The Electrode-Tissue Interface: The Revolutionary Role of Steroid Elution HARRY G. MOND* and KENNETH B. STOKES** From the *Royal Melbourne Hospital, Victoria, Australia and **Medtronic, Inc. Minneapolis, Minnesota

Introduction Until recently, most major developments with cardiac pacing hardware have involved the pulse generator. Although a number of important lead developments have occurred over the years, including reduction in electrode size, porous electrode surfaces, fixation devices, and connector standardization, most of these changes have heen regarded as evolutionary. Apart from tines (the most successful of the passive fixation devices), these changes have had little impact on implantation techniques, pulse generator design, and the management of pacemaker patients. The profound developments in other areas of pacemaker technology meant that pulse generators were evolving that were technologically unsuitable for older style electrodes. In particular, the current drain requirements of these leads when used with dual chamber and rate responsive systems become significant. Coupled with this was an ever increasing physician demand for even smaller pulse generators developed at the expense of reduced capacity power sources. The first step in the solution to these problems lay in the development of more efficient and effective leads. This necessitated the use of basic electrode engineering principles, involving size, shape, and materials. This work emphasized the effect such changes had on factors such as stimulation thresholds and polarization losses. Small, microporous, low polarization, activated carbon, or platinized platinum electrodes evolved. These demonstrated marked improvements in chronic

Address for reprints: Harry G Mond M.D.. Department of Cardiology, Royal Melbourne Hospital, Vic:toria, 3050. Australia. Fax: oil-61-3-3476760. Received |une 17, 1991, revision August 1, 1991; accepted August 1,1991.

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stimulation thresholds compared with their predecessors. Next came the steroid-eluting designs that have produced an even better performance. Threshold Rise and Inflammation The rise in stimulation threshold that normally occurs after lead implantation is a direct result of inflammation at the electrode-tissue interface. As demonstrated in Figure 1, there is an acute elevation in stimulation threshold that reflects the varying stages of the inflammatory process surrounding the electrode. The magnitude of this threshold rise is unpredictable and in some cases excessive. Thus, in this situation it is necessary to use relatively high voltage outputs, at least for the first 3 months postimplant. As the inflammatory process subsides and a fibrous capsule is formed, the stimulation threshold plateaus to a chronic level often considerably higher than at the time of implantation. In order to explain the changes in the electrical performance of pacing electrodes postimplant, it is necessary to understand the complicated processes involved in inflammation. As a general rule, early inflammatory changes include edema, fibrin deposition, capillary dilatation, leukocyte migration, and phagocytic or foreign body activity.^'^ The phagocytes, primarily monocytes and macrophages, undergo lysosomal release of many different inflammatory mediators, including hydrolytic enzymes, oxidants, and chemotactic agents. This release, which occurs onto the device surface and into the surrounding tissues can kill nearby myocytes producing microscopic levels of necrosis."^"*^ The inflammatory mediators can also dissolve the collagen network that holds the surviving nearby myocytes in an ordered array/' The late inflammatory changes result in the creation of a fibrous capsule and include capillary and fibro-

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blast proliferation, together with collagen deposition. During the first 4 weeks postimplant, the acute cellular inflammation in adjacent tissues subsides and the fibrin is resorbed. A fibrous capsule develops between the electrode and endomyocardium. This fibrous capsule is not collagen alone. The area between the electrode surface and the capsule is covered with a layer or layers of macrophages and foreign body giant cells.** These cells also lie within the pores and grooves of the electrode. The foreign body giant cells differentiate from macrophages in an attempt at phagocytosis of the foreign body. The histologic appearance of the typical chronic electrode-tissue interface can be characterized by the presence of phagocytic cells, a collagenous capsule and myofihrillar disarray (Fig. 2). Consequently the fibrous capsule and other nonstimulatable tissue serve to effectively increase the electrode surface area, thus increasing stimulation thresholds. Another factor that has not been well appreciated is the continual and chronic leaking of inflammatory mediators from the cellular components of the fihrous capsule.^"^ Given their well known cytotoxicity, it seems reasonable that they may be increasing the transmemhrane stimulation thresholds of myocytes adjacent to the

