Download Effect of Bipolar Electrode Spacing on Phrenic Nerve Stimulation

Effect of Bipolar Electrode Spacing on Phrenic Nerve
Stimulation and Left Ventricular Pacing Thresholds
An Acute Canine Study
Mauro Biffi, MD; Laurie Foerster, BS; William Eastman, BS; Michael Eggen, PhD;
Nathan A. Grenz, BS; John Sommer, BS; Tiziana De Santo, MSc; Tarek Haddad, MSc;
Annamaria Varbaro, MS; Zhongping Yang, PhD
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Background—Phrenic nerve stimulation (PNS) is a common complication of cardiac resynchronization therapy when left
ventricular (LV) pacing occurs via a coronary vein. The purpose of this study was to evaluate the effects of bipolar
electrode spacing on PNS and LV pacing thresholds.
Methods and Results—Electrophysiology catheters with standard (2 mm-5 mm-2 mm) or modified (1 mm-5 mm-1 mm)
interelectrode spacing was, respectively, inserted in a posterior/lateral cardiac vein in a randomized order in 6 anesthetized
dogs via jugular access. The phrenic nerve was dissected via a left minithoracotomy and repositioned over the vein as
close as possible to one of the electrodes. The presence of PNS was verified (ie, PNS threshold <2 V at 0.5 ms in unipolar
configuration). Bipolar pacing was delivered using the electrode closest to the phrenic nerve as the cathode, and multiple
bipolar electrode spacing configurations were tested. During bipolar pacing, PNS threshold increased as bipolar electrode
spacing was reduced (P<0.05), whereas LV pacing thresholds did not change significantly (P>0.05). Compared with
a standard bipolar electrode spacing of 20 mm for LV leads, 1 and 2 mm bipolar electrode spacing resulted in a PNS
threshold increase of 5.5±2.2 V (P=0.003) and 2.8±1.7 V (P<0.001), respectively. Similarly, PNS threshold increased
by 6.5±3.7 V with 1 mm and by 3.8±1.9 V with 2 mm bipolar pacing (both P<0.001), compared with unipolar pacing.
Conclusions—This study suggests that reducing LV bipolar electrode spacing from the standard 20 mm to 1 or 2 mm may
significantly increase the PNS threshold without compromising LV pacing thresholds. (Circ Arrhythm Electrophysiol.
2012;5:815-820.)
Key Words: interelectrode spacing ◼ cardiac resynchronization therapy ◼ phrenic nerve stimulation
C
ardiac resynchronization therapy (CRT) is an established
treatment of heart failure because of left ventricular (LV)
systolic dysfunction, with evidence of electric and mechanical
dyssynchrony.1,2 The mechanism of improvement with CRT
is based on the stimulation of the mostly delayed LV sites.3–5
Phrenic nerve stimulation (PNS) is a major complication that
may result in withdrawal of CRT. PNS is observed in 33%
to 37% of patients,6–8 and although it is actively addressed
in different ways during implantation,6 it may be difficult to
overcome in the long-term management of CRT patients.9–11
Indeed, ≈15% of patients need to be reevaluated after hospital discharge because of PNS occurrence at follow-up,9–11 and
≈6.6% eventually report PNS symptoms at long-term followup, despite multiple attempts to avoid PNS.10
solution has fully addressed this demanding challenge.12 We
sought to investigate the physiological principles of PNS
occurrence in an animal model to develop a comprehensive
strategy aimed at PNS avoidance in the clinical practice.
Methods
This was an acute open-chest study on 6 anesthetized adult dogs. The
dogs were premedicated with morphine (1 mg/kg IM), and anesthesia was induced with propofol (120 mg IV) and isoflurane to effect.
ECG limb leads were placed and connected to an electrophysiology
(EP) recording station (Prucka; GE Medical Systems) for monitoring.
A jugular access was obtained, and a standard Attain catheter
(model 6216A; Medtronic Inc, Minneapolis, MN) was introduced
in the coronary sinus to perform a venogram (Figure 1A). An
implantable cardioverter-defibrillator lead (model 6935; Medtronic
Inc) was implanted in the right ventricle via jugular access to provide
an anodal electrode for unipolar measurements and to guarantee
backup pacing, if necessary.
