Background

Successive waves of technologic advances have created the modern, sophisticated device comprising a modest-sized, electrically active generator (i.e., active can) implanted pectorally, utilizing defibrillation-efficient biphasic waveforms, one to three transvenously inserted leads, and antibradycardia/antitachycardia and biventricular pacing capability, as well as programmable detection algorithms and defibrillation energy strengths. The success of this technology is mirrored by the estimated 200,000 devices implanted worldwide in 2009. Despite these remarkable achievements, implantable cardioverter-defibrillators (ICDs) still generate controversy, particularly in the United States, where both physicians and the public are questioning ICD reliability and safety. This peaked in 2009 with the withdrawal of the Fidelis lead from the market amid extensive and often critical publicity.^5–11 Further complaints over lead reliability continue, together with concerns over engineering reliability.^6,11

The growing number of lead failures has exposed the Achilles heel of ICDs: the need to attach an electrode directly to the heart via the vascular system. The complicated path that the lead must follow, the hostile environment of the body, and the requirement that leads be supple combine to threaten lead integrity. Moreover, the necessary adherence of the electrode tip to the myocardium and potential attachment of the body of the lead to the veins traversed result in an appreciable risk of injury and death if lead extraction becomes necessary. Reported ICD lead “survival” rates vary from 85% to 98% at 5 years and 60% to 72% at 8 years; Figure 19-1 plots data from 10 studies.¹⁰ Table 19-1 summarizes the reported incidence of complications when lead extraction is judged necessary, with mortality ranging from zero to 2.7%, the latter figure relating to associated overwhelming sepsis.^12–19 These concerns, along with the well-known complications of routine transvenous lead insertion (perforation, tamponade, pneumothorax, hemothorax, sepsis, endocarditis), indicated the need to develop an ICD that would not require transvenous leads.

Figure 19-1 Results of 10 studies of implantable cardioverter-defibrillator (ICD) lead performance selected according to ≥18 months’ follow-up available, publication in a peer-reviewed journal after 1999, and statistical inclusion of patients who died or were lost to follow-up. The size of the data point/circle is proportional to the total number of patients in the study. Data box shows primary author, year of publication, and patient number (n) for the 10 studies.

(Modified from Maisel WH, Kramer DB: Implantable cardioverter-defibrillator lead performance, Circulation 117:2721-2723, 2008.)

 Early Investigation Experience with Subcutaneous Defibrillation

The first efforts to explore subcutaneous defibrillation broke new ground in understanding of energy requirements and the type and location of electrodes. A major corollary was whether a defibrillation threshold of sufficiently low magnitude could be achieved, and if batteries and capacitors then could be small enough to be inserted into a generator of reasonable size. Without these answers, the issue of reliable sensing from an extracardiac location would prove moot.

In August 2001 a collaborative research group explored the index question of how much energy was needed for subcutaneous defibrillation. With appropriate ethics committee approval and patient consent, the first test of subcutaneous defibrillation was performed in humans at Green Lane Hospital in Auckland, New Zealand.²⁰ The original test was conducted in a 56-year-old man undergoing transvenous ICD implantation because of a recent cardiac arrest. A small incision was made over the low lateral chest wall to permit tunneling of an anteriorly and posteriorly situated subcutaneous oval disk electrode of approximately 5 cm² in surface area. A standard transvenous right ventricular lead was used to induce ventricular fibrillation, which was terminated, to the team’s satisfaction, with the first shock, chosen at a strength of 70 joules using a biphasic waveform with a 50% tilt and 100-µF capacitance. This shock resulted in success at an energy level that was much less than was then known possible with transthoracic defibrillation, using two large surface pad electrodes. At that time, the lower limit of average defibrillation threshold efficacy was presumably 100 to 115 J. Clearly, avoiding the resistive effect of the skin was surprisingly beneficial. As discussed later, the energy requirements proved to be even more remarkable.

Although defibrillation with our initial configuration was successful, the posterior space proved too difficult to access and therefore was subsequently abandoned. Attempting to access a posterior subcutaneous space from an anterior approach with a supine patient clearly was impractical, regardless of how low the defibrillation energy would prove to be. Four more patients were tested using various anterior/anterolateral configurations in the latter half of 2001, and defibrillation was successful in all. Each of these pilot explorations led to a more definitive and sequential approach to vector and electrode selection. Our original intention had been to develop a curved generator, resembling a flattened banana, which would mold to the natural contour of the intercostal space (Fig. 19-2). In fact, early prototypes with this shape were tested, but unfortunately it proved too difficult to accommodate the necessary components of the generator to this design and was reluctantly abandoned. Subsequent studies undertaken with additional help (Johannes Sperzel, Jorg Neuzner, and Stefan Spritzer in Germany; Andrew Grace at Papworth Hospital in the United Kingdom; Andrei Ardashev at Burdenko Hospital in Moscow, as well as at Green Lane; Jon Hunt of Cameron Health) allowed rapid progress in identifying a practical lead system.

