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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Background  Application of electrical stimulation to the gut, primarily the stomach, has rapidly advanced in the last two decades, from mostly animal studies to the clinical arena. Most studies focused on the use of electrical stimulation for gastroparesis, the only approved indication for such intervention.

Aim  To review the physiological basis of gastric electrical activity and the technical aspects and clinical outcome of gastric electrical stimulation (GES) for gastroparesis.

Methods  PubMed search from 1966 to 2009, using gastroparesis and GES as search terms. Areas in focus were systematically reviewed.

Results  The literature consists of open-label studies, mostly from single centres, published in the last decade. Improvement in symptoms, quality of life and nutritional status was reported by most studies. Physiologically, stimulation parameters approved in clinical practice do not regulate gastric slow wave activity and have inconsistent effect on gastric emptying. The mechanism of action of GES is not fully known, but data support modulation of gastric biomechanical activity and afferent neural mechanisms.

Conclusions  Gastric electrical stimulation is a helpful intervention in recalcitrant gastroparesis. Controlled studies and better understanding of mechanisms of action of electrical stimulation are needed to evaluate further the clinical utility of this intervention and to exploit its therapeutic potential better.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Electrical stimulation of the gut was used as early as 1963, in an attempt to resolve post-operative ileus.1 Later, studies in animals and humans demonstrated that long pulse stimulation can pace the stomach,1, 2 resulting in enhancement in gastric emptying3, 4 and normalization of gastric dysrhythmia.2, 5, 6 Since then, many patients with gastroparesis have been treated with gastric electrical stimulation (GES) worldwide and multiple studies, mostly from single centres, reported on the clinical outcome of patients with gastroparesis following GES. In gastroparesis, as in other conditions, the physiological and clinical effects of stimulation are determined by the specific pulse parameters applied and the position of electrodes. Thus, through the appropriate selection of these variables, differential control of key autonomic and enteric functions can be achieved, including the entrainment of gastric slow waves, modulation of gastric biomechanical activity and emptying, as well as neurally mediated stimulation of central and peripheral targets.

This article reviews various aspects of this therapy; the physiology of gastric electrical activity, technical aspects of electrical stimulation of gut tissue and the current status of GES as a clinical tool in the treatment of gastroparesis and its mechanisms of action.

Electrical control of gut motility

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Digestion of ingested food, assimilation of its nutrients and waste removal depend on a complex repertoire of motor functions that ensure proper accommodation of meals, mixing of food with digestive juices, reduction in particle size and precisely timed transport of luminal contents. Central to these functions are smooth muscle cells, which perform mechanical work in the form of phasic and tonic contractions under the integrated control of other excitable cells such as systemic autonomic and enteric neurons, which convey sensory information, exert efferent control and generate reflex patterns, and interstitial cells of Cajal (ICC), which serve as rhythm generators and as an interface between nerves and smooth muscle (Figure 1).7–10 Smooth muscle contraction largely depends on Ca2+ entry via voltage-sensitive Ca2+ channels.8 Therefore, effective control over gastrointestinal motility – both in the physiological and therapeutic sense – can be exerted by altering smooth muscle membrane potential either electrically or humorally (pharmacologically). ICC regulate smooth muscle membrane potential via electrical coupling11 and the gaseous mediator carbon monoxide.10 Neural control is exerted by action potential-driven neurotransmitter release. Depending on the neurotransmitters involved, this effect is either direct or indirect via ICC that establish synapse-like connections with nerve terminals (Figure 2).12, 13 The efficacy of excitation-contraction coupling can be further regulated by altering the smooth muscle’s responsiveness to input signals.8, 14 In this article, the mechanisms of electrical control of smooth muscle function are considered further with particular attention to phasic contractile activity.

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Figure 1.  Schematic representation of efferent control of gastrointestinal smooth muscle function. Phasic smooth muscle contractions are controlled by electrical slow waves generated by pacemaker interstitial cells of Cajal (ICC). Chronotropic regulation of slow waves and control of nonphasic contractile activity are provided by the autonomic nervous system either directly or indirectly via intramuscular ICC that mediate neuromuscular neurotransmission. Depending on stimulus parameters, electrical stimulation can influence smooth muscle function indirectly by triggering neurotransmitter release from intramural nerve fibres or, superimposed upon the neurally mediated effect, more directly via ICC and smooth muscle cells.37

