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Effects of restoration of cough via spinal cord stimulation on subject quality of life

  • Anthony F. DiMarco
    Correspondence
    Corresponding author. Department of Physical Medicine & Rehabilitation Case Western Reserve University MetroHealth Medical Center Rammelkamp Center for Education & Research 2500 MetroHealth Drive, R551 Cleveland, OH, 44109-1998, USA.
    Affiliations
    Department of Physical Medicine and Rehabilitation, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA

    Department of Research, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA
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  • Robert T. Geertman
    Affiliations
    Department of Neurosurgery, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA
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  • Gregory A. Nemunaitis
    Affiliations
    Department of Physical Medicine and Rehabilitation, Cleveland Clinic, Cleveland, OH, USA
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  • Krzysztof E. Kowalski
    Affiliations
    Department of Physical Medicine and Rehabilitation, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA

    Department of Research, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, USA
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Published:September 26, 2022DOI:https://doi.org/10.1016/j.jcot.2022.102027

      Abstract

      Objectives

      To determine participant quality of life before and after use of the cough stimulation system (Cough System).

      Design

      Prospective assessment of life quality at 4 timepoints via questionnaire responses.

      Setting

      Out-patient hospital, United States.

      Participants

      28 subjects with spinal cord injury (SCI) completed life quality assessment questionnaires before and at the 28- 40- and 52-week timepoints following use of the Cough System.

      Results

      Each subject demonstrated significant clinical improvements in terms of restoration of an effective cough and ability to manage airway secretions with use of the Cough System. Positive airway pressures and peak expiratory airflows approached values associated with a normal cough. Related to cough/secretion management, use of this system also resulted less interference with family life and daily activities, less financial difficulties, less requirement for caregiver assistance, less stress, less embarrassment and greater control of their breathing problems (p < 0.01), for each comparison). There also significant improvements in that their overall health and quality of life (p < 0.01, for each comparison). Subjects also reported greater ease in breathing, restored ability to sneeze and enhanced mobility. The incidence of acute respiratory tract infections fell from 1.3 ± 0.3 to 0.2 ± 0.1 events/subject year (p < 0.01). Ten subjects developed mild hemodynamic effects consistent with autonomic dysreflexia that abated completely with continued use of the Cough System. Some subjects experienced mild leg jerks during SCS, which were well tolerated and abated completely with reduction in stimulus amplitude, No subjects reported bowel or bladder leakage.

      Conclusion

      Use of the Cough System by SCI subjects is a safe and efficacious method which significantly improves life quality and has the potential to reduce the mortality and morbidity associated with SCI.

