Prevention and treatment of diastolic flow reversal

Abstract

Methods and devices are described for preventing diastolic flow reversal and/or reducing peripheral vascular resistance in a patient. Also described are methods of cosmetic treatment, and methods of promoting delivery of therapeutic agents or contrast agents to bones and related tissues.

Claims

1. A method of reducing or preventing diastolic flow reversal in an artery in a leg of a patient comprising: administering an electrical stimulus having a frequency of from 1 to 3 Hz and a current of between 0 to 100 mA by means of a single negative surface electrode and a single positive surface electrode to a nerve innervating opposed leg muscles sufficient to cause isometric contraction of the muscles, and wherein, in said method, said electrical stimulus is administered to only one nerve wherein the nerve is stimulated from a single stimulation point and wherein said single negative surface electrode is located at said single stimulation point, and wherein the single positive surface electrode is shaped and positioned so as to provide the single positive surface electrode either side of the single negative surface electrode, thereby reducing or preventing diastolic flow reversal in an artery in a leg of a patient.

2. The method of claim 1, wherein the electrical stimulus has a frequency of 1 Hz.

3. The method of claim 1, wherein the electrical stimulus has a current of 15-30 mA.

4. A method of reducing or preventing diastolic flow reversal in an artery in a leg of a patient comprising: administering an electrical stimulus having a frequency of 1 Hz and a current of between 0 to 100 mA by means of a single negative surface electrode and a single positive surface electrode to a nerve innervating opposed leg muscles sufficient to cause isometric contraction of the muscles, wherein said single positive surface electrode is larger than said negative single surface electrode and said single positive surface electrode is shaped and positioned so as to provide the single positive surface electrode either side of the single negative surface electrode, and wherein, in said method, said electrical stimulus is administered to only one nerve wherein the nerve is stimulated from a single stimulation point and wherein said single negative surface electrode is located at said single stimulation point, thereby reducing or preventing diastolic flow reversal in an artery in a leg of a patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A through 1C show the measurements of arterial blood flow in a first subject at levels of stimulation of 20 mA, 5 Hz (FIG. 1A); 5 mA, 5 Hz (FIG. 1B); and at no stimulation (FIG. 1C).

(2) FIGS. 2A through 2C show the measurements of arterial blood flow in a second subject at a level of stimulation of 20 mA, 3 Hz (FIG. 2A); immediately after stimulation (FIG. 2B); and at rest (FIG. 2C).

(3) FIGS. 3A through 3F show the measurements of arterial blood flow in a third subject at levels of stimulation of 10 mA, 3 Hz (FIG. 3A); 1 mA, 3 Hz (FIG. 3B); 20 mA, 5 Hz (FIG. 3C); 5 mA, 1 Hz (FIG. 3D); 5 mA, 3 Hz (FIG. 3E); and at rest (FIG. 3F).

(4) FIG. 4 compares the speed of skin blood flow in stimulated and unstimulated limbs at different levels of stimulation.

(5) FIG. 5 compares skin temperature in stimulated and unstimulated limbs at different levels of stimulation.

(6) FIG. 6 shows oxyhemoglobin levels measured by infrared spectroscopy in the tibia during stimulation cycles.

(7) FIG. 7 shows the change in deoxyhemoglobin levels in all patients during stimulation.

(8) FIG. 8 shows a first desired electrode arrangement.

(9) FIG. 9 shows a second desired electrode arrangement.

(10) FIG. 10 shows several electrode arrangements tested.

(11) FIG. 11 shows asymmetric and symmetric waveforms tested.

(12) FIGS. 12 and 13 show results from electrode and waveform comfort testing.

(13) FIGS. 14 to 17 show views of an embodiment of a device according to the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

(14) A device for electrically stimulating leg muscles is described in detail in WO2006/054118, and the reader is referred to that publication for a full description “of the device. The present invention is primarily based on a number of unexpected effects observed from use of that and similar devices, although we also describe a particularly preferred embodiment of the device.