Decapolar EP catheter with standard (2 mm-5 mm-2 mm) interelectrode spacing (model 041590CS, Torqr; Medtronic Inc) and modified
(1 mm-5 mm-1 mm) interelectrode spacing was placed into a posterior/
Clinical Perspective on p 820
Device manufacturers have developed approaches to manage PNS, such as electronic repositioning, multiple pacing
vectors, and modification of the pacing output, but no definite
Received February 6, 2012; accepted June 29, 2012.
From the Institute of Cardiology, University of Bologna, Bologna, Italy (B.M.); Medtronic Inc, Minneapolis, MN (F.L., E.B., E.M., G.N., S.J., H.T., Y.P.);
and Medtronic Italia S.p.A, Rome, Italy (D.S.T., V.A.).
Correspondence to Mauro Biffi, MD, Institute of Cardiology, University of Bologna Via Massarenti 940138 Bologna, Italy. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org
815
DOI: 10.1161/CIRCEP.112.971317
816 Circ Arrhythm Electrophysiol August 2012
Figure 1. Fluoroscopic image of the coronary vein angiogram (A) and of catheter and
phrenic nerve location (B). TPNE indicates
targeted phrenic nerve electrode.
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lateral cardiac vein, respectively, in a randomized order under fluoroscopic guidance. The phrenic nerve was dissected via a left minithoracotomy and repositioned over the vein as close as possible to one of the
electrodes. Radiopaque markers (model V60 U-Clips; Medtronic Inc)
were placed next to the nerve to document nerve location on fluoroscopy
after the chest was closed (Figure 1B). During pacing, PNS was detected
using tactile feel by placing a hand directly on the chest, and the presence
of PNS was verified (ie, PNS threshold <2 V at 0.5 ms in unipolar configuration). Once the phrenic nerve was repositioned, unipolar electric
measurements of PNS and LV pacing (LVP) thresholds were taken using
all the 10 electrodes of the EP catheters as cathodes and the coil of the
implanted right ventricle lead as anode. The electrode on the EP catheters
with the lowest PNS threshold in unipolar configuration was identified as
the targeted phrenic nerve electrode (TPNE), which was considered to
be closest to the phrenic nerve (Figure 1B). Finally, bipolar pacing was
delivered using TPNE as the cathode (the electrode closest to the phrenic
nerve) to test 9 bipolar electrode spacing configurations of the decapolar
EP catheters. In each configuration, PNS and LVP thresholds were measured at 0.5 ms pulse width by an amplitude step-down protocol from
10 to 0.1 V by pacing at 130 beats per minute using the analyzer (model
2290; Medtronic Inc).The LVP impedance at 5 V and 0.5 ms and the R
wave were also measured using the same pacing analyzer in all bipolar
configurations. The surface ECG was used during the stimulation protocol to validate true LV capture: anodal stimulation was always discarded
for the measurement of LVP threshold. The actual bipolar electrode spacings were also measured on the EP catheter in all bipolar configurations.
This study setting closely mimics clinical practice in the worst-case scenario, where the pacing lead is in proximity of the phrenic nerve. The
study was reviewed and approved by Medtronic’s Institutional Animal
Care and Use Committee.
Results
LVP and PNS thresholds were measured in 6 dogs; the 1/5/1
mm catheter was not used in 1/6 canines because of a surgical complication. Overall, 110 LVP threshold and 110 PNS
threshold measurements were carried out in the 6 animals.
Effect of Cathode Distance From Phrenic Nerve
in the Unipolar Configuration
Figure 2 shows the effect of cathode distance from the TPNE
(phrenic nerve) location on the unipolar PNS and LVP
thresholds at 0.5 ms to the right ventricle coil. The PNS and
LVP thresholds were positively correlated with the cathode
distance from the TPNE (P<0.001, respectively). The effect
of cathode distance from the TPNE on the unipolar PNS
threshold is significantly stronger than that on the LVP
threshold (P<0.001). The unipolar PNS thresholds rapidly
increased while the cathode moving away from the TPNE
reached a maximum of 10 V at 0.5 ms at a distance >20
mm. However, the unipolar LVP thresholds appeared stable
Statistical Analysis
A parametric survival model was used to study the effect of cathode
distance from phrenic nerve for the unipolar configuration because of
the fact that unipolar threshold >10 V was censored. In addition, a random-effects term was incorporated into the survival model to account
for the multiple observations within a canine. A linear mixed-effects
model with canines as the random effect was used to understand the
effect of electrode spacing on observed electric measurements and
safety margin. Natural cubic splines with 2 knots located at the 1/3
and 2/3 percentiles of the predictor variables were used to address
nonlinear relationships in both models described above. To compare the effect of pacing configuration on thresholds for both PNS
and LV, a linear mixed-effects model that accounts for different variances across the different levels of the predictor was used to account
for the observed heteroscedasticity across the pacing configurations.
