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Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

Posted in Cardiac & Vascular Repair Tools Subsegment, Frontiers in Cardiology and Cardiovascular Disorders, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Cheyne-Stokes, Cheyne-Stokes Respiration, CHF, Clinical trial, Conditions and Diseases, CSA, Doctor of Philosophy, health, Heart Failure, Phrenic nerve, Sleep and breathing, Sleep apnea, Zhang Xi on June 20, 2013| 6 Comments »

Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

Writer: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

Transvenous Phrenic Nerve Stimulation in Patients With Cheyne-Stokes Respiration and Congestive Heart Failure:A Safety and Proof-of-Concept Study

Xi-Long Zhang, MD; Ning Ding; Hong Wang; Ralph Augostini; Bing Yang; Di Xu; Weizhu Ju; Xiaofeng Hou; Xinli Li; Buqing Ni, PhD; Kejiang Cao; Isaac George; Jie Wang, MD, PhD; Shi-Jiang Zhang

Author and Funding Information

Chest. 2012; 142(4):927-934. doi:10.1378/chest.11-1899

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Related editorial/commentary:

Sleep-Disordered Breathing, Heart Failure, and Phrenic Nerve Stimulation (Chest. 2012;142(4):821-823.)

Abstract

Background: Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. Phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF. We report the clinical use of transvenous PNS in patients with CHF and CSR.

Methods: Nineteen patients with CHF and CSR were enrolled. A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA.

Results: Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate as well as improvement in oxygen saturation was seen. Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO₂ (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36).

Conclusions: The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

Trial registry: ClinicalTrials.gov; No.: NCT00909259; URL: www.clinicaltrials.gov

http://journal.publications.chestnet.org/article.aspx?articleid=1215995

Transvenous phrenic nerve stimulation in patients with Cheyne-Stokes respiration and congestive heart failure: a safety and proof-of-concept study

Zhang Xi-Long; Ding N, Wang H, Augostini R, Yang B.
CHEST 2012; 142(4):927–934
Trial registry: ClinicalTrials.gov; No.: NCT00909259; URL: http://www.clinicaltrials.gov
http://dx.doi.org/10.1378/chest.11-1899

Introduction

Cheyne-Stokes respiration (CSR), a condition characterized by a cyclic pattern of waxing and waning ventilation interposed by central apneas or hypopneas, may affect up to 40% of patients with congestive heart failure (CHF). Whether CSR is related to significantly increased morbidity and mortality 2 or has no impact on long-term survival in patients with CHF is controversial. Nevertheless, several investigators have reported that CSR might be an independent prognostic index of poor outcome in patients with CHF, so that Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. CSR in patients with CHF is believed to be associated with a hypersensitivity to arterial CO 2 during sleep. The key pathophysiologic mechanism leading to all forms of periodic breathing is the oscillation of blood CO 2 level below and above the apneic threshold. Clinically, these pathophysiologic changes may translate to sleep fragmentation, excessive daytime sleepiness, reduced exercise capacity, and, possibly, ventricular arrhythmias.

Current treatment options for CSR include medications, positive airway pressure devices such as adapt servo-ventilation, or oxygen therapy. Although all these therapies have shown benefi t in some patients, none has shown a consistent benefi t of suffi cient clinical magnitude to reduce mortality and morbidity. In the current study, we explored the initial feasibility, safety, and possible effects of unilateral, transvenous, synchronized PNS on CSR in 19 patients with CHF . This novel treatment resulted in a marked reduction of minute ventilation and possible improvement of CSR. The authors here suggest that phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF.

Study Population

Nineteen patients with CHF and CSR were enrolled. All study patients (N 5 19) had received a diagnosis of CSR and chronic CHF and were hospitalized in The First Affiliated Hospital of Nanjing Medical University (Nanjing, China). Of them, 12 with rheumatic cardiac valve disease were waiting forcardiac surgery, and seven (fi ve with dilated cardiomyopathy and two with hypertensive heart disease) were enrolled from the cardiology ward because of severe heart failure.

The inclusion criteria were aimed at identifying patients with symptoms or a diagnosed condition indicative of CSR who would tolerate the testing procedure. The patients continued on their standard medical regimen during participation, and in the case of an adverse event, medical treatment was at the discretion of the investigator. The inclusion criteria were as follows: (1) both patient and direct family member willingness to sign a Patient Ethics Committee-approved informed consent, (2) age > 18 years, (3) index CSR of > 15 times/h, (4) history of CHF with a left ventricle ejection fraction < 45%, and (5) ability to tolerate the study procedure and remain clinically stable for the duration of the study. Exclusion criteria were as follows: (1) baseline oxygen saturation < 90% on a stable FiO2 ; (2) evidence of phrenic nerve palsy; (3) temperature > 38.0°C; (4) inability to place stimulation lead (eg, coagulopathy, distorted anatomy, etc); (5) current enrollment in another clinical study that may confound the results of the present study; (6) no informed consent; (7) pregnancy or of childbearing potential without a negative pregnancy test within 10 days of the study procedure; (8) pacemaker, implantable cardioverter defibrillator, or cardiac resynchronization device; (9) severe COPD; (10) a history of myocardial infarction within 6 months prior to the study; and (11) unstable angina.