(15) In brief, though, one embodiment of the device as described in WO2006/054118 includes a loop of elasticated material which, in use, may be worn around a user's lower limb. On the interior surface of the elasticated material are disposed first and second electrodes connected by conductive wires to a cradle which is integral with the elasticated material.

(16) Mounted within the cradle is a control module, which includes a, power cell, a control processor, and an external LED.

(17) The control module is removable from the cradle, with a pair of detents and corresponding recesses allowing the cradle and control module to interlock. The control module and cradle carry, corresponding electrical contact surfaces which provide for electrical communication between the control module and the first and second electrodes via the conductive wires,

(18) The control processor includes a timer module, a data store, a program store, and a logic unit.

(19) In use, the device is operated as follows. The elasticated loop is worn on a user's lower limb, such that the first electrode is in contact with the calf muscle at the rear of the limb, and the second electrode is in contact with the anterior muscle of the limb. When the control module is engaged with the cradle, the device is automatically activated.

(20) The program store is preloaded with an operating program arranged to activate the electrodes each minute using a 40 Hz pulsed DC of 20 mA for 0.1 second. Both electrodes are activated simultaneously. The timer module serves to generate appropriate timing signals, while the logic unit executes the program of the program store.

(21) As the electrodes are activated, the user's muscles are stimulated to contract. Contraction of the rear calf muscle, caused by the first electrode, serves to pump blood out of the leg using the calf pump thereby reducing pooling of the blood. Contraction of the anterior muscle, caused by the second electrode, is intended to reduce unwanted movement of the ankle by counterbalancing the contraction of the rear calf muscle. Simultaneously with each activation, of the electrodes, the LED on the outer surface of the control module is also activated; this provides a visual confirmation that the device is operating.

(22) The foregoing is a description of one embodiment of the device. However, a suitable device for stimulating muscles may be assembled from conventional skin, electrodes and a suitable electrical power supply. It is this form of test rig which was used in the following experiments.

(23) Experimental Design

(24) Study Title: A study to determine the effects of a novel method for enhancing lower limb blood flow in Healthy Adult Volunteers.

(25) Objectives: The primary objective of this study was to evaluate the effectiveness of topical electrical stimulation in enhancing lower limb perfusion. The secondary objective was to evaluate with duplex ultrasound and plethysmography techniques the blood flow velocity and volume changes associated with varying the intensity and level of electrical stimulation.

(26) Study Design: One-centre, physiological response study in healthy Volunteers.

(27) Stimulus Application: The effects of electrical stimulation on lower limb blood flow were investigated in healthy volunteers during a 4-hour period of prolonged sitting. Each subject completed his or her study sat in an Industry Standard airline seat. The stimulator used custom stimulation protocols. Superficial electrical stimulation was applied to the lateral popliteal nerve located in the area of the popliteal fossa.

(28) Sample Size: 30 Volunteers

(29) Environmental Conditions

(30) The examinations were carried out in a quiet, stable, draught free environment, both temperature and humidity controlled (24±10 C, relative humidity 30-40%). Volunteers were instructed to have a light breakfast, avoiding fatty foods, tobacco and caffeine and to abstain from vigorous exercise from the previous evening onwards. The volunteers were lightly clad (in shorts), sat in a comfortable position with legs bent at the knees.

(31) The effects of electrical stimulation on lower limb blood flow were investigated in healthy Volunteers during a 4-hour period of prolonged sitting. Each subject completed his or her study sat in an Industry Standard airline seat, which has been specifically obtained for this investigation.

(32) The leg clearance distance was be set at 34 inches, by positioning of a toe-bar. Each subject was positioned in the seat by a safety belt to maintain a close uniformity of posture and actively encouraged to remain as passive as can be tolerated by the individual.

(33) Physiological Assessments

(34) During this phase, the amplitude and frequency of the electrical stimulation was varied and associated changes in blood flow recorded.

(35) Changes in lower limb blood flow were evaluated using routine non-invasive plethysmographic techniques (photoplethysmography, strain gauge plethysmography and air plethysmography), transcutaneous oxygen and where possible, colour flow duplex ultrasound.