A Bonferroni correction was applied to the α level for multiple comparisons made across pacing configuration. All P values for the models
described above were generated using likelihood ratio tests. P<0.05
was considered significant. All analysis was performed in the statistical analysis software R version 2.14.2 (SAS Institute, Cary, NC).
Figure 2. Effect of cathode distance from the phrenic nerve on
both left ventricular pacing (A) and phrenic nerve stimulation
(B) unipolar threshold. The dashed lines represent the effect in
each animal, and the solid line represents the overall trend in the
study. TPNE indicates targeted phrenic nerve electrode.
Biffi et al Short-Dipole Pacing to Avoid PNS in CRT 817
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Figure 3. Effect of bipolar electrode spacing on bipolar left ventricular pacing (A) and phrenic nerve stimulation (B) threshold.
The dashed lines represent the effect in each animal, and the
solid line represents the overall trend in the study.
while the cathode distance to the TPNE was <20 mm, then
increased while the cathode distance to the TPNE was >20
mm. In fact, both unipolar PNS and LVP thresholds showed
large variability at TPNE distance >20 mm, likely because of
phrenic nerve anatomy (ie, divergence in the course of the
phrenic nerve from coronary vein)13 and to the larger vein
diameter when located more proximally (ie, poor electrode
contact): in this experimental setting, the TPNE was located at
the distal end of the decapolar catheter.
Effect of Bipolar Electrode Spacing on Bipolar
PNS and LVP Thresholds, Pacing Impedance,
and R Wave
Figure 3 shows the random correlation of bipolar PNS and LVP
thresholds to the bipolar electrode spacing when TPNE was
used as the cathode (the electrode closest to phrenic nerve). PNS
threshold was significantly inversely related to bipolar electrode
spacing (P<0.001; Figure 3B), whereas no association was found
for LVP threshold (P=0.640; Figure 3A). Figures 4 and 5 show
LVP impedance and R-wave amplitude relationship with the
bipolar electrode spacing when TPNE was used as the cathode.
A decrease in LVP impedance and a decrease in the intrinsic R
wave were, respectively, observed as the bipolar electrode spacing shortened (P<0.001; Figure 4 and P<0.001; Figure 5).
Figure 6 summarizes the comparison of pacing config­
urations: the unipolar pacing was compared, respectively,
with the 1-mm spaced, 2-mm spaced, and 20-mm spaced
(the last one is commonly available in clinical practice using
market-released LV leads) bipolar pacing using TPNE as
the cathode. The pacing configuration affected the PNS
thresholds (P<0.001). However, the pacing configuration did
not affect LVP thresholds (P=0.130). Compared with 20 mm
of standard bipolar electrode spacing, 1 and 2 mm bipolar
electrode spacing resulted in a PNS threshold increase of
5.5±2.2 V (P=0.003) and 2.8±1.7 V (P<0.001), respectively.
Similarly, PNS threshold increased by 6.5±3.7 V with 1 mm
Figure 4. Effect of bipolar electrode spacing on pacing impedance. The dashed lines represent the effect in each animal, and
the solid line represents the overall trend in the study.
and by 3.8±1.9 V with 2 mm bipolar pacing (both P<0.001),
compared with unipolar TPNE pacing. The trend of the bipolar
configuration was clear: a shorter electrode spacing resulted in
significantly higher PNS thresholds (Figure 6).
Effect of Bipolar Electrode Spacing on Safety
Margin of Bipolar PNS to LVP
Figure 7 shows the significant relationship of the difference
between the bipolar PNS and LVP thresholds to the bipolar
electrode spacing, with TPNE as the cathode. The difference
between PNS and LVP thresholds is significantly inversely
related to the bipolar electrode spacing (P<0.001).
Figure 5. Effect of bipolar electrode spacing on R-wave amplitude. The dashed lines represent the effect in each animal, and
the solid line represents the overall trend in the study.
