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EP3727270A1 - Prévention et traitement de la septicémie à l'aide d'un dispositif d'exercice simulé - Google Patents

Prévention et traitement de la septicémie à l'aide d'un dispositif d'exercice simulé

Info

Publication number
EP3727270A1
EP3727270A1 EP17935065.7A EP17935065A EP3727270A1 EP 3727270 A1 EP3727270 A1 EP 3727270A1 EP 17935065 A EP17935065 A EP 17935065A EP 3727270 A1 EP3727270 A1 EP 3727270A1
Authority
EP
European Patent Office
Prior art keywords
pedal
sepsis
patient
rocking
motor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17935065.7A
Other languages
German (de)
English (en)
Inventor
Jose Antonio ADAMS
Marvin A. Sackner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP3727270A1 publication Critical patent/EP3727270A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H1/00—Apparatus for passive exercising; Vibrating apparatus; Chiropractic devices, e.g. body impacting devices, external devices for briefly extending or aligning unbroken bones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H1/00—Apparatus for passive exercising; Vibrating apparatus; Chiropractic devices, e.g. body impacting devices, external devices for briefly extending or aligning unbroken bones
    • A61H1/001—Apparatus for applying movements to the whole body
    • A61H1/003—Rocking or oscillating around a horizontal axis transverse to the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H1/00—Apparatus for passive exercising; Vibrating apparatus; Chiropractic devices, e.g. body impacting devices, external devices for briefly extending or aligning unbroken bones
    • A61H1/005—Moveable platforms, e.g. vibrating or oscillating platforms for standing, sitting, laying or leaning
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H1/00—Apparatus for passive exercising; Vibrating apparatus; Chiropractic devices, e.g. body impacting devices, external devices for briefly extending or aligning unbroken bones
    • A61H1/02—Stretching or bending or torsioning apparatus for exercising
    • A61H1/0237—Stretching or bending or torsioning apparatus for exercising for the lower limbs
    • A61H1/0266—Foot
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
    • A61H23/006—Percussion or tapping massage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/12—Driving means
    • A61H2201/1207—Driving means with electric or magnetic drive
    • A61H2201/1215—Rotary drive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/14—Special force transmission means, i.e. between the driving means and the interface with the user
    • A61H2201/1418—Cam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/16—Physical interface with patient
    • A61H2201/1602—Physical interface with patient kind of interface, e.g. head rest, knee support or lumbar support
    • A61H2201/164—Feet or leg, e.g. pedal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/16—Physical interface with patient
    • A61H2201/1602—Physical interface with patient kind of interface, e.g. head rest, knee support or lumbar support
    • A61H2201/164—Feet or leg, e.g. pedal
    • A61H2201/1642—Holding means therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/16—Physical interface with patient
    • A61H2201/1657—Movement of interface, i.e. force application means
    • A61H2201/1676—Pivoting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/50—Control means thereof
    • A61H2201/5023—Interfaces to the user
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/50—Control means thereof
    • A61H2201/5023—Interfaces to the user
    • A61H2201/5025—Activation means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/50—Control means thereof
    • A61H2201/5097—Control means thereof wireless
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2203/00—Additional characteristics concerning the patient
    • A61H2203/04—Position of the patient
    • A61H2203/0425—Sitting on the buttocks
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2203/00—Additional characteristics concerning the patient
    • A61H2203/04—Position of the patient
    • A61H2203/0443—Position of the patient substantially horizontal
    • A61H2203/0456—Supine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2230/00—Measuring physical parameters of the user

Definitions

  • the present invention is directed to a method of preventing and treating sepsis and septic shock using a motorized machine such as a simulated passive exercise device which increases pulsatile shear stress (friction) to the vascular endothelium of a subject.
  • a motorized machine such as a simulated passive exercise device which increases pulsatile shear stress (friction) to the vascular endothelium of a subject.
  • Sepsis produced by infectious diseases, is a leading cause of death in the United States and the most common cause of death among critically ill patients in non-coronary intensive care units (ICU).
