 Issue 4 of 12, April 2017 Controlled Trials – CENTRAL (Cochrane Library) HTA database (Cochrane Library) 24/05/2017 Issue 4 of 4, October 2016 MEDLINE (Ovid) 24/05/2017 1946 to May Week 2 2017 MEDLINE In-Process (Ovid) 24/05/2017 May 23, 2017 EMBASE (Ovid) 24/05/2017 1974 to 2017 Week 21 PubMed 24/05/2017 n/a JournalTOCS 24/05/2017 n/a The following search strategy was used to identify papers in MEDLINE. A similar strategy was used to identify papers in other databases.

Database: Medline Search Strategy: ------1 (diaphragmat* adj4 pac* adj4 stimulat*).tw. (21) 2 (diaphragmat* adj4 stimulat*).tw. (149) 3 (respirat* adj4 stimulat* adj4 system*).tw. (56) 4 DPS.tw. (1302) 5 Electric Stimulation Therapy/ (18418) 6 (electric* adj4 stimulat* adj4 therap*).tw. (826) 7 5 or 6 (18809) 8 Diaphragm/ (19407) 9 diaphragm*.tw. (36470) 10 exp Respiration/ (107725) 11 respir*.tw. (371422) 12 or/8-11 (466766) 13 7 and 12 (497) 14 1 or 2 or 3 or 4 or 13 (1988) 15 Respiratory Insufficiency/ (28786) 16 (Respirat* adj4 Insufficienc*).tw. (7155) 17 Respiratory Paralysis/ (1791) 18 (respirat* adj4 paralys*).tw. (969) 19 (respirat* adj4 depress*).tw. (6370) 20 (ventilator* adj4 depress*).tw. (599) 21 (respirat* adj4 fail*).tw. (24285) IP overview: intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by high spinal cord injuries Page 23 of 24 IP 746/2 [IPG594]

22 exp Spinal Cord Injuries/ (41716) 23 (spin* adj4 cord* adj4 injur*).tw. (28876) 24 Quadriplegia/ (7548) 25 Quadriplegia*.tw. (2278) 26 tetraplegia*.tw. (2326) 27 Paraplegia/ (12172) 28 Paraplegia*.tw. (9971) 29 Amyotrophic Lateral Sclerosis/ (14953) 30 (Amyotrophic* adj4 Latera* adj4 Sclero*).tw. (15415) 31 ALS.tw. (16153) 32 (gehrig* adj4 diseas*).tw. (93) 33 Motor Neuron Disease/ (3877) 34 (motor* adj4 neuron* adj4 diseas*).tw. (5214) 35 exp Multiple Sclerosis/ (48944) 36 MS.tw. (220519) 37 (multipl* adj4 scleros*).tw. (52772) 38 or/15-37 (398703) 39 14 and 38 (358) 40 animals/ not humans/ (4261687) 41 39 not 40 (318) 42 (201608* or 201609* or 20161* or 2017*).ed. 43 41 and 42

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