STIMULATION THRESHOLD MEASUREMENTS POST IMPLANTATION STIMULATION THRESHOLD

Figure 2. Histoiogic views of the canine right ventricular electrode-tissue interface using a Medtronic grooved Target Tip** electrode, 12 weeks postimpiant (stain Masson's Trichrome, magnification 20 x ). In/Iammation in the ad;acen( (issues has subsided and a fibrous capsule has formed. Phagocytic cells can be seen deep in the grooves.

fibrous capsule.^ From this work it can be concluded that the critical factor that must he controlled to achieve constant low stimulation thresholds postimplant is the suppression of inflammation. *

B 12 16 TIME POST IMPLANTATION (WEEKS)

20

Figure 1. Typical stimulation threshold rise/or a standard electrode post implant. The acute peak rise in stimulation threshold is unpredictable and the chronic plateau level is higheF than that documented at impiantation.

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Basic Design Principles With pacing electrode design, a number of basic bioengineering principles are also important when considering the stimulation threshold. For example, to produce a low stimulation threshold cathode, the electrode should be small enough to

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produce high "current density" or electric field strength. However, the electric field strength decreases as a function of the square of the distance between the electrode surface and the tissue to be stimulated." Consequently, the electrode radius should optimally be equal to or less than the thickness of the fibrous capsule that inevitably envelopes it or stimulation thresholds will actually increase." Despite the importance of small electrodes having a high current density, the effect of electrode surface area on chronic stimulation thresholds in the range of present day clinical use (4-20 mm^) may not be statistically significant.^ Electrode materials that are completely inert and highly biocompatible in the sense that they do not produce an inflammatory response, do not appear to exist. The materials, therefore, must be biocompatible in that they are stable with respect to significant corrosion or degradation. For example, some metals, such as stainless steel"' and zinc^' are unacceptable, as their corrosion can he excessive. The metal ions released at the electrode-tissue interface can cause an excessive foreign body reaction resulting in a thick fibrous capsule around the electrode. Both platinum and carbon are relatively inert and biocompatible. Carbon electrodes have been reported to produce even less fibrous tissue than platinum.^^'^^ The low polarization porous metal electrode has also been reported to produce less fibrosis than a comparable solid electrode.^'* Thus, the generally accepted rules of electrode design include a small size [although not too small), biocompatability, and relatively inert materials together with a porous or microporous structure. To assure good clinical performance, the lead must provide adequate fixation for the electrode. The development of tines has greatly reduced electrode dislodgment.'""' In addition, tissue ingrowths into porous and grooved electrodes results in mechanical stability at the cellular level. To date, these passive fixation devices have been preferable to active fixation for low stimulation threshold performance. The mechanical design of the lead is also important in the control of inflammation and reduction of fibrosis at the electrode-tissue interface. The electrode should be stable and lie gently against the endocardium, causing as little physical irritation as possible. A lead design that allows

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excess pressure to be imparted to the distal electrode can exacerbate injury to the endomyocardium and provoke or accelerate excessive inflammation. In some cases, lead stiffness can result in myocardial ischemia and ventricular perforation. The clinical presentation of this problem can be a progressive and unacceptable rise in stimulation threshold, which may result in a high threshold exit hlock generally within 3 months postimplant.^^^^^ This complication can usually be prevented with good implantation techniques and the use of more flexible silicone rubber bipolar leads with floppy tips."''^^ Physical methods aimed at preventing irritation at the electrode-tissue interface should also be considered. Ripart and Mugica,^^ have suggested interposing an inert biocompatible conductor material between the electrode and endocardium to reduce mechanical irritation. An example given was a hydrogel similar to that used in the eye with soft contact lenses. It is even possible to impregnate these materials with drugs such as anticoagulants or antiinflammatory agents. It should be recognized however, that hydrogel coated pacing electrodes may introduce new problems involving gel hydration and sterilization.