(36) Changes in blood flow and volume in response to the protocols were compared to blood flow and velocity changes determined by voluntary muscle action i.e. Volunteers were be asked to perform 10 plantar flexions (10 toe lifting movements—with the heel on the ground). This is the maximum physiological response that can be obtained in the sitting position.

(37) Volunteers were asked to evaluate acceptance and tolerability of electrical stimulation sequences by use of a questionnaire (Verbal Rating Scores) and a scoring index (Visual Analogue Scores). Discomfort was related to normal measurement of blood pressure, measured on the upper arm using a standard sphygmomanometer cuff.

(38) Following the period of sitting for 4-hours Volunteers will be re-examined with duplex ultrasound to recheck the status of the deep veins to exclude the development of significant thrombi. The study was performed on each subject at two separate occasions which were then averaged to reduce experimental bias.

(39) Stimulator

(40) The device produced a range of pre-Set programmed corresponding to different stimulation currents, and pulse frequencies. The waveform was specifically designed for motor nerve stimulation, as opposed to direct muscle stimulation. Pulse amplitudes ranged from 1 mA to 40 mA, with frequencies ranged from 1 Hz to 5 Hz, which is a significant departure from the Physiotherapy and TENS protocols (which generally apply substantively higher currents and frequencies).

(41) We applied a succession of 15 different stimulation programmes to each subject during the course of each study, according to a 2-dimensional matrix of amplitude and frequency, as shown in Table 1. The duration of each stimulation programme was 5 minutes, and will be followed by a 10-minute recovery phase to allow vascular re-equilibration prior to the next sequence.

(42) TABLE-US-00001 TABLE 1 Stimulation sequence Programme # Amplitude/mA Frequency/Hz 1 1 1 2 1 3 3 1 5 4 5 1 5 5 3 6 5 5 7 10 1 8 10 3 9 10 5 10 20 1 11 20 3 12 20 5 13 40 1 14 40 3 15 40 5

(43) During each of the 15 programmes, non-invasive blood flow and volume parameters were measured as specified above, with reference to the levels observed during voluntary muscle contraction, and with reference to levels observed in the contralateral limb.

Example 1: Blood Flow Patterns

(44) The patterns of venous blood flow in volunteers were monitored using vascular ultrasound of the stimulated leg. Representative examples are shown in FIGS. 1-3, FIG. 1a shows stimulation in a first subject at 20 mA, 5 Hz; FIG. 1b at 5 mA, 5 Hz; and FIG. 1e with no stimulation. FIG. 2a shows a second, subject stimulated at 20 mA, 3 Hz; FIG. 2b the same subject immediately after stimulation; and FIG. 2c the subject at rest. FIG. 3a shows a third subject undergoing stimulation at 10 mA, 3 Hz; FIG. 3b at 1 mA, 3 Hz; FIG. 3c at 20 mA, 5 Hz; FIG. 3d at 5 mA, 1 Hz; FIG. 3e at 5 mA, 3 Hz; and FIG. 3f the subject at rest.

(45) In these examples there was a four-fold increase in venous blood flow velocity from baseline. There was also a significant increase in frequency of cephalad (toward the head) venous blood flow with application of the stimulus.

(46) Flow velocity in the superficial femoral artery doubles and, the reverse flow components of the pulse wave arterial flow waveform are completely abolished with application of the stimulus.

(47) Reverse flow in the superficial femoral artery is due to high resistance of the peripheral vessels; therefore forward flow throughout the cardiac cycle suggests a significant reduction in peripheral vascular resistance.

(48) A fall in total peripheral resistance (consequent of the increase in vascular pump activation by the device) may be illustrated by the laser Doppler and vascular venous vessel ultrasound blood flow increases. The consequence of this is that cardiac output tends to increase. We have also shown that there is no significant increase in the heart rate (beats per minute). This may be demonstrated by the increase in the arterial blood flow and the change in the waveform.

(49) Importantly the increases in blood flow in the various tissues in the leg are proportionate, and therefore there is an increase in blood flow in all of the tissues; hence no ‘steal’ of blood from any adjacent tissue. All tissues, skin, muscle, bone etc have increased perfusion of blood.