      Keywords

      1. Introduction

      Individuals with cervical spinal cord injury (SCI) suffer from devastating muscle paralysis below the level of injury imposing significant and substantial physical limitations.
      • Brown R.
      • DiMarco A.F.
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      Respiratory dysfunction and management in spinal cord injury.
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      Pulmonary dysfunction following traumatic quadriplegia. Recognition, prevention, and treatment.
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      Effect of spinal cord injury on the respiratory system: basic research and current clinical treatment options.
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      Respiratory complications of spinal cord injury.
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      Respiratory aspects of spinal cord injury management.
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      Cough in tetraplegic subjects: an active process.
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      Respiratory management in the patient with spinal cord injury.
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      Incidence of respiratory complications following spinal cord injury.
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      • Luce J.M.
      The diagnosis and management of neuromuscular diseases causing respiratory failure.
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      • Abrams P.
      Recognition and effective management of autonomic dysreflexia in spinal cord injuries.
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      • Solinsky R.
      • et al.
      Diastolic blood pressure changes during episodes of autonomic dysreflexia.
      In addition to the obvious restrictions on movement, less attention has been paid to the fact that most cervical and upper thoracic SCI patients also suffer from expiratory muscle paralysis which results in an ineffective cough.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Kowalski K.E.
      Complete restoration of respiratory muscle function in three subjects with spinal cord injury: pilot interventional clinical trial.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Economic consequences of an implanted neuroprosthesis in subjects with spinal cord injury for restoration of an effective cough.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Case report: minimally invasive method to activate the expiratory muscles to restore cough.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-sponsored clinical trial. Part I: methodology and effectiveness of expiratory muscle activation.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Spinal cord stimulation: a new method to produce an effective cough in patients with spinal cord injury.
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      Lack of an effective cough has dire consequences as these patients have great difficulty clearing secretions and are at risk of developing inspissated secretions, recurrent aspiration, atelectasis, bronchitis and pneumonia. In fact, respiratory tract infections represent one the most common causes of death in this patient population.
      • Brown R.
      • DiMarco A.F.
      • Hoit J.D.
      • Garshick E.
      Respiratory dysfunction and management in spinal cord injury.
      ,
      • Lim J.
      • Gorman R.B.
      • Saboisky J.P.
      • Gandevia S.C.
      • Butler J.E.
      Optimal electrode placement for noninvasive electrical stimulation of human abdominal muscles.
      In recently completed clinical trials,
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Kowalski K.E.
      Complete restoration of respiratory muscle function in three subjects with spinal cord injury: pilot interventional clinical trial.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Economic consequences of an implanted neuroprosthesis in subjects with spinal cord injury for restoration of an effective cough.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Case report: minimally invasive method to activate the expiratory muscles to restore cough.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-sponsored clinical trial. Part I: methodology and effectiveness of expiratory muscle activation.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Spinal cord stimulation: a new method to produce an effective cough in patients with spinal cord injury.
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      we demonstrated that lower thoracic spinal cord stimulation (SCS) applied with both disc and wire electrodes (Cough System) results in the generation of large airway pressures and peak expiratory airflow rates resulting in an effective cough mechanism. Use of the Cough System resulted in greater ease in raising secretions, less requirement of caregiver support and a significant reduction in the incidence of respiratory tract infections.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      ,
      • DiMarco A.F.
      • Geertman R.T.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Comparison of disc and wire electrodes to restore cough via lower thoracic spinal cord stimulation.
      In addition to the physiologic benefits of the Cough System, the effects of the Cough System on components of subject life quality are also critically important. It is well known that life quality is a complex concept which is influenced by a large number of factors including, but not limited to, physical and psychological health, social relationships and responsibilities and personal beliefs.
      • Post M.W.
      Definitions of quality of life: what has happened and how to move on.
      • Umberson D.
      • Montez J.K.
      Social relationships and health: a flashpoint for health policy.
      • Wilson J.R.
      • Hashimoto R.E.
      • Dettori J.R.
      • Fehlings M.G.
      Spinal cord injury and quality of life: a systematic review of outcome measures.
      Important components of life quality, include mental health, satisfaction with life, level of independence, ethnic and racial backgrounds, level of self-esteem, presence of pain and, importantly, the interaction between these components
      • Post M.W.
      Definitions of quality of life: what has happened and how to move on.
      • Umberson D.
      • Montez J.K.
      Social relationships and health: a flashpoint for health policy.
      • Wilson J.R.
      • Hashimoto R.E.
      • Dettori J.R.
      • Fehlings M.G.
      Spinal cord injury and quality of life: a systematic review of outcome measures.
      • Carrard V.
      • Kunz S.
      • Peter C.
      Mental health, quality of life, self-efficacy, and social support of individuals living with spinal cord injury in Switzerland compared to that of the general population.
      • Carlozzi N.E.
      • Graves C.M.
      • Troost J.P.
      • Ehde D.M.
      • Miner J.A.
      • Kratz A.L.
      Association of physical and mental symptoms with cognition in people with spinal cord injury.
      • Kumar N.
      • Gupta B.
      Effect of spinal cord injury on quality of life of affected soldiers in India: a cross-sectional study.
      • Zwecker M.
      • Heled E.
      • Bluvstein V.
      • Catz A.
      • Bloch A.
      • Zeilig G.
      Assessment of the unmediated relationship between neurological impairment and health-related quality of life following spinal cord injury.
      It is not surprising therefore that individuals presented with the same external challenges are likely to respond quite differently.
      To explore this issue, we developed a life quality questionnaire which was directed toward respiratory care management. In previous preliminary reports, we demonstrated that use of the Cough System did result in some improvement in some measures of life quality.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      A significant limitation of this prior analysis however was that previous studies involved a very small number of participants (n = 917 and n = 1019). This limitation is highlighted by the multiple components of life quality and the complex interaction between them, as mentioned above.
      In the present report, we expanded our previous analysis to evaluate quality of life assessments of all subjects who underwent implantation of the Cough System, which involved 28 subjects. Moreover, this assessment was monitored over a 1-year period.