Drug Eluting Electrodes The use of local pharmacological agents is a relatively new and novel way to counter the inflammatory reaction at the electrode-tissue interface. It was with some trepidation that pacemaker engineers ventured into the world of pharmacology and investigated this concept using controlled drug delivery systems.^"'^^ These systems must deliver controlled doses of pharmacological agents directly into the electrode-tissue interface. Three systems were initially developed. The first, used only in animals, was an osmotic minipump attached to a small cannula that could deliver the agent directly. The second, also used exclusively in animals, involved the development of a drug polymer matrix placed within the annulus of a polished platinum ring and or just behind tbe electrode as a collar. The third concept, which is now used clinically has the drug polymer matrix behind or within a porous electrode. Following implantation, tissue fluids pass into the matrix and

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dissolve the drug, which then enters the electrodetissue interface. Using such delivery systems, a variety of agents were studied and compared to controls. Potassium chloride, propylene glycol, phenytoin sodium, epinephrine, sulphinpyrazone, heparin, albumin, azathioprine, tunicamycin, cis-hydroxyproline, and a variety of nonsteroidal antiinflammatory agents including ibuprofen and diclofenac were used as antiinflammatory, anticoagulant, and antiextraceilular matrix formation agents. In all cases, no consistent improvement in stimulation threshold was found and in some cases significant deterioration occurred. Heparin for instance, by inhibiting fibrin formation prevented the development of a protective fibrous barrier during acute inflammation allowing more physical damage.^" Other agents that prevent extracellular matrix formation without altering the inflammatory response, namely tunicamycin and cis-hydroxy-proline, also caused an elevation in stimulation threshold,^^ indicating again that prevention of inflammation was the most important consideration in reducing the chronic stimulation threshold. First Generation Steroid-Eluting Electrode It is not surprising that glucocorticosteroids, hecause of their potent antiinflammatory action, resulted in a significant reduction in peak and chronic stimulation threshold levels in studies on the effects of pharmacological agents at the electrode-tissue interface.^**^^ Glucocorticosteroids are believed to limit the early and late stages of inflammation and dexamethasone sodium phosphate was found to be much more effective than prednisolone.^" Prednisolone, unlike dexamethasone has a high affinity for protein binding rendering it pharmacologically inactive. The early edema at the electrode-tissue interface is protein rich and, therefore, minute amounts of prednisolone released by a drug eluting device may be immediately inactivated.^" The use of systemic glucocorticosteroids in the treatment of chronic high threshold exit block is well known.^^-^•' The response is rapid and persists only as long as the drug is administered. The stimulation threshold reducing effect was not originally attributed to the drug's antiinflammatory ac-

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tion, but rather to a more direct, possibly cellular effect. However, it has now been demonstrated that at least one potent antiinflammatory glucocorticoid, dexamethasone, has no direct myocardial membrane threshold altering effects.^^' While the antiinflammatory cellular effects of glucorticosteroids are still not well understood, there is enough information available to propose a theory to explain these phenomena." Systemic glucocorticosteroids have been shown to stabilize the membranes of phagocytic cells.^ As discussed earlier, the chronic fibrous capsule surrounding an electrode is not composed of collagen alone, but contains phagocytic cells to varying degrees. Thus, the administration of systemic glucocorticoids can stabilize the membranes of cells chronically resident in the fibrous capsule, reducing or stopping the release of threshold increasing mediators. This may allow stimulation thresholds to decrease, as long as the steroid continues to be administrated.** Dexamethasone sodium phosphate has been used in the clinical development of a numher of steroid-eluting electrode systems. The original design, still used, is composed of a platinum coated titanium electrode.^^ The electrode is hemispherical in shape with a geometric surface of about 8 mm^ (Fig. 3). The electrode surface is porous and immediately hehind it lies a plug of silicone rubber compounded with dexamethasone sodium phosphate. This plug is referred to as a "monolithic controlled release device" and the amount of steroid is < 1 mg. Implant experience with the steroid-eluting electrode, in the experimental animal and man, has demonstrated low acute and chronic stimulation thresholds in the atrium and ventricle with virtual elimination of the early postoperative peak.^*^"^** In particular, excellent results have been obtained in children-'^ and in patients with a previous history of high threshold exit 20.38.38