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Figure 2.  Innervation of intramuscular interstitial cells of Cajal (ICC) by enteric nerves in the circular muscle layer of the murine fundus. Synaptotagmin-like immunopositive nerve varicosities (green) form close morphological associations with intramuscular ICC labelled with an anti-Kit antibody (red). The region outlined by the white dashed box in (a) is shown in greater magnification in (b). Scale bars: 10 μm in (a) and 5 μm in (b). Reproduced, with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.38

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Phasic contractions are driven by relatively monotonous oscillations in membrane potential termed electrical slow waves. Depolarizations provided by this activity enable voltage-dependent Ca2+ entry into smooth muscle cells which, if sufficiently large, result in mechanically productive contractions.8, 11 Electromechanical coupling depends on the magnitude and duration of suprathreshold depolarization and the presence or absence of the slow-wave-associated, regenerative Ca2+ action potentials, which are regulated by neural and humoral inputs. Thus, slow waves only determine the maximum achievable frequency of phasic contractions and not necessarily their actual rate, a principle that can most strikingly be demonstrated during different phases of the interdigestive motor activity.15 Although electrical slow waves can be recorded from the smooth muscle, this activity ultimately originates from ICC (Figure 3).11 In mutant rodents deficient in pacemaker ICC slow waves are absent and motility and the survival of the animals depend on Ca2+ action potentials produced by the smooth muscles.7, 16, 17 However, the resultant contractile activity is weak and irregular7 and cannot adequately compensate for comparable ICC loss that occurs after intrauterine development.18

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Figure 3.  Role of mitochondria in the generation of slow wave activity by interstitial cells of Cajal (ICC). (a) Rhythmic pacemaker activity in cultured small intestinal ICC purified by immunomagnetic sorting of Kit+ cells. Slow wave activity was detected by monitoring oscillations in mitochondrial [Ca2+] using the Ca2+-sensing fluorescent dye rhod-2 and confocal line-scanning microscopy. (b) Tetramethylrhodamine methyl ester (TMRM) fluorescence in immunomagnetically purified ICC. TMRM is a positively charged, membrane-permeable dye that rapidly redistributes between the extracellular space, the cytoplasm and the mitochondria depending on transmembrane potential differences. Note predominantly mitochondrial localization of TMRM. A.U., arbitrary units; scale bar, 30 μm. (c) Rhythmic pacemaker activity in immunomagnetically purified ICC reported by rhythmic oscillations in mitochondrial TMRM fluorescence detected by confocal line-scanning microscopy. Reproduced, with permission, from Ordog et al.39

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Interstitial cells of Cajal are an evolutionarily preserved,19 heterogenous group of mesenchymal cells that nevertheless share several ultrastructural features20 and the dependence on stem cell factor signalling via Kit, a receptor tyrosine kinase.21, 22 Although the division of labour between ICC classes is not absolute,23 some have the primary function of electrical rhythm generation (e.g. multipolar ICC in the myenteric region of phasic muscles),11 whereas others (e.g. spindle-shaped, intramuscular ICC) mainly contribute to regulation of contractile activity by generating tone,24 by mediating certain types of neuroeffector inputs to the smooth muscle and pacemaker ICC11, 12, 25, 26 and by serving as mechanotransducers (Figure 1).12, 27, 28 ICC loss and dysfunction play a central role in the pathogenesis of several of gastrointestinal neuromuscular disorders29 by causing impaired fundic accommodation, abnormal visceral sensing, gastric dysrhythmias, gastroparesis, impaired pyloric function, intestinal pseudo-obstruction and constipation.10, 30

The elementary event underlying the generation of slow waves by pacemaker ICC is the so-called unitary potential; a small, randomly occurring depolarization reflecting release of small quanta of Ca2+ from the smooth sarco-endoplasmic reticulum via inositol 1,4,5-trisphosphate-receptor (IP3R) channels and subsequent activation of pacemaker conductances.11, 23, 31 For the latter, nonselective cation channels and Cl channels have been proposed.11, 23, 32 The intracellular Ca2+ signals indirectly govern the openings of the pacemaker channels by stimulating the influx of Ca2+ into energized mitochondria (Figure 3).33 As mitochondria are not in equilibrium with the cytoplasm, they take up more Ca2+ than the amount released through the IP3R, causing a net decrease in [Ca2+] in the vicinity of the pacemaker ion channels, which respond by increasing their open probability.11, 33 The unitary potentials reflect ion fluxes in small subcellular spaces called pacemaker units.11 The development of slow waves requires the synchronization of many such pacemaker units, which is achieved by the summation of unitary potentials, subsequent activation of voltage-sensitive, dihydropyridine-insensitive Ca2+ currents and the recruitment of additional IP3Rs by Ca2+-induced Ca2+ release.11, 31