818 Circ Arrhythm Electrophysiol August 2012
Figure 6. Comparison of pacing configurations of bipolar and
unipolar phrenic nerve stimulation (A) and left ventricular pacing
(B) using the targeted phrenic nerve electrode (TPNE) as a cathode. The solid lines represent 95% CI.
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Figure 8 shows the effect of the bipolar electrode spacing on
the probability to achieve a safety margin >3 V in the worstcase scenario, using TPNE as the cathode (closest to phrenic
nerve). This safety margin is obtained reliably in all the
cases using 1 mm bipolar electrode spacing. The success rate
dropped dramatically for bipolar electrode spacing >6 mm,
which are those typically used for LV leads in clinical practice.
Discussion
The main finding of our study is that both the distance from
the LV cathode to the phrenic nerve and bipolar electrode
spacing affect the PNS threshold: the farther the LV cathode
from the phrenic nerve or the shorter the bipolar electrode
spacing, the lower the chance of PNS. The difference between
PNS threshold and LVP threshold was used to provide a PNS
safety margin to relate the results to clinical practice. Indeed, a
difference ≥3 V is associated with freedom from PNS-related
complications in the majority of clinical reports,6,8,10,11 which
Figure 8. Probability of a phrenic nerve stimulation (PNS)-left
ventricular pacing threshold (LVP) difference >3 V, with bipolar
electrode spacing.
involved ≈600 patients. This safety margin was obtained reliably in all the cases using 1 mm bipolar electrode spacing
and keeping TPNE as the cathode (Figure 8). The success
rate dropped dramatically for bipolar electrode spacing >6
mm, which are those typically used for LVP in clinical practice. Two strategies for PNS management are highlighted by
this study: placing the LV cathode remote from the TPNE or
shortening the bipolar electrode spacing with the LV cathode
at TPNE.
PNS needs to be managed at the same pacing sites that
are deemed optimal for CRT.6,7,9,11 When PNS is detected at
implantation, several approaches are used: moving the lead to
a different position in the vein, programming the LV cathode
to a different electrode in devices featuring this technology, or
lowering the LV output to avoid PNS when the other options
have failed.6,11,14 LV lead repositioning to another vein is the
last resort and is possible only when other coronary veins are
suitable for LV lead placement.
Each of these approaches has its own drawbacks: LV lead
placement at an alternative site poses an increased risk of a
suboptimal LVP threshold and of LV lead dislodgement, with
need for repeated surgery.6,8 Surgery increases the risk of complications because of increased risk of infection.15 Abandoning
the target site or loss of capture because of a high LVP threshold may cause failure to achieve CRT and clinical improvement.4,5 Our observations highlight the need to develop new
strategies for PNS management through implant techniques
and lead technology.
Impact of Cathode Distance From the Phrenic
Nerve in Unipolar Configuration
Figure 7. Relationship of the difference between bipolar phrenic
nerve stimulation threshold (PNS) and left ventricular pacing
threshold (LVP). The dashed lines represent the effect in each
animal, and the solid line represents the overall trend in the
study.
PNS threshold has a linear relationship with distance from the
phrenic nerve (Figure 2). This is the physiological background
for the strategy most commonly used in clinical practice to
avoid PNS: placement of the LV cathode far from the phrenic
nerve. Nowadays, this is achieved by reprogramming the LV
cathode in multielectrode leads to maintain lead stability and
decrease the risk of lead dislodgement.6,8–10,14 This strategy has
not proved to ensure PNS avoidance in 100% of patients,10–12,16
most likely owing to the electrode spacing of bipolar LV
leads that ranges from 10 to 20 mm, whereas our observation
Biffi et al Short-Dipole Pacing to Avoid PNS in CRT 819
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dictates that the LV cathode be at least 20 to 30 mm from the
TPNE. To overcome this limitation, a quadripolar S-shaped
LV lead that spans a length of ≈50 mm from the tip to the
proximal electrode and allows 10 pacing configurations has
been developed.16 The preliminary short-term experience with
this lead in highly trained centers is that during implantation,
5 of 75 (6.6%) patients had the lead placed at a vein different
than the target one because of PNS that could not be managed
by reprogramming.16 Furthermore, the incidence of PNS at
7.5 V when programming the LV cathode 30 or 47 mm from
the lead tip was 14% and 23%, respectively, with an average
PNS threshold around 5±2 V.16 The LVP threshold in those
settings was, respectively, 2.5 and 3.5 V on average, meaning that a 3-V difference between PNS and LVP thresholds
was not obtained in all patients and that PNS avoidance was
a trade-off with high LVP threshold. This represents a potential limitation in managing PNS at follow-up.10 Hence, owing
to the variability of both coronary vein and phrenic nerve
anatomy, a strategy based on a multielectrode LV lead with
conventional bipolar electrode spacing in the range of 10 to
20 mm does not seem to provide a comprehensive approach
to manage PNS.