The precise role of the dexamethasone sodium phosphate in this first generation electrode was initially uncertain. It was considered possible that the unique design and construction of the electrode itself may have been responsible for the favorable results. However, it has now been demonstrated conclusively that it is the steroid that prevents stimulation threshold rise. In double blind clinical trials comparing identical electrodes with and without steroid, stimulation thresholds

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Figure 3. (Left) Steroid-eJuting porous plalinum coated titanium elecfrode (Medtronic CapSure**). (Righl) Cross-sectional diagram of the same eJectrode. Behind the electrode is the silicone rubber pJug compounded with dexamefhasone sodium phosphate. beyond the first 2 days postimplant were significantly lower for electrodes containing steroid.^^•''° This effect has now been shown to persist for at least 6 years of follow-up (Fig. 4). What are the histologic effects of steroid elution at electrode-tissue interface? In one animal study, the chronic fibrous capsule surrounding a steroid-eluting electrode tended to be thinner than the one surrounding an identical electrode without steroid, although the correlation coefficient was poor. There was, however, cellular evidence that the chronic inflammatory reaction was diminished by the steroid.^^•'*^ In another blinded canine study, there was no significant difference in the acute cellular response in adjacent tissues, with or without steroid (Fig. 5).^ Compared to steroid-free implants there is usually little or no myofibrillar disarray adjacent to the steroid-eluting electrode. These findings support the theory that the steroid is not present in sufficient quantity to prevent or significantly reduce inflammation as measured by the presence and numbers of phagocytic cells. It does however, appear to be present in sufficient concentration to prevent or minimize the release of the damaging inflammatory mediators, acutely

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and chronically, thus attenuating the formation of the fibrous capsule. How long does the effect of steroid elution last? It is probable that once the initial inflammation settles, there is no further chronic inflammation so that the stimulation threshold remains stahle and low. A thin fibrous capsule may prevent mechanical irritation of the endocardium by the electrode and will also act as a physical barrier to retard, but not stop steroid loss from the electrode. Sufficient steroid still finds its way into the electrode-tissue interface to maintain a chronic antiinflammatory effect. Analysis of explanted steroideluting leads shows that 20% of the steroid remains after 4 years (Fig. 6).'*^ The rate of elution in vivo has been shown to decrease exponentially with time. Knowing this, it is more than likely that the stimulation threshold lowering effect of steroid will last the life of the vast majority of patients who receive this design of electrode. Steroid-eluting electrodes appear to improve sensing. There are many studies with steroid-eluting electrodes demonstrating excellent R wave testing at lead implantation coupled with satisfactory long-term sensing or telemetered ventricular

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STEROID (4003) Vs NON STEROID (4003) Mean Autothreshold Putse Width (1.5V) MSEC

0.3 -

3M

6M 1Y TIME POST IMPLANTATION

3Y

6Y

Figure 4. Graphs demonstrating Ihe mean autothreshoid pulse tvidfh reduction values fmsec) at 1.5 V output, from two series of identical Medtronic CapSure^ modeJ 40Q3 electrodes, one with steroid and one steroid-free. From 2 weeks posfimplant, the lead containing steroid has slafisticaliy superior slimu/ation threshold levels. At 3 years and beyond, the stimuJation threshold vaiues remain markedly different but are not statistically significant because of the small numbers of palients remaining in Ihe study. (W = iveeks, M = months, Y = years).

^-3°'3'^35.*"'.45 Qther studies have

shown superior R wave sensing with steroid-eluting electrodes when compared to steroid-free electrodes.•*^'^^ This improvement in sensing may result from the steroid mediated reduction in inflammation. However, ventricular undersensing is rare with modern pacemaker electrodes. Consequently, R wave sensing is not regarded to be as important as P wave sensing where undersensing remains a critical issue. Steroid-eluting electrodes have shown superior P wave sensing compared to platinized porous platinum. Target Tip"^ electrodes (Medtronic, Inc., Minneapolis, MN, USA).^^ Much more work, however, needs to be done in this area particularly with specific atrial steroid-eluting electrode designs. Steroid-eluting electrodes have other features that make them superior to steroid-free electrodes. For example, there has been a documented decrease in sensing (source) impedance.*^-^^ An-