Figure 19-2 Torso model showing original curved electrode designed to mold to the lateral intercostal space.

 Optimal Defibrillation Configuration

Having demonstrated proof of concept, the research aim was then to evaluate systematically which of many electrode configurations would be most effective, as well as most practical from a surgical perspective. Although multiple systems were examined and abandoned, four viable configurations were eventually chosen for detailed study. In this next phase of development, these four defibrillation systems compared the utility of retaining the conventional pectoral generator site versus a novel, left lateral placement of the generator. In addition, a variety of electrode shapes, lengths, and positions were examined. The specific four combinations chosen were as follows (Fig. 19-3):

Figure 19-3 Four lead systems acutely tested for the “optimal” system.

1, Left lateral pulse generator with 8-cm coil electrode at left parasternal margin, designated LGen-S8. 2, Left pectoral pulse generator with left parasternal 4-cm coil electrode positioned at the inferior sternum, designated PGen-S4. 3, Left pectoral pulse generator with 8-cm coil electrode curving from left inferior parasternal line across to inferior margin of left sixth rib, designated PGen-C8. 4, Left lateral pulse generator with left parasternal 5-cm² oval disk, designated LGen-S5 (disk).

(Modified from Bardy GH, Smith WM, Hood MA, et al: An entirely subcutaneous implantable cardioverter-defibrillator, N Engl J Med 363:36-44, 2010.)

Defibrillation testing of these temporary lead configurations was completed immediately before permanent transvenous ICD implantation in a total of 78 patients in a number of centers, most at Green Lane and Papworth Hospitals. These data have been published previously.²¹ A Latin Square design was used for testing with analysis of variance (ANOVA). A step-up/step-down protocol was used to determine defibrillation thresholds (DFTs) using a 50%-tilt biphasic waveform. An initial test shock of 40 J was delivered after 10 seconds of induced VF, incrementing to a maximum of 80 J or decrementing to a minimum of 10 J. Bardy et al.²¹ fully describe the DFT testing protocol. Unsuccessful shocks were followed by prompt, transthoracic rescue defibrillation.

For the four configurations just described, the mean DFT (±SD) was as follows, respectively (Fig 19-4):

Figure 19-4 Delivered defibrillation threshold energies.

Defibrillation threshold data (mean ± SD) for four practical lead/electrode configurations (see Fig. 19-3) in acute human trials (total of 78 patients).

(Modified from Bardy GH, Smith WM, Hood MA, et al: An entirely subcutaneous implantable cardioverter-defibrillator, N Engl J Med 363:36-44, 2010.)

These data suggested the optimal configuration was a left lateral canister placement and an 8-cm parasternal electrode with both a low DFT and a relatively narrow standard deviation range (±SD; CI, confidence interval; ANOVA P = .07). Despite being a novel location, the left lateral position proved to be “user friendly,” with easy tissue planes to dissect and good visibility for electrode and generator placement. With meticulous attention to hemostasis, no pocket hematomas were encountered, and the incisions healed soundly, even during these early years and with relatively limited procedural experience.

The next phase of the research involved a comparison between DFTs with the “optimal” subcutaneous system just identified and a standard transvenous system. The purpose was not only to examine relative efficacy in terminating VF in the same patients, but also to ensure that there would be a comparatively parallel degree of energy reserve in any design of a subcutaneous-only ICD (S-ICD).

For the direct, Paired Transvenous Defibrillation Efficacy Trial a total of 49 patients were enrolled between April 2004 and June 2005. Importantly, the subcutaneous electrode was placed using only anatomic landmarks, and its position documented by fluoroscopy only after testing was complete. A typical electrode position is shown in Figure 19-5. After both systems were in place and both pockets closed, DFTs were compared in a randomized and interleaved manner, using the same protocol previously described.²¹ The mean DFT for transvenous and subcutaneous ICD systems, respectively, was 11.1 ± 8.5 J (95% CI: 8.6-13.5) and 36.6 ± 19.8 J (95% CI: 31.1-42.5), P < .001. Only one patient failed to defibrillate with the subcutaneous system, and subsequent screening showed that the electrode was grossly malpositioned laterally, with the coil electrode outside the left lateral margin of the cardiac silhouette (Fig. 19-6). As part of this study, it should also be noted that one patient also failed to defibrillate with the transvenous system, although with appropriate electrode location.