The ion channels responsible for this voltage-sensitive Ca2+ current also represent the substratum of slow wave propagation34 as their activation, e.g. by depolarization of electrically coupled neighbour cells or electrical stimulation can phase-advance slow waves and thus lead to active propagation of activity (Figure 4). Intrinsic frequencies of ICC show an orad-to-aborad gradient and thus the tuning of the slower pacemaker cells to the frequency of the dominant (faster) ones ensures anally directed slow wave propagation.35 A similar frequency gradient also appears to be responsible for the spread of slow waves across the thickness of the circular muscle layer via ICC that lie within intermuscular septa.36 Moreover, orderly propagation of contractions down the length of the tubular gastrointestinal tract requires anisotropic slow wave propagation velocities that allow the rapid circumferential spread of slow waves before their wavefront (and the resultant ring of contraction) can advance aborally. The faster circumferential entrainment of pacemaker ICC in the stomach may be as a result of the rapid propagation of electrical signals along the low-resistance pathway provided by intramuscular ICC that are embedded within, and run parallel to, the circular smooth muscle cells.23 However, studies utilizing two-dimensional multielectrode arrays suggest that slow wave propagation may not be truly anisotropic.41 Rather, slow waves may propagate from the dominant pacemaker site in a uniform manner in all directions, longitudinally and circumferentially, before organizing themselves into circumferential rings of excitation a few centimetres distal to the pacemaker. Thus, circumferential propagation may not be regenerated at every point during the organoaxial spread after the initial, omnidirectional propagation from the dominant pacemaker site. This mechanism would only require the orad-to-aborad frequency gradient that exists in the myenteric ICC network for the propagation of ring-like excitation waves. Recently, data consistent with this hypothesis have been reported in the canine stomach.42

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Figure 4.  Role of interstitial cells of Cajal (ICC) in the control of smooth muscle function by ICC. See text for details. (Reproduced, with permission, from Sanders et al.40)

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Contractions of gastrointestinal smooth muscle cells can be elicited by direct electrical stimulation or indirectly by triggering slow waves in ICC or by stimulating intramural nerves. A cell type’s responsiveness to a depolarizing current depends on its membrane properties such as resistance (Rm) and capacitance (Cm) and commonly characterized by the time constant (τ = RmCm), which represents the duration of the current pulse (t) that can elicit ∼63% of the intended depolarization [100(1 − e−t/τ) if t = τ]. In the case of the fine nerve fibres, τ ≤ 1 ms, but it is longer in the case of ICC and smooth muscle cells. Thus, short pulses can only be used for indirect (neural) stimulation, whereas longer pulses will also activate ICC and smooth muscle cells. Slow waves can be paced by repetitive single pulses or pulse trains either directly or indirectly via neural stimulation.25 Slow wave frequency can also be increased by delivering net excitatory neural stimulation at a rate that is higher than the maximum frequency of slow waves (nonpacing stimulation).26 Furthermore, rhythmic smooth muscle contractions can be evoked independent of the endogenous slow waves by forceful repetitive neural stimulation.43

When designing treatments involving electrical stimulation, it is also very important to consider the possibility that pathological changes may alter or attenuate the responses seen in normal tissues. For example, selective loss of nitrergic inhibition in diabetic stomachs44 may alter the balance between inhibitory and excitatory neurons that respond to a given stimulus. Intramuscular ICC have been proposed to mediate cholinergic excitatory and a part of nitrergic inhibitory input to the smooth muscle, whereas purinergic inhibition and noncholinergic (peptidergic) excitation are rather independent of ICC.12, 17 Thus, depletion of these cells may only affect some, but not all, types of neural control mechanisms. Moreover, chronic loss of intramuscular ICC has also been shown to increase the responsiveness of the smooth muscle to certain neurotransmitters including the inhibitory neurotransmitter ATP.14 Depletion of pacemaker ICC in various disorders including diabetic gastroparesis30 may interrupt the propagation of not only spontaneous electrical signals but also of slow waves paced by electrical pulses.33 Better understanding the complexities of electrical control of gastrointestinal motility will help circumvent these problems and permit the development of more efficient ways to restore normal motor functions in a wide range of diseases.