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other favorable feature of the steroid-eiuting electrode are the reported low polarization potentials.^^ This has the obvious benefit in allowing reduction in electrode size, which in turn may further reduce stimulation threshold.^" It is, however, the electrode design that causes the reduction in source impedance and polarization potentials rather than the effect of steroid. A comparison of the first generation steroideluting lead with several other modern designs has helped to point the way for a next generation device. The original steroid-eluting electrode was composed of platinum coated titanium. Without steroid, this electrode showed relatively high, unpredictable stimulation thresholds, appreciably higher than the platinized porous platinum Target Tip^ electrode (Figs. 4 and 7). When the mean chronic stimulation thresholds from the platinized porous platinum electrode were compared to those of the steroid-eluting electrode, only minor differences were noted particularly after 3 years implantation (Fig. 7). There was, however, a small somewhat attenuated peak with the platinized porous platinum electrode and a slight, but persistently higher stimulation threshold."^•^"•^^ This is in contrast to the data from the polished platinum ring electrode that mimics results obtained from the steroid-free titanium electrode (Figs. 4 and 7) as well as other designs of polished and porous platinum electrodes.'*^-^^ The platinized porous platinum electrode is, therefore, far superior to the polished platinum or the porous titanium electrode without steroid. The question remains whether a steroid-eluting electrode is really necessary when almost comparable chronic data can be presented with electrodes composed of microporous carbon or platinized porous platinum? All steroid-free electrodes still develop an unpredictable acute peak stimulation threshold, which makes it necessary to implant pulse generators at 5-V output and 0.5-msec pulse width to assure an adequate margin of safety. Despite low mean chronic stimulation thresholds with platinized porous platinum electrodes, unpredictable rises in chronic stimulation threshold can still occur.^^ In careful studies with steroideluting electrodes, significant chronic stimulation threshold rises have not been reported, provided mechanical causes such as myocardial perforation

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Figure 5. Histologic views of the canine right ventricular electrode-tissue interface using a platinized porous pJafinum electrode (Medtronic CapSure*^) at 1 week [left] and 4 weeks (right) postiniplant (stain Masson's Trichrome. magnification 20 x ), The 1-week interface is characterized by interstitial edema and extensive ceJiular in/fommation with trapped red ceiJs and fibrin. The 4 week impiant shows more globai edema although the celluJar inflammation has been essentially resolved with most of the red cells and fibrin having been absorbed. A coilagenous capsuJe has formed containing resident phagocytes. Comparing steroid eluting and steroid-free electrodes, no significant histologic differences could be discerned with similar implants.

or lead dislodgment have been excluded. As discussed earlier, steroid-eluting electrodes are superior to other electrodes in the presence of previously documented high threshold exit block^'''"''" and their use should, therefore, be encouraged whenever this situation is encountered or anticipated. Patients with steroid-eluting electrodes coupled with a good lead design and implantation

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technique can be safely paced from the day of implantation at 2.5-V output. Where stimulation threshold measurements are performed regularly, the majority of patients with steroid-eluting electrodes can he safely paced at 1.5 V.'*'* The ability to safely use pacing systems at low current drains has important ramifications for longevity especially with dual chamber and rate responsive systems.

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STEROID ELUTION RATE MODELS 4003 & 4503 HUMANS & CANINES

Second Generation Steroid-Eluting Leads

100

so6040-

(1)

^ 20E

• w

6-

^

4-

% Steroid Remaininq

= 96.9T-» Corr. st .967 2

3 4

G a 10

20 40 EO 100 Impianl Tlma (Weeks)

200

Figure 6. The in vivo elution rate of steroid from Medtronic steroid-eluting electrodes. The data were obtained by defermining Ihe amount of steroid remaining in the silicone rubber plugs of leads explanted from canines and humans. Both axes have been plotted on logarithmic scales and the figures in parenthesis indicate the number of subjects studied at that time frame. There was a dost; correlation belween the amount of steroid remaining in the elecfrode plug and the time postimpJant. yr ^ years; corr. = correlation coefficient.