Figure 19-5 Chest radiograph of patient in the permanent implant pilot study.

White arrow shows location of parasternal electrode of subcutaneous ICD with a laterally placed generator. An episode of induced ventricular tachycardia and its termination is shown along bottom of radiograph. The patient (WC) is a 46-year-old, 114-kg, secondary prevention male patient with coronary disease, NYHA Class I, and ejection fraction of 30% to 35%. The transvenous lead was implanted 9 years earlier through the right subclavian vein because left-sided venous access was not possible and no right cephalic vein was present. At this (second) generator replacement, the transvenous lead showed noise and R-wave oversensing.

Figure 19-6 Fluoroscopy image of the malpositioned parasternal electrode in the one patient who failed to defibrillate in the Paired Transvenous Defibrillation Efficacy Trial.

In summary, the data derived from these preliminary trials helped the engineers determine battery and capacitor requirements, as well as lead system design, to ensure that the device would work with the same degree of efficacy in terminating VF as transvenous leads. Without this work, the next phase of the development process, a reliable detection algorithm, could not be undertaken.

 Other Investigator Approaches to Subcutaneous Defibrillation

Before reviewing the steps leading up to the development of the Cameron Health S-ICD detection algorithm, it is appropriate to acknowledge the efforts made by others who have explored the need for avoiding transvenous lead systems.

In 2005, Burke et al.²² evaluated the defibrillation energy requirement of a hybrid left chest anterior cutaneous patch to a pectoral subcutaneous emulator canister. With this can-to-patch shocking vector, they reported 78% success in nine patients starting with 70 J and 91% success in a further 11 patients starting with 50 J. Seven of nine patients in this second group (78%) were successfully defibrillated with a 30-J shock. Further efforts to develop a subcutaneous ICD system seemed warranted.

In 2008, Lieberman et al.²³ reported an 81% success rate in 32 patients using a step-down protocol beginning at 35 J. Although our group had abandoned a posterior approach, their defibrillation configuration consisted of an electrically active generator emulator with a surface area of 60 cm² implanted in a low pectoral position, together with a 25-cm coil electrode tunneled around the back of the left thorax between the sixth and tenth intercostal spaces, with the lead tip as close to the spine as possible. Postshock pacing by the subcutaneous electrode was not attempted. No complications were reported.

Isolated case studies in the pediatric population also demonstrated the feasibility of shocking the heart between an abdominally sited generator and a subcutaneous array, or an electrode variably positioned toward the left axilla.^24–28 Each of these patient-specific adaptations, however, still required some form of transvenous or epicardial sensing electrodes. Also, these were primarily adapted to developments in patient clinical status, surgical limitations or lead failures, and the clinically limited options to repair the previously implanted intrathoracic defibrillation lead system.

Sensing with a Subcutaneous Lead

The subcutaneous electrode has two sensing electrodes, one positioned distally adjacent to the manubrium-sternal junction and one positioned in the vicinity of the xiphoid (Fig. 19-7). Electrograms may be detected either between the two electrodes or between either sense electrode and the pulse generator. The S-ICD system automatically selects the vector optimal for rhythm detection and avoidance of double QRS counting or T-wave oversensing. The need for treatment is predicated by feature analysis of signals followed by rate detection. Also, a conditional discrimination zone can be programmed at 170 to 240 beats per minute (bpm) to identify and exclude supraventricular tachycardia (SVT). Extensive testing of these sensing algorithms in the studies conducted to date and in-vitro showed an excellent capability to correctly identify VF and rapid ventricular tachycardia (VT).³⁰ The capability exists to screen patients by comparing the QRS/T-wave amplitudes from the surface electrocardiogram at chest wall locations with a simple ruler, to confirm myocardial sensing will be adequate for a subcutaneous device. Figure 19-8 shows the programmer screen with the parameters available for programming.

Figure 19-7 Locations of the subcutaneous implantable cardioverter-defibrillator (S-ICD) system components in situ. A and B designate the distal and proximal sensing electrodes, respectively; C, shock coil electrode.

(Modified from Bardy GH, Smith WM, Hood MA, et al: An entirely subcutaneous implantable cardioverter defibrillator, N Engl J Med 363:36-44, 2010.)

Figure 19-8 Programmer screen for the subcutaneous ICD shows the four parameters available for programming: device on/off, postshock pacing on/off, supraventricular tachycardia (SVT) discrimination zone on/off, and if on, the upper rate of its use.