Electrical stimulation of the gut – technical considerations

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Several technical parameters contribute to the effect of electrical stimulation on gut tissue. These parameters include the biocompatibility and the electromechanical properties of the delivery system (the electrodes) and the waveform applied by the pulse generator (waveform shape, amplitude and frequency) and consequently, the energy delivered to the tissue. This section will examine some of the important properties of electrodes and waveforms and the way these properties contribute to tissue stimulation.

Electrodes

The first important point in the combined design of waveform and electrodes is to ensure that the electrical effect on the electrode–tissue interface is reversible, meaning that the maximal electrical charge applied at any time point on the electrodes will not exceed the maximum charging of the electrode–tissue capacitance.45, 46 Exceeding this limit results in electrolysis, with a change in the current carrier from free electrons to metal ions. The results are damage to the electrodes and formation of toxic electromechanical products in the tissue, because of irreversible injection of metal ions into the tissue. Such system cannot be safely used for long-term purposes. To determine whether a stimulation system complies with this limit, one must calculate the theoretical capacitance from the known electrode properties and compare it with the total charge applied in each cycle of the desired waveform.

For a given electrode shape and dimensions, the theoretical capacitance of the system depends on the electrode material as the maximal charge density per unit cross section area varies greatly. The following two examples help explain the concept: Assume a wire electrode of 10 mm length and 1 mm in diameter (round profile) through which we would like to apply rectangular current waves of 10 mA in amplitude and 6ms in phase duration. The maximal charge density applied to electrode–tissue capacitance would be:

  • image

where q stands for the charge density in coulomb per mm2 (electrical charge per unit area of wire wall); Q is the total charge applied in coulomb (c) and is the product of I (pulse amplitude mA) and Tphase (pulse width in ms); and S is the cross-section area of the wire in contact with the tissue expressed in mm2, which is the product of L (the length of the electrode in mm) and D (the electrode diameter in mm). These variables provide a value that greatly exceeds the maximal charge density for platinum wires, which is 25 μc/cm2 (micro coulomb per centimetre squared). Using platinum wires with these pulse parameters would therefore result in corrosion of the electrodes and formation of toxic products inside the tissue. Coating the wire with iridium oxide (IROX), which increases its surface area, increases the maximal charge density to 3500 μc/cm2 and the maximal net charge would not exceed the capacitance, allowing for long-term use of the electrodes.47, 48

If electrode material cannot be changed, then the safety limits can be kept by reducing the pulse amplitude or shortening the pulse width so that the total charge Q = I × Tphase is reduced. For example, if we use a pulse width of 330 μs with the same current amplitude rather than 6 ms, the pulse charge will be 18 times smaller, resulting in a charge density of 11.1 μc/cm2, well within the limit of platinum electrodes. Another alternative is using larger electrodes (longer or wider) if applicable, thereby increasing the surface area in contact with the tissue and reducing charge density.

Even if the charge delivered by a single pulse does not exceed the maximum limit of the system (for example, the monophasic, upward positive portion, of the bi-phasic pulse in Figure 5), damage can still occur when the pulse is repeated. The reason is that a full discharge of the electrode–tissue interface needs to occur in between pulses. The discharge capability depends in turn on the time between consecutive pulses, i.e. the basic frequency and the ohmic resistance of the electrode during discharge (the lower the resistance the faster the discharge can occur). Thus, with high frequencies, there may not be sufficient time for discharge between consecutive pulses and charge accumulation can occur, eventually exceeding the limit and causing irreversible electrode damage. This can be overcome in many cases by applying a bi-phasic symmetric pulse, i.e. a waveform with equivalent positive and negative charge components (Figure 2), as the total net charge applied by both cycles is zero as both phases have the same amplitude and duration. One needs only to ensure not to exceed the maximal charge at each phase, as this, over time, would induce electrode corrosion, as discussed above.

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Figure 5.  Schematic depiction of a biphasic square wave pulse. The positive and negative components have the same amplitude and duration and hence the total net charge is zero.

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The time needed for passive discharge of the electrodes depends on the resistance of the circuit connecting the electrode. A good estimation for the time constant required for discharging can be achieved by multiplying the electrode capacitance C and the wire ohmic resistance R. Allowing five times this multiplication is a good estimation of a full discharge of the capacitor between pulses. Note that as we require full discharge of the electrode between cycles, the discharge time does not depend on the amplitude or pulse width used, but only on the properties of the electrode.