(50) Resistance of blood flow can influence arterial pressure, cardiac output, distribution of cardiac output to systemic organs, distribution of organ blood flow to the various organ tissues, partitioning of tissue blood flow between capillaries and arteriovenous anastomoses, capillary hydrostatic pressure, and the distribution of blood flow within the cardiovascular system. All of which, are, upregulated by the device at certain, defined settings.

(51) A parallel is in exercise, where the total peripheral resistance also decreases as work load, measure by oxygen consumption increases. The fall in vascular resistance is accompanies by a progressive increase in cardiac output. The device mimics this event without a substantive increase in workload and hence minimal oxygen consumption compared to exercise.

(52) Increases in microcirculatory blood flow may additionally be explained by an increased utilisation of previously closed or ‘resting’ capillary networks, which become available for local exchange. The effect of this is a greatly increased tissue perfusion and a further effect on peripheral vascular resistance.

(53) This is a novel and unique observation, which has significant impact on the cardiovascular system and vascular therapeutics.

(54) Thus, application of the electrical stimulus can increase venous blood flow, and can reduce or prevent diastolic flow reversal in the artery. Note that this does not occur at all settings; FIG. 3d shows no flow reversal when stimulated at 5 mA, 1 Hz.

(55) This effect has the potential for a wide range of therapeutic and diagnostic applications. For example, as the effect only occurs at certain settings, it is likely that the current and frequency at which it appears in individual patients may be characteristic of their normal arterial flow and/or peripheral vascular resistance. This may be used to diagnose the presence and/or severity of circulatory disorders in a patient. Therapeutically, the modified arterial flow and reduced peripheral vascular resistance may be of benefit in treatment of a range of conditions, including ischaemia, cardiac vessel disease, ulceration, and so on.

Example 2

(56) Laser Doppler Fluxmetry (LDF) was used to measure the speed of skin blood flow; the results are shown in FIG. 4. LDF flux (speed of blood) is increased up to ˜1000% in stimulated leg compared to baseline and the unstimulated leg, which showed values only around baseline level.

Example 3

(57) Skin temperature was measured in stimulated and unstimulated legs; the results are shown in FIG. 5. There is a slight increase in temperature at all stimulations in the stimulated leg compared to unstimulated leg. Temperature in the body is generated by metabolism and blood flow. As the metabolism is not altered during the stimulations the slight increase in skin temperature is an indicator for increased blood flow in superficial layers of the skin.

Example 4

(58) Therapy for Osteoporosis

(59) Every year there are approximately 2 million osteoporotic fractures worldwide. (in 1990 there were 1.66 million, and 6 million per year forecast by 2050 according to World Health Organisation). High-risk groups include the elderly population, and people with spinal cord injuries.

(60) In the healthy individual, bone is constantly being remodeled according to physical requirements. Osteoclast cells remove minerals from bone, allowing collagen matrix to resorb, while osteoblasts lay down new collagen matrix and mineral deposits.

(61) Various theoretical models have been proposed over the last century for the mechanism by which the body controls bone density. Wolff, in 1892, proposed that bone deposits followed the patterns of stress in the bone. Frost's 1987 “mechanostat” theory suggested that bone was maintained to maintain uniform strain under habitual loads.

(62) Models for explaining why some individuals developed problems with maintaining bone density initially focused on disuse. In the ageing individual, decreasing use of the bone leads to lower doses of the stresses and strains required to signal bone maintenance. More recently, however, it has been suggested that there is a vascular component to the etiology. Osteoporosis appears to occur in individuals with impaired bone perfusion, either by reduced angiogenesis (itself aggravated by disuse), atherosclerosis restricting flow in existing vessels, or simply lower activity levels causing less blood circulation. (Trueta J. The role of the vessels in osteogenesis. J Bone Joint Surg Br. 1993).

(63) The present invention has the potential to mitigate vascular risk factors for osteoporosis, by increasing perfusion of bone. This can help in two ways. Firstly, augmenting blood supply overcomes limitation of bone modelling caused by reduced perfusion. Secondly, pharmaceutical interventions for osteoporosis can be delivered more effectively to the bone by improving bone perfusion.