      2. Material and methods

      This investigation was approved by the Institutional Review Board of Metrohealth Medical Center, the National Institute of Neurological Disorders and Stroke and the Food and Drug Administration. Informed consent was obtained from each participant prior to enrollment in the study.
      With the exception of one subject who suffered a spinal cord infarct related to spinal surgery and another who suffered a spinal cord infection, each subject had suffered from a traumatic spinal cord injury (Table 1). One subject had a high thoracic SCI while the remaining had cervical SCI. Importantly, each subject had marked expiratory muscle weakness as demonstrated by maximum expiratory pressure (MEP) measurements of less than 30% of predicted values, measured at total lung capacity. Individuals with significant lung, cardiac or brain disease were excluded from participation. Subjects who had suffered from a recent infection (within 6 weeks), regardless of source or/and untreated lung, cardiovascular or brain disease or/and unmanaged hypertension or hypotension, were also excluded.
      Table 1Clinical data of the participants.
      ParticipantSexAge at Implantation (y)Cause of InjuryLevel of InjuryASIAElapsed Time Since Injury (y)Spontaneous Vital Capacity (L) (% predicted)Peak Expiratory Flow (L/s) (% predicted)Maximal Expiratory Pressure (cmH2O) (% predicted)
      1M52MVAC5/C6A72.0 (39)2.1 (21)21 (10)
      2F28MVAC3A220.4 (11)0.7 (12)16 (10)
      3M42GSWC4A191.2 (29)1.4 (16)21 (10)
      4M28SportC4/C5A22.6 (45)2.28 (21)26 (11)
      5M50ViolenceC5/C6A122.4 (47)2.0 (21)24 (11)
      6M23DivingC4/C5A10.9 (17)1.8 (19)24 (11)
      7M45TrampolineC5/C6A21.4 (23)2.1 (20)20 (9)
      8M49DivingC3/C4A341.7 (30)2.0 (18)22 (10)
      9M52MVAC3A191.7 (30)2.4 (23)28 (13)
      10M60FallC2A40.3 (7)0.4(4)3(1)
      11M21MVAC4A22.2 (42)2.0 (21)28 (12)
      12F63SurgeryC5A192.1 (62)3.2 (51)22(16)
      13M51FallT5A33.7 (76)6.5 (68)59 (25)
      14M34DivingC3A11.4 (24)2.7 (26)45(15)
      15F20MVAC3A31.3 (34)2.5 (36)35 (16)
      16M45GSWC4A31.2 (19)1.0 (9)15 (5)
      17M64MVAC5/C6A471.1 (25)2.6 (32)36 (18)
      18M50GSWC4A21.2 (28)2.0 (22)20 (9)
      19M27FallC3/C4A51.6 (27)2.2 (20)18 (8)
      20M28FallC2A91.6 (26)1.2 (11)41 (18)
      21M57Farm AccidentC4A371.1 (22)2.8 (28)15 (7)
      22M48MVAC1–C4A90.4 (7)0.4 (4)4 (2)
      23M58MVAC5–C7A42.2 (51)4.2 (48)29 (14)
      24M50Equipment AccidentC4–C6A33.4 (67)5.9 (60)59 (25)
      25M36Infection/AbscessC3–C6A31.8 (31)2.7 (25)21 (9)
      26M35FallC6A43.5 (73)2.7 (29)21 (9)
      27M30DivingC3A21.5 (35)2.6 (28)33 (14)
      28M33MVAC7/T1A21.1 (21)2.6 (26)16 (7)
      MEAN42.110.01.7(33.9)2.4(25.7)25.8(11.6)
      SE2.52.30.2(3.5)0.3(2.9)2.5(1.1)
      ASIA, American Spinal Cord Injury impairment scale; M, Male; F, Female; MVA – Motor Vehicle Accident; GSW – Gunshot Wound; SE – Standard Error.