Waveform selection and frequency bands

As discussed in the previous section, pulse variables are an important factor in determining the physiological effect of electrical stimulation. Another important parameter related to the electrical stimulation is daily timing and synchronization to food intake. Most studies published used 24 h/day stimulation, whereas some others limited stimulation to meal times or specific times of the day. These timing parameters determine the amount of energy applied daily to the tissue. The total energy delivered at each pulse is determined by the multiplication of pulse amplitude and width of each pulse. The rate of pulse delivery and the daily regime used (continuous 24 h/day, fixed duration per day or based on some asynchronous events) together determine total daily energy. The physiological and clinical effect of this additional timing issue remains to be explored.

Gastric electrical stimulation for gastroparesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

The evolution of GES

Interest in electrical stimulation of the gut stems from the fact that organs along the GI tract, like the heart, have natural pacemakers, and the myoelectric activity they generate may be controlled and manipulated by the application of electrical stimuli. An early report by Bilgutay et al.49 in 1963 proposed the feasibility of using electrical stimulation of the GI tract to treat ileus. Application of electric stimuli to the stomach, via the tip of a nasogastric tube, resulted in augmented gastric contractions and increased gastric emptying, assessed by fluoroscopy. Subsequent randomized controlled studies, however, failed to confirm any significant effect of electrical stimulation on the duration of post-operative ileus.50, 51 In the late 1960s and early 1970s, experimental works, primarily in the canine model, began to elucidate the nature of gastrointestinal myoelectric activity and its relation to contractile activity.1, 52–54 These studies showed that the natural gastric pacesetter potential arose in the body of the stomach and that rectangular electric pulses given in that region can control (entrain) gastric electrical activity. Subsequent studies in animals and humans showed that stimulation at a frequency that is slightly higher than the intrinsic gastric slow wave frequency (approximately 3 cycles/min in humans), and with pulse duration in the range of milliseconds achieves the best pacing results (Figure 6) and can also improve gastric emptying in health and disease.2–4, 55, 56

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Figure 6.  Gastric electrical stimulation in a patient with gastroparesis. The recording is obtained from an electrode positioned in the antrum (S4), while stimulation is delivered through an electrode positioned in the mid body of the stomach. Pacing stimuli, marked by dots, drive the electrical frequency as recorded in the antrum on a 1:1 ratio, indicating pacing (entrainment). In this experiment, stimulation with rectangular pulses of 30 ms, amplitude of 4 mA, and frequency up to 10% higher than the intrinsic gastric frequency was able to entrain completely the gastric slow wave and normalize gastric dysrhythmia. (Reproduced, with permission, from Lin et al.2)

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The era of clinical use of GES was prompted by studies in animals and humans that showed that GES with higher frequency and shorter pulse duration (in μs) can improve nausea and vomiting and enhance gastric emptying.57, 58 The low power consumption of this type of pulses, unlike long duration pulses used for pacing, allowed for incorporation of such pulses in devices using current battery technology. A number of clinical studies then followed and on the basis of their results, the FDA granted the Enterra system a Humanitarian Use Device status, which provides treatment to uncommon conditions (<4000 implantations/year) for which no effective therapy is available. A Humanitarian Device Exemption allows for marketing of the system under restricted conditions, as described above, and also requires approval by Institutional Review Boards. It is important to note that the above restrictions do not imply that treatment with the Enterra system is experimental.

Since then, GES, utilizing the Enterra system (Medtronic, Minneapolis, MN, USA) has been used in many patients with gastroparesis worldwide. It is the only system currently approved for clinical use.

Equipment and procedural details

The Enterra gastric stimulation system consists of three main elements: a pulse generator, a pair of leads and a programming system. The pulse generator was adapted from existing devices in clinical use. The permanent implantable pulse generator is controlled by an external programmer, which allows for adjustment of all stimulation parameters via a radio-telemetry link. Two Medtronic 4300 leads are surgically placed in the gastric muscle wall, 10 cm proximal to the pylorus on the greater curvature. The two leads are then connected to the pulse generator, placed in a subcutaneous pocket in the abdominal wall. The pulse generator is programmed to specific parameters, shown in Figure 7. These parameters derive from earlier canine and human studies.57, 58

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Figure 7.  An illustration of the type of electrical stimulation used by the Enterra system. Short bursts of short duration rectangular pulses (330 μs each) are given at a frequency of 14 Hz in each burst. Bursts in turn last 0.1 s and are delivered every 5 s.