 Prelude to First Use of Stand-Alone Subcutaneous Defibrillator

The substantial body of research completed over 8 years showed that defibrillation could reliably be achieved with a laterally situated, electrically active canister and a parasternal subcutaneous electrode. The required energy levels proved as such to allow a reasonably sized generator, and patient comfort seemed acceptable. A pilot study of a chronically implanted generator in the new lateral site had been satisfactory in terms of patient acceptability and comfort. The subcutaneous electrode had proved surprisingly easy to position reliably using only anatomic landmarks. This latter feature obviated the need for x-ray screening. Cardiac capture was feasible, so temporary postshock backup pacing was possible with the subcutaneous device. However, because the large stimulus strength required for cardiac capture resulted in a global excitation of all thoracic musculature, chronic pacing or antitachycardia pacing (ATP) was impractical for this system. In addition, accurate sensing of myocardial electrograms and reliable discrimination from noise and stray electric currents, a critical aspect of defibrillator performance, had been carefully validated with the new system.

The time seemed appropriate for definitive human implants. The first permanent implant of a subcutaneous-only ICD was in Auckland, New Zealand, on July 28, 2008, by the authors, Gust Bardy, Margaret Hood, and Warren Smith. A schematic of the S-ICD system in place is shown in Figure 19-7. Thereafter, implants were also performed at Christchurch Hospital (by Ian Crozier and Iain Melton), resulting in a total of six patients with class I indications for ICD treatment implanted with a subcutaneous system in New Zealand for the initial pilot experience. Patients were excluded if they required antibradycardia pacing or were known to have VT slower than 170 bpm or monomorphic VT, known to be reliably terminated with ATP. The primary endpoint was two successful conversions from VF with 65 J in a maximum of four attempts. An example of a successful conversion is shown in Figure 19-5. All patients underwent implantation as planned, and after 33 months’ follow-up, the system has been well tolerated without complication. The full detail of this experience has previously been reported.²¹

Since this initial experience, the S-ICD has undergone successful completion of a European regulatory trial, the details of which are reported earlier.²¹ Of 55 patients, 52 satisfied implant criteria of two successive VF conversions at 65 J; 12 episodes of spontaneous VT were treated in three patients in that early experience, with only one death, in an 85-year-old man with end-stage renal failure who asked that his S-ICD be turned off in the weeks before his death from kidney disease. The subcutaneous defibrillator is currently released for clinical use in Europe. A U.S. Food and Drug Administration (FDA) trial is also currently underway, with the experience to date proving that S-ICD therapy has a growing role to play in prevention of sudden cardiac death.

 Overview of Experience to Date

A totally subcutaneous ICD system bodes to be a valuable extension to the options presently available to treat patients who present with, or are at risk of, malignant ventricular rhythms. Although a substantial experience has established the standard subpectoral pocket as a safe and convenient generator location, the novel lateral pocket has also proved user friendly, with easy-to-establish tissue planes resulting in a short learning curve for operators experienced in conventional implantation techniques. Long-term follow-up and larger patient numbers will be necessary for clinicians to become completely comfortable with this approach; however, the preliminary experience is very encouraging.

The early experience of some lead dislodgments has emphasized the need for adequate anchorage of the distal tip. This experience also led to the introduction of an anchoring sleeve at the xiphoid, essentially eliminating the problem of dislodgment in subsequent experience, even in novice implanters. Implementation of these new anchoring techniques minimized lead dislodgment in more than 600 subsequent cases. No chronic lead extractions have yet been necessary, but any future removals could reasonably be anticipated to be straightforward and certainly safe.

As potential limitations, one must be cognizant that there will be a few patients in whom body habitus may render myocardial sensing marginal. Fortunately, this is readily identifiable before implant with the use of a special surface electrocardiographic (ECG) template that mimics the S-ICD sensing algorithm and easily identifies those few patients who might have difficulty with subcutaneous sensing. There are several more definitive exclusions to use of the S-ICD. The absence of a chronic pacing capability presently excludes patients requiring antibradycardia pacing, and a transvenous device is more appropriate for patients with relatively slow VT or who demonstrated reliable antitachycardia termination of VT. There is no substantive evidence to demonstrate that empiric ATP is superior to shock-only therapy in patients not demonstrating monomorphic VT before implant. Indeed, the only randomized trial to date shows increased mortality and shock rates with ATP. This is consistent with recent observations showing that a majority of primary prevention patients have polymorphic nonsustained VT, which would easily be accelerated into VF with empiric ATP during charging.^31,32 Consequently, we remain conservative in this domain.