  • Respiratory tract infections particularly pneumonia, are the most common site of infection, and associated with the highest mortality.
  • Recent studies suggest that acute infections worsen preexisting chronic diseases or result in new chronic diseases, leading to poor long-term outcomes in acute illness survivors.
  • Elderly males, African Americans, and individuals with pre-existing chronic health conditions are particularly prone to develop severe sepsis. Therefore, preventative strategies should be strongly considered in such vulnerable populations but owing to the safety and potential of the invention described in this submission, even a healthy population may benefit.
  • Severe Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, Severe Sepsis is included in this definition.
  • Septic shock is a subset of sepsis in which profound circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone; its clinical criteria is hypotension requiring use of vasopressors to maintain mean arterial pressure > 65 mmHg and having a serum lactate >2 mmol/l persisting despite adequate fluid resuscitation.
  • Sepsis is a medical emergency that requires urgent attention and treatment.
  • MAP mean arterial blood pressure
  • LPS lipopolysaccharide
  • Potential treatments counteract the inflammatory cytokines elevated by sepsis which disrupt the endothelial barrier, produce intense inflammation, increase oxidative stress and shortens life span in a dose- dependent way.
  • Our review of survival data in the scientific literature revealed that only 0 to 20% of mice survive 48 hours with LPS intraperitoneal doses of 30 to 40 mg/kg without treatment.
  • Anti-inflammatory, chemotherapeutic, or pesticide agents administered after LPS provide 80 to 90% survive up to 48 hours.
  • a method of treating a patient for septic shock or preventing sepsis in the patient by using a motorized machine said machine having a housing, an axis-defining mechanism coupled to the housing, the axis-defining mechanism configured to define a rocking axis, at least one pedal positioned to receive a foot of the user and mounted on the rocking axis for rocking movement of the at least one pedal; a motor arranged within the housing, the motor configured to generate rotational motion to an output shaft of the motor, a pedal rocking mechanism coupled to the output shaft and driven by the motor, the pedal rocking mechanism being configured to translate the rotational motion generated by the motor to reciprocating rocking motion of the at least one pedal about the rocking axis, and at least one bumper, height-adjustably coupled to the housing, located spaced apart from a bottom portion of the at least one pedal, the reciprocating rocking motion of the at least one pedal provided by the pedal rocking mechanism providing a positive application of force for moving the bottom portion of the pedal towards and away from the at least one
  • the method in the case of sepsis prevention, is performed twice daily for the therapeutically-effective amount of time.
  • the method in another embodiment, in the case of potential sepsis exposure, is performed twice daily, each time for the therapeutically-effective amount of time, the therapeutically-effective amount of time being at least 30 minutes, and wherein the twice daily performance of the method beginning at least three days prior to the potential exposure to sepsis.
  • the method is performed upon detection of one of an unexpected fever, elevated heart rate and respiratory rate of the patient.
  • FIGs. 1 A and 1 B show an experimental motion platform for use on mice to increase pulsatile shear stress to the endothelium
  • FIG. 2 is a plan view of an apparatus in accordance with an embodiment of the present invention.
  • FIG. 3 is a section view taken along the lines 3-3' in FIG. 2;
  • FIG. 4 is a section view taken along the lines 4-4' in FIG. 2;
  • FIG. 5 is a section view taken along the lines 5-5' in FIG. 2;
  • FIG. 6 is a section view taken along the lines 6-6' in FIG. 2;
  • FIG. 7 is a perspective view of the apparatus of FIG. 1 with the top cover and one foot pedal removed;
  • FIG. 8 is a perspective view of the underside of a foot pedal according to one embodiment of the present invention.
  • FIGs. 9 and 10 are graphs showing that the CONT & pGz did not significantly differ for the first 360 minutes after LPS but diverged at 420 minutes with signs of illness until all CONT mice were dead at 24 hours.