Impact of Electrode Spacing on PNS Threshold and
Implications for a PNS-Avoidance Strategy
We observed an inverse relationship of PNS threshold with
bipole electrode spacing (Figure 3B) that warrants a PNSLVP threshold difference >3 V at a spacing <2 mm (Figures
7 and 8).
This allows the implanting physician to keep the LV cathode at the target site for CRT (though being the TPNE), thus
minimizing the risk of nonresponse to CRT,5,17–20 which carries the risk of significant morbidity and mortality.1,2,5,19,20
Furthermore, this approach is neutral on the LVP threshold
compared with longer/standard electrode spacing (Figure 6B),
thus minimizing the risk of high LVP threshold and loss of
ventricular capture when pacing elsewhere than lead tip.16 Our
results are in complete agreement with the recently published
experience by Wecke et al21 that reported similar results in
a canine model, using a networked multielectrode LV lead.
They demonstrated21 that a short pacing dipole (≤1 mm),
obtained by pacing between adjacent segments of networked
electrodes, can achieve PNS avoidance in 100% of the worstcase scenarios (phrenic nerve dissected and positioned above
the LV lead).
Practical Implications
We believe that our study provides the rationale for the development of multielectrode LV leads with a 1 to 2 mm bipolar electrode spacing to maximize PNS management either
at implant or at follow-up. The short-spaced dipole could be
part of either multielectrode or active fixation leads, where all
efforts are focused to avoid both a high LVP threshold and
PNS at the same time. The advantage of such an approach is
the use of an already established and reliable LV lead technology, whereas the new lead technology described by Wecke et
al21 might be vulnerable to the risks of any new highly sophisticated electronic technology.
Study Limitations
This was an acute animal study that requires confirmation
first in acute human studies and later during long-term followup. The healthy animals used in the study could not mimic a
high LVP threshold caused by ischemic scars, which could
possibly alter the study results. We used commercially available EP catheters, both standard and modified, to provide a
shorter bipolar electrode spacing instead of leads designed
for chronic pacing. This catheter and electrode design may
have increased the LVP threshold compared with conventional
LVP leads because of unpredictable electrode contact with the
myocardium. PNS was determined via tactile feel, and this
may not reflect the clinical perception of PNS felt by patients.
The phrenic nerve was surgically repositioned over a coronary
vein, and this difference from physiological conditions could
impact the contact between the nerve and the catheter within
the vein.
Disclosures
Dr Biffi has received modest honoraria from Medtronic, Boston
Scientific, and Biotronik for scientific presentations at Medical
Simposia and for Educational Activity. All the other authors are employees of Medtronic.
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CLINICAL PERSPECTIVE
This animal study highlights that left ventricular stimulation by a short-spaced dipole (1–2 mm length) may be an effective
strategy to manage phrenic nerve stimulation at no compromise with left ventricular pacing threshold. A safety margin useful to manage phrenic stimulation was achieved in all the cases by a short-spaced dipole without any significant increase in
left ventricular threshold. Hence, a short-spaced dipole may enhance the chances to pace a targeted site for cardiac resynchronization therapy, despite phrenic stimulation. A short-spaced dipole can become part of newly developed multipolar left
ventricular pacing leads.
Effect of Bipolar Electrode Spacing on Phrenic Nerve Stimulation and Left Ventricular
Pacing Thresholds: An Acute Canine Study
Mauro Biffi, Laurie Foerster, William Eastman, Michael Eggen, Nathan A. Grenz, John
Sommer, Tiziana De Santo, Tarek Haddad, Annamaria Varbaro and Zhongping Yang
Downloaded from http://circep.ahajournals.org/ by guest on May 13, 2017
Circ Arrhythm Electrophysiol. 2012;5:815-820; originally published online July 11, 2012;
doi: 10.1161/CIRCEP.112.971317
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