STEROID (40031 Vs RING (6971) VsTARGEH4011| Mean Autothreshold Pulse Width (1.5V) *

2W

3M

P < 0 . 0 5 W I T H STEROID

GM lY TIME POST IMPLANTATION

3Y

6Y

Figure 7. Graphs demonstrating the mean autothresbold puise width reduction values (msec) at 1.5 V output, from three series of Medtronic electrodes; steroideJuting CapSure** (model 4003}, ring (model 6971}. and Target Tip** (model 4001). There are only minor di//erences in stimulation threshold between the Target Tip** and Steroid-eJuting electrodes 6 months post implant. The ring electrode shows the typical peak and plateau stimulation thresholds, statistically higher thon the steroid-eluting electrode.

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With the technical and clinical information currently available on stimulation threshold and polarization, a lead has been designed that encompasses all known favorable features of electrodes. A steroid-eluting, platinized microporous platinum electrode with a 5.8-mm^ surface area {Fig. 8], bas completed clinical trials.^^"^^ It was found to have lower stimulation thresholds than tbe original platinum coated titanium design (Figs. 9 and 10).^^ Even tbe "high" stimulation thresholds in this study were relatively low. Tbere were two cases of unexplained relatively high stimulation thresholds at 1.5-V output; one early and one 6 months postimplant. Tbe first bebaved like an electrode without steroid. The other responded as if the steroid had become depleted or more likely tbat late myocardial iscbemia or perforation bad occurred. In botb cases, stimulation threshold data at 2.5 V were satisfactory. These cases may well represent situations where high threshold exit block would bave occurred witb steroid-free electrodes. Tbis belps confirm tbe clinical impression that bigh threshold exit block bas been substantially reduced with steroid-eluting electrodes. Tbe second generation steroid-eluting lead, is a bighly efficient and effective device. From tbese data, it can he concluded tbat the platinized micro-

Figure 8. (Above) The 5.8 mm^ surface area, platinized porous platinum, steroid-eluting electrode (Medtronic CapSure SP** model 502.3). (Below) The 1.5 mm^ surface area, platinized porous platinum, steroid-eluting eJectrode (Medtronic NanoTip**). The arrow points to the extremely smoJI eJectrode.

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porous platinum, steroid-eluting electrode can be safely used with programmed pulse generator outputs of 2.5 V or less.

CAPSURE SP (5023) 0.8

Maan AutothrashoM Pulsa Width at 1.5V

0.7 ma O.S

•

CASE

New Steroid-Eluting Designs

6^/

0.B

CASE 4

0.4

J/

0.3 /

0.2

/

0.1 0

^

1 1,

3W

f

-Si*. I

'

6W

1

3M

6M Tlrna Poat Implantation

13 PATIENTS

12M

18h

Figure 9. Graphs demonstrating the mean autothreshold puise ividtb reduction values (msec) at 1.5 V output of a series o/J3 platinized porous platinum, steroideluting leads (Medtronic CapSure SP'^ model 5023). Thirteen of the leads behaved identically. Case 4 had an early rise in stimulation threshold and the patient was lost to foliow-up after 6 months. Case 6 had an unexpected rise in stimulation threshold after 6 months (see text for more details).

CAPSURE Vs CAPSURE SP 0.12

Mean Autothreshold Pulse Width at 1.5V

mt

0,1

CAPSURE (4003) (10 PATIENTS)

0,08

A steroid-eluting epicardial lead bas recently been described.^^ Unlike otber permanent pacing leads implanted via a transthoracic approach, tbe electrode is not a screw and is thus not myocardial. The electrode is a platinized porous platinum button-shaped plaque (Fig. 11). As in tbe original transvenous steroid-eluting electrode, there is a dexametbasone sodium pbospbate impregnated silicone rubber plug witbin tbe electrode. Its action postimplant is probably similar to tbe endocardial design. Early animal data comparing a model witb and without steroid, implanted in the atrium and ventricle bave shown encouraging results.**° Tbis suggests tbat such an electrode can be placed on the epicardium and tbat tbe steroid will inbibit inflammation and fibrosis and hopefully prevent excessive rises in stimulation threshold. Snch a lead would be particularly belpful in tbe pediatric age group.'^^•^^ A silicone rubber plug within tbe electrode is not the only method by which steroid can be delivered to the electrode-tissue interface. Another design uses a porous ceramic or silicone rubber ring or collar, positioned immediately bebind tbe electrode. Human implant data bas sbown a