  • FIG. 1 1 is a composite graph for the preconditioning experiments to show the role that NO2 plays in sepsis.
  • FIGs. 12 and 13 are graphs depicting in mice heart muscle Western Blot values in Optical Units (O.U.) referenced to protein/GADPH/SHAM at 90 and 360 minutes, respectively, after initiation of investigation.
  • FIGs. 14 and 15 are graphs depicting in mice heart muscle Western Blot values in Optical Units (O.U.) referenced to protein/GADPH/SHAM at 90 and 360 minutes, respectively, after initiation of investigation.
  • FIGs. 16 and 17 are graphs depicting the effects of pGz Pre- and Postconditioning on TIE2 Expression/ Phosphorylation and Microvascular Permeability at 90 and 360 minutes, respectively.
  • Fig. 18 is a graph depicting results of in vivo injection of Evans Blue dye in mice to estimate fluid leakage from destruction of the endothelial barrier through post-mortem analysis.
  • FIGS. 2-8 and 1 1 show an exemplary embodiment of passive simulated exercise apparatus for use in treating sepsis and septic shock.
  • the apparatus includes a pair of foot pedals, each of which are driven to up and down, rocking movement about an axis transverse to the feet, preferably alternating, i.e., anti-phase, motion of the two foot pedals.
  • the apparatus is configured such that each movement of the foot pedals can be associated with a percussive contact of a portion of the underside of the foot pedal, which percussive contact passes along to the user a pulsatile impact which, as is discussed above, increases shear stress to mechanically stimulate the endothelial cells to increase the activity of genes responsible for release of beneficial mediators.
  • the tapping simulates the beneficial effects that occur, for example, while running, in which Pulsatile shear stress (PSS) is increased by addition of pulses generated by the tapping.
  • PSS Pulsatile shear stress
  • a pulse is added to the circulation that is superimposed upon the body's own pulses and is detected in the radial arterial pressure waveform.
  • the feet will be placed on the pedals such that the toes will be raised (and then lowered) in relation to the heels by the rocking of the pedals, and the tapping applied to the toe portion of each foot.
  • the apparatus is advantageously symmetrical in design so as to permit the heels, rather than the toes, to be raised and lowered, by the user turning the apparatus around 180. degree and placing his or her feet in the opposite direction. Such reversed usage of the apparatus results in the pulse being delivered to the heel of the user rather than to the toe.
  • the apparatus 1 in accordance with an embodiment of the present invention, includes a housing top 14, a housing bottom 15, and left and right foot pedals, 10 and 12, having surfaces 1 1 a and 1 1 b, respectively, for receiving the feet of a user.
  • the bottom of the apparatus preferably includes bottom stabilizer posts 13, e.g., made of rubber, to contact the ground, provide a leveling function and prevent slippage of the apparatus during use.
  • the apparatus 1 may include a speed adjustment control 16, which can vary the speed of the up and down motion of the pedal 10 and 12.
  • the adjustment control can be in the form of a knob, switch, lever or other user- selectable device.
  • the control 16 is depicted in the figures as a knob.
  • the housing top 14 and housing bottom 15 are preferably coupled to one another using screws 17.
  • a force adjustment control 18 is provided, a portion of which is accessible through an opening in the housing top 14 to allow adjustment of the intensity of tapping or striking force provided by the motorized machine or device 1 .
  • the ability to adjust the speed of the up and down motion of the pedals 10, 12 is optional and may be omitted.
  • FIGS. 3-6 show the interior workings of the motorized machine, exercise device 1 in the sectional views of FIGS. 3-6, as well as the perspective view of FIG. 7, which shows the interior without the housing top 14 and without right pedal 12.
  • the interior of the device 1 includes mechanical and electrical elements that cooperate to cause the pedals to rockingly reciprocate, e.g., anti-phase to one another, between up and down positions, the pedals being rotatable, preferably at a rearward portion of each pedal, about a common axis.
  • the rocking motion for the movement of the pedals is provided in the first embodiment by a driving mechanism that includes a motor 20, the drive shaft of which drives a motor pulley 22.