      Implantation of the Cough System involved use of disc or wire electrode technology. Disc electrodes (4 mm) (Freehand Epimysial Electrode: NeuroControl Corp., 833 Rockside Rd, Valley View, OH 44125, USA were placed at the T9, T11 and L1 levels via hemilaminotomy incisions. A separate ground electrode was positioned in the thoracolumbar fascia. Place of wire electrodes (Ardiem Medical Inc (AM)., Indiana, PA, USA) involved a less invasive procedure which required only a small incision at the L1-L2 interspace. The cephalad electrode of each lead was positioned at the T9 spinal cord level which resulted in the more caudal electrode of each lead positioned at the T11 spinal level. With the disc electrodes, monopolar stimulation was applied via combined stimulation of 2 of the 3 electrode discs, usually at the T9 and T11 spinal sites. With wire electrodes, bipolar stimulation was applied at the T9 and T11 spinal levels. With both systems, the electrodes wires were tunneled subcutaneously and connected to a radiofrequency receiver (Finetech Medical Ltd, 13 Tewin Court, Welwyn Garden City, Herfordshire AL7 1 AU, UK) positioned in a subcutaneous pocket over the anterior portion of the chest wall.
      Subjects were instructed to apply electrical stimulation every 30 s for 5–10 min, 2–3 times/day on a chronic basis and also as needed for management of airway secretions or removal of foreign bodies such as aspiration of food particles.
      Currently, there are no generally accepted quality of life assessments with regard to restoration of respiratory muscle function in patients with SCI. More importantly, there are no specific measuring instruments that relate to secretion management. For this reason, we developed a life quality assessment questionnaire that addresses issues related to respiration, cough, and secretion management including the need for suctioning. We have utilized this questionnaire in previous analysis
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      and believe that it more accurately assesses the potential impact of restoration of an effective cough. The study participants were asked 7 questions with a rating of 0–3 which corresponded to not at all (0) to very much
      • Carter R.E.
      Respiratory aspects of spinal cord injury management.
      and 3 more open-ended questions with a rating of 0–7 which corresponded to very poor (0) to excellent.
      • Kelly B.J.
      • Luce J.M.
      The diagnosis and management of neuromuscular diseases causing respiratory failure.
      This questionnaire was completed prior to implantation of the Cough System and repeated at the 28 and 40-week timepoints and, also at the 52-week timepoints.
      The prevalence of acute respiratory tract infections, defined by a change in the character, color, or amount of respiratory secretions and requiring antibiotic administration was tracked over the 2-year period prior to implantation of the Cough System. The incidence of respiratory tract infections was determined by study participant medical history and validated by review of medical records, when available. After implantation of the Cough System, the incidence of acute respiratory tract infections was documented.
      Data obtained prior to implantation of the Cough System were compared with data obtained following implantation at 4 different timepoints using a non-parametric analog (Freidman Test) to the standard repeated-measures analysis of variance. Statistical significance was accepted with p values < 0.05. This level of alpha was selected to account for possible inflated type I error rates given the multiple comparisons. All results are reported as mean ± SE.