(64) A study carried put under the supervision of the inventors has demonstrated that 1) Blood flow in the tibia and femur are enhanced when the device is active; and 2) Perfusion indices indicate that the bone is less hypoxic when the device is active.

(65) FIG. 6 shows Oxyhaemoglobin level measured by infrared spectroscopy in the tibia, during stimulation cycles (100 seconds on, 100 seconds off). Total blood content (top line) drops during stimulation, indicating that the calf pump aids evacuation, and that oxyhaemoglobin levels, rise during stimulation, indicating better oxygenation (reduced hypoxia).

(66) FIG. 7 shows the results for 12 subjects summated, showing the mean and standard deviation reduction of deoxyhaemoglobin relative to baseline. The device (labelled NMS) on the chart shows a significant reduction when active. As an idea of scale, this is compared with the reduction achieved by augmenting blood supply using the tilt-table method. This is a known hydrostatic step-change, which consists of the subject lying supine on a tilt table, and while strapped to the table they are tilted into a standing upright position, providing a very large hydrostatic vascular stimulus. This chart may be considered analogous to comparing DVT parameters with the device to foot flexion.

(67) The foregoing examples indicate that the device and method may be used to address new clinical targets. These include: Lower limb arterial disease—Peripheral Arterial Disease Enhanced lower limb lymphatic drainage. Cardiac diseases Fractures Enhancement of bone marrow perfusion—for example the management of sickle cell crises, ischaemic bone marrow, stem cell and bone marrow harvest procedures—as well as improving treatment of cancers by delivering drugs to the bone Marrow. Soft tissue injury of the lower limb—skin and muscle bruising and micro tears. Sports training and rehabilitation. Restless Leg Syndrome (Wittmaack-Ekbom's syndrome) Enhancement of endothelial-derived nitric oxide and prostacyclin release.

Example 5

(68) Discomfort

(69) Neuromuscular stimulation is commonly used to elicit muscle activity for several different applications. These include exercise, rehabilitation and restoration of function (eg drop foot stimulator) and more recently augmentation of blood supply using the soleus pump for various purposes,

(70) NMS has commonly been used previously for restoration of function in insensate individuals, eg with spinal cord injury. In these users, discomfort or pain associated with the stimulation is not an issue.

(71) In the sensate user, however, discomfort or pain during stimulation is an issue, and sometimes a limiting factor in the level of stimulation applied.

(72) In NMS, an electrical stimulus is used to cause contraction of a system of skeletal muscles. Unfortunately, efferent (motor) and afferent (sensory) nerves are typically bundled together in the same nerve conduit, and additional sensory nerves are present in the skin. This means that, as well as stimulating motor nerves, NMS causes some stimulation of sensory nerves. If sensation signals arrive at the brain, in large numbers and rapid succession, they may be perceived as pain in some individuals.

(73) Relationships have been found between electrode size and stimulatory response. It has also been found that stimulation quality and tolerance are sensitive to electrode position. These relationships have now been investigated further by the inventors, in a series of experiments.

(74) One hypothesis tested was that smaller electrodes would be better tolerated, since they allow us to target accurately the region of the peroneal lateral popliteal, without unnecessary stimulation of surrounding areas of skin receptors. This was not found to be reliably the case in our experiments. This finding may be rationalised as follows.

(75) Current density is usually maximal at the skin/electrode interface, whereas the quality of muscle contraction is determined by the current density at the point of excitation.

(76) For a given current, a smaller electrode provides increased current density at the skin. However, this does not necessarily translate to maximal current density at the point of excitation. The electrodes are necessarily spaced from each other to avoid short circuit Charge flows through the tissues from one electrode to the other electrode in a plurality of indirect routes. Therefore the charge takes a wider path in the tissue than at the interface between electrode and skin, with the effect that the charge density is at its highest in the skin, and lower within the tissue, and at the excitation point of the nerve.

(77) Experiments were conducted with various arrangements of electrodes to allow smaller differentials between current density at the skin interface and at the desired stimulation point.