  • a stop/start button 21 is preferably provided to start the operation of the motor.
  • the motor 20 is preferably a motor of a well-known type, such as a DC brushless motor, of a power sufficient to drive pedals of the apparatus. Power to the motor 20 is supplied, e.g., using power connector 23, or by disposable or rechargeable batteries, not shown.
  • the motor pulley 22 contacts a belt 24 which is also contacting a camshaft pulley 26.
  • the belt transfers rotational motion of the motor pulley 22 to provide rotational motion to the camshaft pulley 26.
  • This rotation in turn causes a camshaft 28, arranged along an axis perpendicular to the camshaft pulley 26 and transverse to the feet, to rotate.
  • a cam 30 is eccentrically coupled to each end of the camshaft 28.
  • the eccentricity is provided, in the present embodiment, by the camshaft 28 coupling with the cam 30 in an off-center manner, that is, coupling to the cam 30 at a point on the cam 30 axially offset from the center of the cam 30.
  • the off-center coupling causes eccentric rotating motion of each cam 30. While the cam 30 and the camshaft 28 are shown in the first embodiment as being distinct elements, the cam 30 can also be an integrally formed portion of each end of the camshaft 28.
  • each cam 30 is arranged in a channel 31 provided in a pedal coupling member 32.
  • the channel 31 is configured such that the eccentric motion of the cam 30 causes the coupling member 32 to reciprocate, such that a front end of the coupling member 32 moves up and down to a greater extent than the rear end of the coupling member 32.
  • each coupling member 32 is affixed, for example, by screws 34, to the underside of the respective foot pedals 10 and 12.
  • the cams 30 are arranged in the channel 31 of the respective pedal coupling members 32 such that the motion provided to the two pedal coupling members 32 by virtue of the eccentricity of the cams 30 at each end of the camshaft 28, generates alternating, i.e., anti-phase, reciprocating up and down motion of the pedals 10 and 12, so that, preferably, when one pedal is moving up, the other is moving down.
  • the cams can be configured to provide in-phase movement of the pedals.
  • the motion of the camshaft 28, driven by the pulleys 22 and 26 and the motor 20, drives the pedals in an up and down motion about a common axis 34.
  • the common axis 34 is preferably provided towards the rear of each pedal 10, 12 being rotatably mounted around a pedal axle 36, disposed along the common axis 34. While the disclosed embodiment shows the common axis disposed at an extreme end of each pedal, the invention is not limited to this configuration, and the device could be alternatively set up with the axis of rotation located away from an extreme end, while still providing the rocking motion
  • the motor 20 is mounted on a mounting plate 38, to which various elements of the driving mechanism described above are also coupled, either directly or indirectly.
  • the mounting plate 38 is located between the housing top 14 and the housing bottom 15 and acts as a chassis for mounting internal components of the exercise device 1 .
  • the mounting plate 38 is preferably made of a lightweight metal, for example aluminum, steel, or the like. However any sufficiently strong and lightweight material can used, such as carbon reinforced plastic, or other similar material, that will result in a lightweight travel-friendly device.
  • the mounting plate 38 includes two pedal mounting flanges 40 structured to secure each pedal axle 36 and the rear of each pedal 10, 12. Also coupled to the mounting plate 38 are bearing blocks 42, each of which receives and secures an end of the camshaft 28, or a tubular extension thereof, to allow rotation of the camshaft 28.
  • the output shaft of the motor 20 can be arranged perpendicular to the camshaft, and a bevel gear configuration used to drive the camshaft.
  • Another variation would use a motor having output shafts along the rotational axis of the camshaft so as to directly drive the camshaft
  • the motor 20 can be adjustable to increase or decrease the speed of the movement of the pedals.
  • a motor controller 56 is provided, which controls the speed of the motor 20 in accordance with the position of the speed adjustment knob 16.