      3. Results

      The demographic and clinical data of these subjects is presented in Table 1. A total of 29 subjects were implanted with the Cough System. One subject was eliminated from this analysis since he underwent removal of the device within a few months of implantation secondary to the development of spasms which were unrelated to applied electrical stimulation. Of the 28 participants in this study, 17 were implanted with the disc electrode while the remainder were implanted with the wire electrode technology. Vital capacity measurements ranged between 7 and 76% of predicted values (mean 34 ± 4% predicted). Each subject had evidence of marked expiratory muscle weakness as demonstrated by markedly reduced maximum expiratory pressure measurements, which ranged between 1 and 25% of predicted values (mean 12 ± 1% predicted).
      Mean peak airflow and expiratory pressure generation during spontaneous efforts pre-implantation were 2.4 ± 0.3 L/s and 25.8 ± 2.5 cmH2O, respectively. While using the Cough System, peak airflow rates and airway pressure generation values were significantly higher at TLC (8.3 ± 0.9 L/s and 112.4 ± 9.9 cmH2O) and TLC with subject effort (9.7 ± 1.0 L/s and 125.5 ± 9.0 cmH2O), (p < 0.01 for each comparison compared to baseline values).
      The mean results of the suctioning/assisted cough and sputum index are shown in Fig. 1. There was significant improvement in each of the assessed parameters at the 28-week timepoint and maintained at each of the subsequent timepoints. The frequency of secretion management improved from occasional (3–5 times/day) to none or rare (#1). The difficulty in raising secretions improved moderate to between none and mild (#2). The need for assistance with managing airway secretions on a typical day improved from moderate (must stop activity for at least brief periods) to between none and mild (did not interfere with usual daily activities) (#3). Finally, there was marked improvement in the ease in raising secretions (#4).
      Fig. 1
      Fig. 1Subject responses to frequency of need for conventional means of secretion clearance, severity of such episodes, difficulty in raising secretions and change in ease in raising secretions using the Cough System compared with previous methods. Compared to pre-implant, there were significant improvements in all parameters of secretion management at the 28-week timepoint and maintained at each of the subsequent timepoints. (p < 0.01 compared with pre-implant values for each).
      The number of respiratory tract infections fell significantly from a mean of 1.4 ± 0.3 prior to implantation of the Cough System to 0.2 ± 0.1 events/subject year at the one-year timepoint (p < 0.01).
      The mean responses to the life quality questionnaire are presented in Fig. 2. Participants indicated that their overall physical condition or medical treatment had less interference with family life (question #1). Their physical condition or medical treatment caused less financial difficulties (question #2). There was less requirement for suctioning or some other form of assisted cough (question #4). The need for cough interfered less with daily activities (question #5), level of stress related to the need for coughing assistance was reduced (question #6), there was also less embarrassment associated with coughing or respiratory problems in the prior 2 wks (question #7.) On a scale of 0–7 (0 = very and 7 = excellent), subjects felt they were in much better control of their breathing problems since this rating increased from 3.8 ± 0.4 (poor) to 6.6 ± 0.1 (excellent) (question #8). Their rating of overall health increased from 4.5 ± 0.4 (poor) pre-implant to 6.1 ± 0.1 (excellent) and finally subjects rated their overall quality of life 4.3 ± 0.4 (poor) to 6.0 ± 0.2 (excellent). In each instance, improvements noted at week #28, were maintained at all subsequent timepoints (p < 0.01 for each comparison, at each of the timepoints).
      Fig. 2