0.0B CAPSURE SP(5023) (15 PATIENTS)

0,04 0.02 3W

6W

3M

6M

12M

18M

Time Post Implantation

Figure 10. Graphs demonstrating the mean autothreshold pulse width reduction values (msec) at 1.5 V output, from tu'o series o/steroid-eluting electrode designs; platinum titanium (Medtronic CapSure"*, model 4003} and platinized porous platinum (Medtronic CapSure SP'^. model 5023). The two cases o/relatively high stimulation threshold in the 5023 series hove been excluded. The 5023 leads had superior stimulation thresholds throughout the study. Statistical analysis was not performed because of the slightly different method of measuring autothresbold and the removal of two cases (W = weeks, M ^ months).

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Figure 11. Platinized porous platinum steroid-eluting electrode designed to be sutured to the epicardium (Medtronic. Inc.j.

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significant reduction in stimulation threshold values for those electrodes containing steroid, with unipolar''-^""'' and bipolar'*^ leads. Tbese studies used doses of < 0.5 mg of dexametbasone sodium pbospbate. Altbougb a silicone rnhber collar would be expected to act like tbe internal silicone rubber plug, the long-term properties of porous ceramic as a drug delivery system are as yet unknown. In animal studies, tbe reduction of stimulation threshold by dexametbasone elntion from a ceramic collar was comparable to tbe silicone rubber collar for at least 6 montbs postimplantation.^" Tbe dynamics of drug elution from ceramic, however, are quite different to that of silicone rubber. Following implantation, ceramic releases its stored steroid rapidly, witb 50% on tbe first day and virtually all tbe drug gone within 11 There may be advantages in placing the steroid-eluting device outside the electrode. The steroid-eluting collar would allow any type of electrode or fixation to be used. A steroid-eluting collar bas been incorporated into an active fixation screw-in lead. The screw electrode is surrounded with a steroid-eluting collar (Fig. 12). Alternatively, tbe screw could simply be an ancboring device, wbich is surrounded by the electrode, and around this again tbe steroid-eluting collar. Animal studies using such leads bave sbown significantly lower stimulation tbresholds than comparable leads without steroid.''"''^ Tbe revolutionary role of steroid elution at tbe electrode-tissue interface does not end here. Tbe main determinant of current loss from an electrode is its pacing impedance. Since pacing impedance varies exponentially witb tbe electrode's geometric surface area, small catbodes can greatly reduce current drain. To date tbere has been little clinical work on electrodes smaller tban about 5 mm^ because of tbeoretical concerns about loss of pacing as well as R and P wave attenuation in the pulse

Figure 12. Active fixation lead n'ith an electrically active screw. There is a steroid-eluting collar surrounding the screw (Medtronic, Inc.).

generators amplifier, witb consequent loss of sensing. Animal studies, however, bave recently confirmed that excellent pacing data can be obtained with steroid-eluting electrode tips as small as 1.5 mm^ (Fig. 8).^^ Using the proven advantages of platinized porous platinum and steroid elution, such an electrode is about to enter clinical trials. Conclusions The remarkable advances in lead tecbnology over the last decade have resulted in new electrode designs able to take up the formidable pacing challenges of tbe 21st century. The low stimulation threshold, low polarization electrode bas a surface area as small as 6 mm^ and is usually composed of porous platinum or carbon. The introduction of steroid elution at the electrode-tissue interface has played a pivotal role in maintaining chronic low stimulation thresholds and in particular bas allowed tbe development of electrodes as small as 1.5 mm^. The use of steroid elution with active fixation leads is another new and exciting development about to enter clinical trials.