  • Such adjustment is well-known in the art and can be done in any conventional manner, for example by use of a potentiometer controlled by the knob 16, in which the motor speed is varied proportionally to a position of the knob 16, or electrical or digital equivalents thereof.
  • the controller 56 is digitally or otherwise configured to receive information from the knob 16 and, based on this information, control the speed of the motor 20.
  • each pedal 10, 12 is configured to contact a top portion of a bumper 46, at an inside contact surface 44 of each pedal, at the bottom of the downward toe stroke of each pedal provided by the reciprocating motion of the coupling members 32.
  • Each bumper 46 one arranged under each pedal respectively, includes a bumper cover 48, for example made of rubber, and a bumper body 50, the lower part of which is a threaded cylindrical portion having threads 51 .
  • the bumper body 50 is threadingly coupled to the mounting plate 38 such that rotation of the bumper body 50 effects an adjustment of its height with respect to the bumper body 50, as well as its proximity with respect to the contact surface 44 of the pedal 10, 12.
  • an annular screw jack 52 is configured such that inner threads 53 of each annular screw jack 52 mate with corresponding threads 51 of the cylindrical portion of the bumper body 50, so as to cause, upon a rotation of the annular screw jacks 52, a corresponding rotation of the bumper body 50, causing a change in the height of the bumper body relative to the mounting plate 38.
  • Each screw jack 52 having threads 53 is coupled to a tension cable 54 that wraps around the screw jack 52.
  • the tension cable 54 is adjusted by the force adjustment control 18.
  • the force adjustment control can be in the form of a knob, switch, lever or other user- selectable device.
  • the control 18 is depicted in the figures as a knob.
  • the force adjustment control knob 18 is coupled to the tension cable 54 so that adjustment of the knob 18 in a first direction bumpers 46, by twisting the screw jack 52 in one direction, e.g., clockwise, and adjustment of the control knob 18 in a second direction lowers bumpers 46, by twisting the screw jack 52 in an opposite direction, e.g., counter-clockwise.
  • the knob 18 is preferably coupled to the mounting plate 38 at a dedicated rectangular portion 58 of the mounting plate 38, as can be seen in the figures
  • the configuration of the bumper 46 and the control knob 18 allows for adjustment of the intensity of striking of the pedal 10, 12, in particular the contact surface 44, with the top of the bumper 46 by the turning of the control knob 18. The higher the position of the top of the bumpers 46, results in an increase of the pulsatile force applied to the bumpers 46.
  • the height of the bumper 46 is adjusted to allow for tapping that provides a range of pulsatile acceleration having a force sufficient to increase pulsatile shear stress to the endothelium, of sufficient magnitude to cause the release of beneficial mediators, such as nitric oxide, prostacyclin, tissue plasminogen activator, adrenomedullin, SIRT1 , Brain and Glial Derived Neurotrophic Factors (BDNF & GDNF), Kruppel Like Factor 2, Superoxide Dismutase, Glutathione Peroxidase 1 , Catalase, Total Antioxidant Capacity, Anti Apoptotic Proteins: p-Akt, Bcl2, and Bcl2/Bax, HSP27.
  • beneficial mediators such as nitric oxide, prostacyclin, tissue plasminogen activator, adrenomedullin, SIRT1 , Brain and Glial Derived Neurotrophic Factors (BDNF & GDNF), Kruppel Like Fact
  • Such tapping to the feet provided by the apparatus can increase pulsatile shear stress as related to the addition of pulses into the vascular circulation, heart, lymphatic channels, interstitial spaces, skeletal muscle and bone interstices, as well as slight increases of cyclic strain to the blood vessels and lymphatic channels.
  • the tapping is also settable so as to increase the activity and content of endothelial nitric oxide synthase (eNOS) in blood vessels, heart and skeletal muscle, as well as to increase the activity of neuronal nitric oxide synthase (nNOS) in the heart and skeletal muscle.