      Fig. 2Subject responses to life quality assessment. There was significant improvement in all parameters at weeks 28, 40, 52 compared to pre-implant values (p < 0.01 for each).
      Fig. 2
      Fig. 2Subject responses to life quality assessment. There was significant improvement in all parameters at weeks 28, 40, 52 compared to pre-implant values (p < 0.01 for each).
      The responses to the question concerning the most significant effect of use of the Cough System demonstrated additional benefits which are provided in (Table 2). In each instance, the responses were positive and, in some cases, overwhelmingly positive. Several responses indicated greater ease in breathing. Others indicated more clear lungs, restoration of ability to sneeze and greater energy.
      Table 2Most significant effect of the cough system.
      SubjectComments
      1Works great, without it I would have died
      2Mom wrote: “The system keeps his lungs clear that there is no congestion in the mornings!“, “He said he feels like his nose is so clear that he feels his nostrils are open as wide as penny rolls.” “It keeps my airway so clear that I forget about the stimulator and don't think to use it.” “My abdominal muscles are getting stronger. When they take off my binder, my gut doesn't hang out!"
      3“I can breathe so much better now!” Form F#4 ″Indicate change in ease using Cough Stim vs. previous methods” stated “Best possible [method]!!"
      4So, good system
      5Works great. Thanks so much
      6I can breathe easier. My lungs are clearer. I would have been hospitalized by now for pneumonia before I had the implant. I have food particles coming up often and this is how I had developed pneumonia in the past, now my lings are clear of this problem.
      7Much better breathing while sleeping per wife, “not shallow & fast like before” I have no trouble singing at church, voice is stronger. I went back to work because of this system. I'm very thankful for this system.
      8I have more energy.
      9Great for clearing phlegm
      10Best invention ever. Helps even for blowing nose
      I wanted to say “Thank you” again. This device has been a life saver. The knowledge and ideas, research and production of this product is appreciated more than you know. Before I had the implant, I was hospitalized at least twice a year for upper respiratory complications and pneumonia. Each time was life threatening. I was almost intubated numerous times and placed on Bi-pap. I was almost tracheid on two occasions. Since the implant there has only been one upper respiratory infection. This is the best thing we have done since my surgery. It is a game changer for anyone with compromised respiratory function that comes with spinal injuries. Thank you, Thank you!
      It seems a simple Thank you isn't enough but Thank you from the bottom of our hearts for introducing the cough system to us. It definitely is a positive part of our lives since the injury. My quality of life has improved greatly, enough that others have noticed the difference. We are very grateful for the implantation and your encouragement. It is very helpful with the bathroom routine. A huge Blessing indeed.
      Use of the Cough System was associated with some side effects, most notably increases in blood pressure and decreases in heart rate, consistent with autonomic dysreflexia (AD).
      • Wan D.
      • Krassioukov A.V.
      Life-threatening outcomes associated with autonomic dysreflexia: a clinical review.
      This side effect occurred with both the disc and wire electrodes and was not associated with any symptoms. AD was limited to the early phase of SCS and occurred in a total of 10 subjects. Over a period of several weeks of daily SCS however, this response gradually abated and eventually resolved in each subject. Mild back and leg jerking without associated discomfort was also observed in some subjects. This effect was well controlled by reducing the intensity of SCS. There was no evidence of bowel or bladder leakage.