Study Design

This short-term, prospective, open-label, nonrandomized feasibility study consisted of a treatment-only cohort in which each patient served as his or her own control. After patients were screened and enrolled in the study, PNS leads were placed through an interventional procedure for observation of 1 night only. During the 1-night study, we examined whether PNS caused pain, arousal during sleep, arrhythmia, changes in BP, and changes in either normal breathing or sleep apnea. We also examined the impact of PNS on central, obstructive, and mixed sleep apnea. Alterations in sleep apnea and hypopnea events were compared before and during PNS. “Before stimulation” was defined as the number of sleep apnea and hypopnea events occurring during a segment of 10 min just before delivery of PNS and served as the control for the effects of PNS. The total number of the 10-min segments before PNS, the total number of sleep apnea and hypopnea events occurred during the sum of the 10-min time were calculated, then averaged (total number of sleep apnea and hypopnea events/total hours of the 10-min segments from all patients) and presented as the apnea-hypopnea index (AHI) for statistical analysis. AHI during PNS were also calculated and compared with AHI prior to PNS.

Sleep Study and Monitored Parameters

All participants underwent a nocturnal, in-laboratory polysomnography (Embla S4500 PSG Amplifi er; Natus Medical Inc) and were monitored for at least 7 h overnight. The standard polysomnography recorded the EEG, bilateral electrooculograms, submental electromyogram, ECG, chest and abdominal movement using respiratory effort bands, body position, nasal airflow using a pressure sensor, and oxygen saturation as measured by pulse oximetry (Sp o 2 ).

EEG, sleep staging, and arousals were monitored and scored using 30 epochs according to the method of Rechtschaffen and Kales. Classification of apnea and hypopnea was described by standard methodologies. CSR was identified as a special kind of CSA behaving as a cyclic pattern of periods of hyperventilation with waxing and waning tidal volumes alternating with periods of central hypopnea/apnea .

Lead Placement and PNS

A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA.

Results

Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. No new arrhythmias, muscle contractions, arterial BP variations, pain, or unpleasant sensations were observed once PNS was delivered during sleep for these patients. It was confirmed that the catheter could be secured adequately to obtain consistent predictable stimulation thresholds without arousal from sleep. During occurrence of CSR, intermittent PNS signals were first confirmed to be successfully captured in 16 patients. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate. An improvement in oxygen saturation and elevation of end-tidal CO2 was observed as longer continuous stimulation was performed. The period of stable breathing lasted as long as 10 to 20 min in some patients after stimulation. They found that when electric connection to the nerve was consistent, stimulation resulted in a reduced hyperventilation followed by the reduction or elimination of CSR.

Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO2 (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36).

Discussion

CSR is characterized by cyclical oscillations of respiration and apnea. The incidence of CSR ranges from 10% to 20% in patients with stable CHF and up to 40% to 50% of all patients with New York Heart Association functional class III?IV CHF. Nocturnal breathing alterations in patients with CHF are believed to be due to hypersensitivity to CO 2 during sleep. Breathing is controlled by a negative feedback system in which an increase in Pa co 2 stimulates breathing, whereas a decrease in Pa co 2 inhibits breathing. Normally, Pa co 2 is maintained within a narrow range. Patients with CHF and CSA have a more brisk ventilatory response to CO 2 than those without CSA.

The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

The study was performed using temporary catheters or leads in the right-side brachiocephalic vein, SVC, or left-side pericardiophrenic vein to transvenously stimulate the hemidiaphragm through either the leftside or the right-side phrenic nerve. To consistently stimulate the phrenic nerve using acceptable and safe current levels ( < 10 mA), the stimulation electrode needs to be within 2 to 5 mm from the phrenic nerve. This type of stimulation caused significantly improved respiratory parameters in patients with CHF and further support that oscillation of CO 2 level in the blood below and above the apneic threshold is a central mechanism leading to the CSR pattern of breathing. Stabilization of CO 2 levels through PNS produced a regular breathing pattern, improvement in oxygen saturation, and fewer apneic events.

Dr. Isaac George: contributed to data evaluation and drafting of the manuscript.

Hypothyroidism increased mortality risk in patients with congestive HF. (zedie.wordpress.com)

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