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The Enterra system is implanted surgically, by laparotomy or laparoscopy. Laparotomy with a small incision is also used in patients with no previous abdominal surgery. A pair of electrodes is implanted in the muscular layer of the body of the stomach, along the greater curvature, approximately 10 cm from the pylorus. The pulse generator in positioned in a subcutaneous pocket in the left or right upper quadrant. Hospital stay following laparoscopic insertion is short, approximately 2 days,59 and is shorter when compared with placement via laparotomy.60 Battery life of the pulse generator is estimated to be at least 5 years, depending on the pulse parameters used.61 When the battery is depleted, the pulse generator is replaced by local intervention. Long-term studies show that the main complication associated with the device is infection on the subcutaneous pocket, occurring in up to 10% of all subjects.62, 63 Less common complications include erosion of the abdominal wall by the device, penetration of the leads through the gastric wall or tangling of wires in the generator pocket and formation of adhesions. These complications are generally managed surgically. In case of infection of the pocket, the pulse generator needs to be removed; however, it can be reinserted once infection is fully controlled.63

Results of clinical studies

This section will focus on the current clinical status of Enterra, based on published reports. With the exception of one study that included a double-blind phase of sham stimulation for 1 month after implantation,64 the published literature consists of reports from open-label studies, mostly performed in a select number of centres with large experience in this therapy. As shown in Table 1, the studies consistently demonstrate that GES has a beneficial effect in patients with gastroparesis. Besides improvement in symptoms, GES was found to improve quality of life64, 65 and nutritional status62, 66 and to reduce health care costs associated with this condition, related to reduced utilization of health care facilities.68, 69

Table 1.   Studies of gastric electrical stimulation for gastroparesis
ReferenceStudyFollow-upNo. patients Results/outcomes
  1. n, number (of patients); TSS, Total Symptom Score; QOL, quality of life; DG, diabetic gastroparesis; IG, idiopathic gastroparesis; GES, gastric electrical stimulation.

64Multicentre, prospective, double-blind placebo-controlled phase of 1 month, followed by open-label phase Aim: To evaluate the long-term effect of GES on GI symptoms1 yearn = 33 17 DG, 16 IGSignificant improvement in vomiting frequency and TSS in the first phase. Significant improvement in vomiting, TSS and QOL during open-label phase
63Open-label study from 3 regional centres. Evaluation of long-term effects of GES on symptoms, QOL and survivalMedian of 4 yearsn = 214 (156 with permanent implantation). 45 DG, 146 IG, 23 postsurgicalSignificant improvement in vomiting frequency, TSS and QOL
73Open-label, prospective, multicentre study, with temporary GES in the first phase. Evaluation of permanent GES in patients who responded to temporary GES1 yearn = 38 9 DG, 24 IG 5 postsurgicalMarked reduction (>80%) in nausea and vomiting in 33 patients. Alternative nutrition discontinued in 9/14.
67Evaluation of long-term effects of GES vs. medical therapy on symptoms, QOL and costs3 yearsn = 18, 2 DG, 16 IG. 9 had GES, control group of 9 patients on medical therapyBetter control of symptoms and lower health care costs the GES group.
91Evaluation of GES in patients with delayed vs. normal gastric emptying6 monthsn = 15, 7 with normal emptying, 8 with delayedComparable improvement in symptoms and quality of life in both groups
92Evaluation of GES in paediatric population8–42 monthsn = 9 Average age = 14 yearsImprovement in symptoms and QOL
69Describe predictive factors for outcome of GES5 monthsn = 28 16 IG, 12 DGImprovement in nausea and vomiting, but not in bloating or abdominal pain. Use of opiates associated with poor response. Better response in diabetic compared with idiopathic group
83Evaluation of GES in postsurgical patients1 yearn = 16Improvement in symptoms and QOL and reduced hospitalizations and health care costs. Alternative nutrition discontinued in 4 patients
85Evaluation of GES in patients post-Roux-en-Y gastric bypass6 monthsn = 5Improvement in symptoms and TSS
76Evaluation of GES effect on glucose control in DM patients1 yearn = 17, all DG Improvement in symptoms and reduction in HbA1c
66Evaluation of long-term outcome of GES≥3 yearsn = 55 39 DG, 9 IG, 7 postsurgical Improvement in TSS, sustained. Reduced hospitalizations, use of medications and need for alternative nutrition. Diabetic patients showed a significant reduction in HbA1c from 9.5% to 7.9%
99Evaluation of the effect of GES on symptoms of gastroparesis20 monthsn = 29 24 DG, 5 IGSignificant increase in BMI, 70% reported good-to-excellent outcome, reduced need for alternative nutrition
59Evaluation of the effect of GES on symptoms of gastroparesis12 monthsn = 50 20 DG, 25 IG, 2 postsurgical, 3 connective tissue disorderSignificant improvement in nausea, vomiting and TSS
100Evaluation of the effect of GES on symptoms of gastroparesisMean follow-up = 38 weeksn = 19 10 DG, 6 IG, 3 postsurgicalImprovement in symptoms and TSS, but not in QOL