  • eNOS endothelial nitric oxide synthase
  • nNOS neuronal nitric oxide synthase
  • adding the pulses, using the striking of the bumper with the foot pedals, to the body's fluid filled channels over the body's own pulse stimulates endothelial release of at least one of nitric oxide, prostacyclin, tissue plasminogen activator (t-PA), adrenomedullin, endothelial dependent hyperpolarizing factor (EDHF), endothelial dependent relaxing factor, endothelial growth factors, and transcription factors, etc.
  • t-PA tissue plasminogen activator
  • EDHF endothelial dependent hyperpolarizing factor
  • endothelial dependent relaxing factor endothelial growth factors, and transcription factors, etc.
  • the device disclosed in U.S. Patent No. 9,622,933 can increase pulsatile shear stress (friction) to the vascular endothelium.
  • This non-invasive device passively increases pulsatile shear stress to the endothelium of individuals seated or lying down or those at risk or suffering from acute illnesses that have as a major component endothelial barrier dysfunction.
  • Increased pulsatile shear stress mechanically distorts endothelial cells to activate genes that increase release of nitric oxide, prostacyclin, SITR1 , and adrenomedullin among others into the circulation as well as to up-regulate expression of Tie-2 at endothelial cell junctions.
  • Pulse wave analysis uses a validated transfer function to calculate the central aortic waveform from a peripheral, noninvasively-obtained, arterial pressure waveform.
  • the transfer function is a mathematical model that describes the relation between the central and peripheral arterial waveforms. Augmentation is defined as the difference between the second systolic peak (caused by wave reflection) and the first systolic peak (caused by left ventricular contraction).
  • the augmentation index (Alx) is this difference expressed as a percentage of the central pulse pressure. Increasing values of this index indicate a good prognosis as endothelial function improves while decreasing values that approach 0.5% or less a poor prognosis.
  • the SphygmoCor or similar systems that provide aortic waveform analysis aid in decisions for frequency of use of the device disclosed in this patent application.
  • the vascular endothelium covers the inner lining of all lymphatic and blood vessels and the heart, thereby acting as a highly widespread“organ” along the 100,000 km of everyone’s vascular tree. It is engaged in the regulation of blood pressure, hemostasis, inflammation and defense and in organ-specific perfusion.
  • the endothelium functions as a selective barrier that tightly balances the exchange of water, solutes, macromolecules and mobile cells between the flowing blood and the underlying tissues. This balance is essential to achieve systemic and site-specific vascular homeostasis by responding to a wide variety of physiological and pathological stimuli, resulting in changes of intercellular junctions or trans-cellular transport processes. Apart from their biological relevance in maintaining and regulating barrier function, endothelial cell junctions are major targets in many vascular and infectious diseases and in cell regeneration and repair, as they affect shape changes, barrier breakdown/ apoptosis or cell migration, and proliferation.
  • Endothelial barrier maintenance and the response of the quiescent barrier to locally produced vasoactive agents, such as histamine, prostaglandins, thrombin and VEGF is primarily mediated by dynamic changes in cell to cell junctions.
  • Described herein is a simple, cost-effective means to preserve and maintain endothelial barrier integrity through the increase of substances upregulated and released during operation of a passive simulated exercise device of the type disclosed in U.S. Patent No. 9,622,933.
  • the administration of a lethal dose of lipopolysaccharide (LPS) to mice and survival from death is the basis for“proof of concept”, as explained below and illustrated in the graphs of Figs. 9-18.
  • FIGs. 1 A and 1 B The platform and restraining cylinder are depicted in FIGs. 1 A and 1 B. Preconditioning
  • mice Wild type mice were used for this investigation. o 18 mice were selected as controls (CONT) and received the same diet and granted unrestricted physical activity as mice used for pGz treatment. o 18 mice were placed on the motion platform, each within a Plexiglas restraining cylinder (figure above) that moved at 480 cycles per second for one hour daily for 3 days (pGz).
  • CONT controls
  • o 18 mice were placed on the motion platform, each within a Plexiglas restraining cylinder (figure above) that moved at 480 cycles per second for one hour daily for 3 days (pGz).