(78) It has been found advantageous to have two electrodes of different size. Since excitation of the nerve is achieved by depolarising the nerve (which normally has a positive extracellular charge and a negative intracellular charge) it is the negative electrode (cathode) that causes the nerve to achieve action potential. It is found to be advantageous to position a small cathode in the precise region to be stimulated, and a larger anode at a site somewhat, removed, allowing high current density at the stimulation site only, and low current density (below action potential) generally.

(79) A refinement to this technique is to provide anodes either side of the cathode, giving a much wider spread of (accordingly lower) charge density at the anodes. Two possible embodiments of electrodes include three parallel strips (centre negative)—see FIG. 8—and target (bull's-eye negative)—see. FIG. 9. The target variant may have a closed or open outer circle, and, may be oval.

(80) The electrode structures were tested experimentally.

(81) Ten normal healthy subjects were used, ranging in age between 24 and 50. A Visual Analog Score was measured by asking each subject to draw a mark on a standard 10 cm line segment, representing where their sensation was on a scale from no discomfort (far left) to extreme pain (far right). A system was adopted for normalising these scores relative to a standard sensation, which was taken to be the existing electrode configuration and waveform used in the previous studies.

(82) A normalised discomfort score was then derived for each configuration based on the horizontal distance between the VAS for this configuration and the VAS for the standard configuration. Thus, a positive score will indicate less comfortable, and a negative score will indicate more comfortable,

(83) FIG. 10 (A-F) describes the electrode configurations used.

(84) Two waveforms were used, symmetric and asymmetric (see FIG. 11). In both cases, the overall charge is balanced (area A is equal), so no galvanic irritation is possible.

(85) Table 2 gives the key to the electrode/waveform combinations used.

(86) TABLE-US-00002 TABLE 2 Electrode Config configuration waveform  1 A Asym  2 A Sym  3 B Asym  4 B Sym  5 C Asym  6 C Sym  7 D Asym  8 D Sym  9 E Asym 10 E Sym 11 F Asym 12 F Sym

(87) FIG. 12 shows each stimulation configuration as a number on the x axis. For each, the median normalised VAS is shown as a blue bar, with the range between first and third quartiles shown as whiskers.

(88) It can be seen that the most preferred combinations are C, D, and to a lesser extent B, all with the asymmetrical waveform.

(89) Note that configuration 1 shows a shore of 0 in every case by definition.

(90) FIG. 13 shows the Normalised VAS ratings for each subject as a separate coloured line. This representation makes still more obvious the preference for the asymmetrical waveform.

(91) Optimal configuration is the symmetrical/target arrangement, negative electrode in the middle, and positive larger than negative. Waveform findings indicate that asymmetrical but charge-balanced (large positive spike followed by smaller but longer duration negative current) is optimal for comfort.

(92) A preferred embodiment of a device according to the invention is shown in FIGS. 14 to 17. The device 10 comprises a flexible, non-stretchable thermoplastic elastomer substrate 12 which includes an elongate tongue 14 at one end, and a moulded recess 16 at the other.

(93) On the tongue 14 are printed positive 18 and negative 20 electrodes. The positive is slightly larger than the negative. Each electrode includes a conductive track 22, 24 leading from the electrode to a respective contact point 26, 28 located in the recess 16.

(94) Not shown in the figures are an insulative strip arranged between the positive track 22 and the negative electrode 20, and similar strips at the edges of the tongue, to prevent unwanted leakage of current.

(95) Within the recess 16 are placed an electrical cell (not shown), and a PCB (not shown) including suitable circuitry to control the electrodes. Together with the conductive tracks 22, 24 and contact points 26, 28, this forms a complete circuit. A plastic cover is then sonically welded over the recess 16 to seal the components. A layer of gel is then placed over the whole device 10; this provides an electrical contact with a user's limb and helps keep the device adhered to a user. The gel may be protected in transit by a peel able backing layer.

(96) The outer surface of the recess 16 is formed with an integral diaphragm button 30 and an aperture 32 for displaying an LED. The button 30 is arranged to contact a corresponding button on the battery housing or PCB to activate the device. The aperture 32 displays an LED which indicates whether the device is operating.