While the response to therapy of an individual patient is unpredictable, a few clinical features are associated with less than optimal response, such as the use of opiates.70 Pain and bloating do not improve as well as well as nausea and vomiting70 and diabetic patients with gastroparesis have a better outcome with therapy than those with idiopathic disease.64, 69 Thus, diabetic patient with gastroparesis, with nausea and vomiting as their predominant symptoms, appear to be the best candidates for GES. Loss of ICC on gastric full thickness biopsy70 was also reported to be associated with inadequate response; however, the need for full thickness gastric tissue, taken at the time of implantation of the Enterra device, makes this variable less useful in clinical practice. There is evolving evidence that an abnormal electrogastrogram, based on a tachygastric rhythm, is a predictor of depleted ICC status and this finding may prove clinically useful in this area.

Mechanisms of GES

Conceptually, the application of electrical current to GI tissue can modulate the neuromuscular function of the organ involved and/or afferent neural activity and these effects may also be linked to one another.

Initial studies in animals and later in humans have clearly shown that entrainment (pacing) of gastric slow waves can be achieved with GES using low-frequency/long-duration pulse parameters and that these parameters can enhance gastric emptying.3, 4 Some results from animal and human studies suggested that that similar effects can be achieved with GES with application of short duration pulses.57, 58 The Enterra system uses the specific pulse parameters described in the previous section. This section will discuss the various studies that examined the mechanism of action of the Enterra system.

Modulation of gastric electrical rhythm.  Gastric electrical stimulation with Enterra did not control vasopressin-induced gastric dysrhythmia in an animal model, although it improved vomiting.71 Likewise, gastric electrical activity, measured by electrogastrography, in patients with gastroparesis was not affected by GES.72 Thus, Enterra pulse parameters have no demonstrable effect on the frequency of gastric electrical rhythm and do not entrain gastric slow waves.

Modulation of gastric emptying.  Data on the effect of Enterra system are inconsistent. Two multicentre studies showed a modest improvement in gastric emptying,73 which was significant only in the diabetic patients at the end of 1 year.64 Single centre studies have shown either no effect74 or significant enhancement of gastric emptying,59 a result also observed in a study from regional centres.63 A recent study reported a correlation between reduced gastric retention at 4 h and clinical improvement after GES therapy in those patients with normalization of delayed gastric emptying.75 A number of factors may account for these conflicting results. The duration of follow-up and mix of patients varied among studies. An improvement in glycaemic control in diabetic patients was observed with Enterra therapy,74, 76 perhaps contributing to improvement in gastric emptying. Spontaneous resolution of idiopathic gastroparesis over time has been reported77 and in an implanted patient, such resolution may be attributed to therapy with GES. Given the variable correlation between gastric emptying and symptoms of gastroparesis,78 the importance of a prokinetic effect of GES is questionable. This is important as patents are sometimes referred for consideration of GES therapy for symptoms which are attributed directly to delayed gastric emptying, such as bezoar formation or severe gastro-oesophageal reflux disease and its complications. However, improvement in these conditions should not be expected and such patients are not candidates for GES. While GES has inconsistent effect on gastric emptying, it has consistent effects on gastric biomechanical activity, which are observed with different pulse parameters. Thus, in animal model, bothlow-frequency/long-duration and high-frequency/short-duration pulses reduce gastric tone79, 80 and reduce distension-induced symptoms.80 Given the documented impairment in gastric accommodation in patients with functional dyspepsia and diabetic gastropathy81, 82 and the association of such impairment with GI symptoms, primarily early satiety and weight loss,81 this physiological effect of GES may contribute to improvement in symptoms.