      4. Discussion

      The results of this investigation demonstrate that use of the Cough System was associated with significant improvements in several measures of life quality related to respiratory management. In addition, there were significant improvements in questions directed to overall health and life quality, as well. Moreover, these improvements were noted at week #28 and importantly, were maintained over several timepoints of follow-up, extending over a 1-year period.
      As in our previous reports involving both the disc
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Economic consequences of an implanted neuroprosthesis in subjects with spinal cord injury for restoration of an effective cough.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-sponsored clinical trial. Part I: methodology and effectiveness of expiratory muscle activation.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • Hromyak D.R.
      Spinal cord stimulation: a new method to produce an effective cough in patients with spinal cord injury.
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      and wire
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Kowalski K.E.
      Complete restoration of respiratory muscle function in three subjects with spinal cord injury: pilot interventional clinical trial.
      ,
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.
      ,
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Polito R.R.
      • Kowalski K.E.
      Case report: minimally invasive method to activate the expiratory muscles to restore cough.
      electrodes, the present analysis confirms the generation of large peak expiratory airflows and airways pressures, in the range of that associated with a normal cough, associated with use of SCS. Moreover, these physiologic improvements were associated with significant and substantial improvements in secretion management and reductions in the incidence of respiratory tract infections.
      In previous studies of the Cough System with use of the disc electrode, we also evaluated these same measures of life quality.
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      This analysis however was limited to a much smaller group of only 9
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      or 10
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      subjects. These studies demonstrated significant improvements in measures of life quality related to respiratory management which were maintained over long-term follow-up of a mean 4.6 ± 0.6 years period.
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      In contrast to the present study however, these previous studies did not demonstrate any significant improvements with questions related to overall health nor overall life quality. The reason for these differences may relate to the fact that the current analysis involved a much larger sample size.
      The assessment of life quality utilized in the present study, which was primarily focused on respiratory issues, in particular secretion management, had far reaching effects on multiple aspects of daily living. These included reductions in interference with family life, reduction in financial difficulties, less interference with daily activities, less stress and less embarrassment associated with their respiratory problems. These findings highlight the importance of expiratory muscle function and restoration of an effective cough which may not have been otherwise apparent.

      4.1 Other side effects of the Cough System

      It is important to note that the Cough System was developed to restore expiratory muscle function to provide an effective cough and, it is likely that much of the improvement in life quality measures observed in this study are related to this important function. However, it should be noted that restoration of expiratory muscle function had other beneficial side effects including improvement in pulmonary function
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.
      and bowel management (BM).
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Case report: effects of lower thoracic spinal cord stimulation on bowel management in a person with spinal cord injury.
      ,
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Effects of lower thoracic spinal cord stimulation on bowel management in individuals with spinal cord injury.
      In a previous analysis, we demonstrated that significant improvements were noted in inspiratory capacity and maximum inspiratory pressure, which is a measure of inspiratory muscle strength.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Restoration of cough via spinal cord stimulation improves pulmonary function in tetraplegics.
      These improvements were consistent with several participants’ anecdotal reports of the ability to take deeper breaths and breathe more easily in prior studies
      • DiMarco A.F.
      • Kowalski K.E.
      • Geertman R.T.
      • et al.
      Lower thoracic spinal cord stimulation to restore cough in patients with spinal cord injury: results of a National Institutes of Health-Sponsored clinical trial. Part II: clinical outcomes.
      ,
      • DiMarco A.F.
      • Kowalski K.E.
      • Hromyak D.R.
      • Geertman R.T.
      Long-term follow-up of spinal cord stimulation to restore cough in subjects with spinal cord injury.
      and also in the current study following which subjects were asked to relay the most significant effect of the Cough System. Related to BM, this parameter was assessed prospectively in 5 subjects who underwent implantation of the Cough System wire electrodes.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Nemunaitis G.A.
      • Kowalski K.E.
      Effects of lower thoracic spinal cord stimulation on bowel management in individuals with spinal cord injury.
      The time required for BM routines was reduced from ∼118 for ∼18 min. Importantly, the reduction in BM routines was indirectly related to the magnitude of airway pressure development. Mechanical methods for BM were eliminated in 4 subjects. Importantly, none of the participants experienced fecal incontinence. Therefore, it is possible, even likely, that some of the observed improvements in the life quality assessment were related to these important side effects.