One of the less obvious advantages of the S-ICD will be its role in the preservation of the intravascular system for later use, especially in younger patients. The 30-year-old patient with hypertrophic cardiomyopathy at increased risk for sudden death would be fortunate not to need one or more lead extractions in his lifetime. For such patients, the subcutaneous ICD has the potential to confer a long-term morbidity and mortality benefit separate from that intrinsic to its treatment of ventricular tachyarrhythmias. In other patients, being able to defer the possible need for transvenous access by starting with the subcutaneous system is likely to be a clinically useful strategy. Children are another group likely to benefit substantially. Present technology in children requiring ICDs is associated with a disturbing frequency of serious complications, which reflects their smaller veins and more rapid growth rates^24,25 (see Chapter 18). Also, we are currently exploring the value of the S-ICD in women because it is unlikely to interfere with mammography; neither the lead nor the generator is within the breast tissue.

 Future of Subcutaneous Defibrillators

The advent of a viable subcutaneous defibrillation option has implications beyond a mere technical advance. The financial pressure from the need to contain health care costs is constant and growing. The savings from being able to implant devices in a sterile but otherwise “low-tech” room (no expensive lead lining, lead-lined jackets, or fluoroscopy) will be important to all health care administrators, but especially those in third world countries where limited capital is best prioritized to devices rather than expensive support infrastructure. Physicians and nurses will also be grateful for the freedom from radiation exposure and from the heavy jackets with resulting back problems. In addition, the simple, predictable surgery allows for reliable scheduling of cases. The transvenous ICD that is more complex and takes longer than anticipated will have a cascade effect on the timing of subsequent procedures. Often, this type of delay “bumps” the last patient to the next day. This has cost implications largely hidden from the physician but readily apparent to the administration of any hospital complex. Also, because programming is so simple with the S-ICD, manufacturer representatives are not required. Removal of corporate liaisons in health care will help simplify the care of patients.

Since the first device implanted by Mirowski, a progressive increase in complexity may have ultimately become counterproductive, if a substantial proportion of patients do not need or are unlikely to benefit from excessive sophistication, and a few are actually harmed by physicians confused by the plethora of programming options. There is a virtue in simplicity, as exemplified in the limited subcutaneous device options, provided this translates over longer-term follow-up to lives saved with minimal inappropriate shocks. Appropriate trials should be designed to compare transvenous to subcutaneous defibrillation and confirm the population best served by each device. Parallel with such trials is the issue of routine defibrillation testing at implantation. Once essential, such testing is now of debatable utility; it certainly seems time to test its value in randomized trials. Abandoning routine testing would abbreviate an already-short implant time for subcutaneous devices, likely with further cost savings and elimination of the occasional adverse outcome related to failure to terminate VF.

Perhaps the most controversial issue is deciding which physicians are best suited to implant such devices. The very real risks and uncertainties associated with the early years of ICDs mandated that a fully trained electrophysiologist join the cardiac surgeon, whose expertise was also desirable for placement of epicardial patches. The simplification of transvenous device placement has eliminated the cardiac surgeon from most implanting centers. It may also be time for electrophysiologists, expensive to train and relatively limited in number, to surrender some jurisdiction to other colleagues. Given the increasing numbers of heart failure patients in most societies, many of whom will be candidates for prophylactic defibrillation, workforce issues suggest that devolvement of uncomplicated implants to less highly trained individuals would be highly desirable to meet demand at a sustainable societal cost. Perhaps this is a further parameter for those contemplating future trials to consider.

 Conclusion

The journey over 9 years from the unknown feasibility of a novel approach to the availability of a commercial device has been a gratifying experience for those involved. In particular, the collaboration between clinicians and engineers as data were acquired and the research advanced has been a rewarding experience. We gratefully acknowledge the altruism of the many patients who selflessly agreed to allow research testing at the implant of a standard device in order that future patients might benefit. We believe their commitment has not been in vain and that subcutaneous defibrillation will enhance the treatment options available to patients with serious heart rhythm disorders.

The advent of ICD technology began in 1961 with Zacuoto and de Boissoudy³³ using automated antiarrhythmia therapy through temporary transvenous catheters in hospitalized patients. Subsequently, Schuder et al.³⁴ and then Mirowski et al.¹ developed a fully implantable defibrillator for animal use by 1970. Prototype human implants by Mirowski et al.² in 1980 were followed by the advances of biphasic waveforms, transvenous leads, and active generator technology. Where an entirely subcutaneous ICD fits in this history, and whether or not it proves a significant advance, awaits further evidence.