Neural mechanisms.  Central and peripheral neural mechanisms have been explored in humans and in animal modes. In dogs, the antiemetic effect is vagally mediated, as it is abolished by vagal disruption,71 but GES was also shown to improve symptoms in postsurgical gastroparesis, some with vagal disruption.83–85 In rats, GES has excitatory effects on neurons of the nucleus of the tractus solitarius86 and in humans, GES increases activity in the thalamus of patients with gastroparesis, as detected by positron emission tomography.87 GES was found to modulate heart rate variability (used as a surrogate marker for efferent sympathovagal activity) in patients with gastroparesis.88 However, it is intuitive that perturbation of the gut will have a central representation and thus the exact neural mechanisms involved in GES remain to be defined.

Areas of uncertainty

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

In spite of the encouraging data provided by the studies published thus far, several questions remain concerning this therapy. An important issue is the lack of double-blind, placebo (sham-stimulation)-controlled study, sufficiently powered to provide conclusive data regarding efficacy. One such study was just recently concluded and its results, it is hoped, should clarify some of the controversies concerning GES. Adequate follow-up is necessary, particularly given the natural history of idiopathic gastroparesis, with report of spontaneous resolution of symptoms occurring a number of years after the onset of disease. Applications of GES to patients with conditions other than diabetic or idiopathic gastroparesis have been explored. Thus, GES was tried in patient with postsurgical gastroparesis,83–85 with intestinal pseudo-obstruction89 and patients postorgan transplant,90 with encouraging results. Data, however, are too few and more studies are needed to determine the efficacy of GES in these groups of patients. Finally, given that GES effect on gastric emptying is inconsistent and that a beneficial effect on symptoms of nausea and vomiting is observed in patients with normal gastric emptying,91, 92 GES perhaps may be considered for the treatment of intractable nausea and vomiting, regardless of the presence of delayed gastric emptying.

Given that GES therapy involves surgical intervention, it is very important to find a reliable way to predict response to therapy, as is the case with sacral stimulation, another electrical stimulation therapy aimed at helping patients with faecal incontinence,93 in which response to short-term the sacral stimulation is used for selection of patient for long-term therapy. There is great interest in the use of temporary GES, using trans-nasal mucosal electrodes, as a predictor of response to long-term therapy with the Enterra system,94 but there are no data thus far from double-blind, control studies to support its use for such purpose. Once implantation is performed, there is no clear strategy for addressing patients who do not respond to GES. Various manipulations of pulse parameters have been suggested,95 but data are not yet sufficient to support such approach.

Different concepts of stimulation are being investigated. A variation on the single channel gastric stimulation is the use of a number of electrodes, positioned at intervals along the long axis of the stomach, with application of sequential stimulation. Multichannel pacing requires a fraction of the energy used in single channel pacing96 and it improves gastric emptying and symptoms in experimental models of gastroparesis97 and in diabetic patients with gastroparesis.98 A different approach applies high frequency stimulation, applied to circumferential electrodes. Sequential stimulation induces sequential contractions that induce gastric empting.43 The efficacy of such systems remains to be explored in clinical trials.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Considerable scientific and clinical evidence supports the use of GES for the treatment of drug refractory gastroparesis. The Enterra system is the only one approved for such purpose. Improvement in pulse parameters, the potential use of temporary stimulation and the incorporation of variables that can predict better response to stimulation may improve the efficacy of the current system. New systems under investigation may prove more efficacious and provide control of symptoms coupled with a prokinetic effect.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References

Declaration of personal interests: The authors wish to thank Ms Jeanne Keith-Ferris and Mr Robert Humble for editorial help. The 16th International Workshop on Electrogastrography was supported by unrestricted educational grants from Medtronic, TAP, Smart Pill, EZM. Dr Soffer: research grant by Takeda and Smart Pill. Dr Abell: speaker, consultant, licensure for Medtronic. Dr Lin and Dr Lorincz: nothing to disclose. Dr McCallum: Research grants for Medtronic and NIH. Dr Parkman: advisory board of SmartPill and Tranzyme. Mr Shai Policker: employee of Metacure. Dr Ordog: National Institutes of Health Grant DK58185. Declaration of funding interests: None.

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  2. Summary
  3. Introduction
  4. Electrical control of gut motility
  5. Electrical stimulation of the gut – technical considerations
  6. Gastric electrical stimulation for gastroparesis
  7. Areas of uncertainty
  8. Conclusion
  9. Acknowledgements
  10. References
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