      4.2 Comparison to previous studies

      With regard to BM, surface abdominal stimulation has been applied to activate the expiratory muscles in patients with multiple sclerosis.
      • Lin S.D.
      • Butler J.E.
      • Boswell-Ruys C.L.
      • et al.
      The effect of abdominal functional electrical stimulation on bowel function in multiple sclerosis: a cohort study.
      Subjects used the device, 1 h/day for 6 weeks. While there were no significant changes in colonic transit times, this study also demonstrated an improvement in quality of life in these individuals.
      Related to restoration of inspiratory muscle function, a life quality assessment has also been performed following institution of diaphragm pacing (DP).
      • DiMarco A.F.
      • Onders R.P.
      • Kowalski K.E.
      • Miller M.E.
      • Ferek S.
      • Mortimer J.T.
      Phrenic nerve pacing in a tetraplegic patient via intramuscular diaphragm electrodes.
      • DiMarco A.F.
      • Onders R.P.
      • Ignagni A.
      • Kowalski K.E.
      • Mortimer J.T.
      Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects.
      • DiMarco A.F.
      • Onders R.P.
      • Ignagni A.
      • Kowalski K.E.
      Inspiratory muscle pacing in spinal cord injury: case report and clinical commentary.
      • DiMarco A.F.
      • Geertman R.T.
      • Tabbaa K.
      • Kowalski K.E.
      Complete restoration of respiratory muscle function in three subjects with spinal cord injury: pilot interventional clinical trial.
      • DiMarco A.F.
      • Takaoka Y.
      • Kowalski K.E.
      Combined intercostal and diaphragm pacing to provide artificial ventilation in patients with tetraplegia.
      With injuries cephalad of the C3–C5 spinal level, patients are dependent upon mechanical ventilation. In many of these patients with intact phrenic nerve function however, diaphragm pacing (DP) utilizing electrical stimulation techniques, can be provided as a means to liberate patients from mechanical ventilation. DP provides a more natural form of breathing, increases mobility, increases occupational opportunities, improves the sense of smell and possibly reduces the incidence of respiratory tract infections.

      4.3 Limitations

      The questionnaire utilized to evaluate life quality in this study is not a validated instrument. In this regard, there are no generally accepted quality of life assessments specific for the spinal cord population. More specifically, there are no assessment measures which address respiratory issues, particularly secretion management. Despite this limitation however, we feel confident that the questionnaire developed for this study provides a reasonable estimate of the clinical impact of use of the Cough System.
      While the number of participants in this study is substantially larger than our previous analyses of life quality following use of the Cough System, the total number is still relatively small and limited to a single study site. Further investigations, including a multi-center trial will be necessary therefore to confirm the results presented herein.

      5. Conclusion

      Activation of the expiratory muscles via lower thoracic SCS (with either disc or wire electrodes) in subjects with cervical and high thoracic SCI, results in significant improvements in several parameters of life quality. These improvements can be attributed to restoration of an effective cough and, to some extent, improvements in pulmonary function and bowel management.

      ClinicalTrials.gov identifier

      NCT00116337, NCT01659541, FDA IDE: G980267.

      Funding

      This work was supported by the National Institute of Neurological Disorders and Stroke ( R01 NS049516 and U01 NS083696 ), Neilson Foundation ( 278855 ), NCRR ( M01RR000080 and UL1RR024989 ). This project was supported by the Clinical and Translational Science Collaborative (CTSC) of Cleveland which is funded by the National Institutes of Health (NIH) , National Center for Advancing Translational Science (NCATS) , Clinical and Translational Science Award (CTSA) grant, UL1TR002548 .

      Declaration of competing interest

      Dr. DiMarco holds two United States Patents for technology related to the content of this paper: Method and Apparatus for Electrical Activation of the Expiratory Muscles to Restore Cough (5,999,855); Bipolar Spinal Cord Stimulation to Activate the Expiratory Muscles to Restore Cough (8,751,004); System and Method for Activating Inspiratory and Expiratory Muscle Function (10,549,100).
      This investigation was approved by the Institutional Review Board of MetroHealth Medical Center (IRB98-00091 and RB15-00014).

      Acknowledgements

      The authors gratefully acknowledge the surgical assistance of Dr. Kutaiba Tabbaa, MD and statistician Charles Thomas, B.A.

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