References 1. Anderson JA. Inflammation, wound healing and foreign body response. In: Biomaterial Science. An Introductory Text. Soc Biomater, 1991 [tn press). 2. Anderson |A. Inflammatory response to implants. ASAIO Trans 1988; 11:101-107. 3. Henson PM. Mechanisms of exocytosis in phago-

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cytic inflammatory cells. Am J Path 1980; 101:494-514. Salthouse TN. Some aspects of macrophage behavior at the implant surface. ) Biomed Mater Res 1984; 18:395-401. Robinson TF, Cohen-Gould L, Factor SM. Skeletal framework of mammalian heart muscle: Arrange-

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ment of inter- and pericellular connective tissue structures. Lab Invest 1983: 29:482-498. Stokes KB, Anderson JA. Low thresbold leads: The effect of steroid elution, In: Proceedings of tbe Second International Symposium on Cardiac Pacing Leads. Amsterdam. Tbe Netherlands, Elsevier Science Publisbers BV, 1991 (In press). Henson PM. TJje immunologic release of constituents from neutrophil leukocytes II. Mecbanism of release during pbagocytosis and adherence to nonpbagocytosable surfaces. J Immunol 1971; 107:1547-1557. Irnich W. Engineering concepts of pacemaker electrodes. In M Scbaldacb, S Furman (eds.J: Advances In Pacemaker Technology. New York, NY, Springer-Verlag, 1975. pp. 241-272. Stokes K. Bird T, Taepke R. The mytbology of thresbold variations as a function of electrode surface area. PACE 1991; 14:1748-1751. Tbalen HJTh, van den Berg JW, van der Heide JN. et al. Tbe Artificial Cardiac Pacemaker. London. England, William Heinemann Medical Books Ltd., 1969, pp. 161-168. Hirsborn MS. Holley LK, Hales JRS, et al. Screening of solid and porous materials tor pacemaker electrodes. PACE 1981; 4:380-390. Timmis GC. Hellana J, Westveer DC. Tbe evolution of low thresbold leads. Clin Prog Pacing Electrophysiol 1983; 1:313-333. Mund' K. Ricbter G. Weidlicb E, et al. Electrochemical properties of platinum, glassy carbon, and pyrograpbite as stimulating electrodes. PACE 1986; 9:1225-1229. Amundson DC, McArthur W, Mosbarrafa M. The porous endocardial electrode. PACE 1979; 2:40-50. Mond H. Slonian G. Tbe small tined pacemaker lead—absence of dislodgement. PACE 1980; 3:171-177. Kertes P, Mond H, Tonkin A, et al. Higb tbresbold exit block witb stiff bipolar ventricular pacing leads, (abstract) RBM 1990; 12:107. Cameron J, Ciddor C, Mond H, et al. Stiffness of tbe distal tip of bipolar pacemaker leads. PACE 1990; 13:1915-1920. Kertes P, Mond H, Sloman C, et al. Comparison of lead complications witb polyuretbane tined, silicone rubber tined and wedge tipped leads: Clinical experience witb 822 ventricular endocardial leads. PACE 1983; 6:957-962. Ripart A, Mugica J. Electrode-beart interface: Definition of tbe ideal electrode. PACE 1983; 6:410-421. Stokes K. Bornzin C. Tbe electrode-biointerface: Stimulation. In SS Barold (ed.): Modern Cardiac Pacing. Mount Kisco, NY, Futura Publisbing Company, Inc., 1985, pp. 33-77. Brewer C, McAuslan BR, Skalsky M, et al. Initial screening of bio-active agents witb potential to re-

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Anderson N, Mathivanar R, Skalsky M, et al. Active fixation leads—long term threshold reduction using a drug-infused ceramic collar, (abstract) PACE 1991; 14:639. Anderson N, Skalsky M, Ng M. et al. Active fixation leads—Threshold reduction using dexamethasone acetate, (abstract) RBM 1990; 12:109. Stokes K, Bird T. A nevv' efficient nanotip lead. PACE 1990; 13:1901-1905.

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