  • mice received intraperitoneal (i.p.) injections of 40 mg/kg LPS and were observed with video monitoring for 48 hours.
  • mice pre-treated with pGz began to die 20 hours after LPS, but 60% survived for 48 hours, the predetermined outcome duration of the trial.
  • L-NAME a nitric oxide synthase inhibitor was orally administered in drinking water in 8 non-LPS administered mice for 7 days and in 8 mice prior to LPS 40 mg/kg i.p. (L- NAME-pGz) and mortality compared to 8 mice given LPS only.
  • L- NAME that blocks nitric oxide release even if combined with pGz produces the same fatal outcome in 14 hours.
  • a composite graph for the preconditioning experiments is depicted in Fig. 1 1.
  • SFIAM mice placed within restraining cylinder. o 4 mice sacrificed at 90 minutes o 4 mice sacrificed at 360 minutes.
  • LPS mice given 40 mg/kg LPS i.p. & placed within restraining cylinder. o 4 mice sacrificed at 90 minutes o 4 mice sacrificed at 360 minutes.
  • mice • pGz-LPS mice: pGz for 1 hour within restraining cylinder followed by 40 mg/kg LPS i.p. o 4 mice sacrificed at 90 minutes o 4 mice sacrificed at 360 minutes.
  • Figs. 1 1 and 12 depict in mice heart muscle Western Blot values in Optical Units (O.U.) referenced to protein/GADPFI/SFIAM at 90 and 360 minutes after initiation of investigation. Interpretation of NOS changes by LPS and pGz
  • nNOS is the content of a possible beneficial form of NOS in cardiac muscle and is approximately the same level at 90 and 360 minutes.
  • the graphs of Figs. 14 and 15 depict in mice heart muscle Western Blot values in Optical Units (O.U.) referenced to protein/GADPH/SHAM at 90 and 360 minutes after initiation of investigation.
  • IL-1 beta the most important inflammatory cytokine was lower at 360 than 90 minutes with pGz-LPS along with higher values of IL-10, an anti-inflammatory cytokine.
  • TNF-alpha and NF-kB had similar values at 90 and 360 minutes.
  • TIE2 is a mediator upregulated by endothelial derived nitric oxide that promotes tightening of endothelial intracellular junctions.
  • TIE2 Phosphorylated TIE2
  • the active form of TIE2 was lower during LPS and pGz-LPS at 360 compared to 90 minutes.
  • Fig. 18 illustrates the effects of preconditioning on microvascular permeability with pGz at 360 minutes of in vivo injection of Evans Blue dye in mice to estimate fluid leakage from destruction of the endothelial barrier through post-mortem analysis
  • Fig. 18 depicts results of in vivo injection of Evans Blue dye in mice to estimate fluid leakage from destruction of the endothelial barrier through post-mortem analysis.
  • pGz provides protection to the endothelial barrier in the LPS mice model.

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Abstract

L'invention concerne une méthode de traitement de la septicémie et du choc septique à l'aide d'un dispositif d'exercice simulé passif. Le dispositif d'exercice fonctionne de manière à augmenter la contrainte de cisaillement pulsatile (frottement) sur l'endothélium vasculaire. Une contrainte de cisaillement accrue stimule la libération de médiateurs bénéfiques depuis l'endothélium dans la circulation, lesquels favorisent l'intégrité de la barrière endothéliale, ce qui empêche la rupture de cette dernière par suppression de l'inflammation et du stress oxydatif. Ce dernier est à la base des effets délétères de la septicémie et du choc septique. L'échec de la protection de l'intégrité de la barrière endothéliale favorise une fuite excessive de fluide et de protéines du système vasculaire dans le fluide interstitiel environnant, ce qui peut s'aggraver rapidement et entraîner une morbidité majeure, un choc et la mort.
EP17935065.7A 2017-12-20 2017-12-20 Prévention et traitement de la septicémie à l'aide d'un dispositif d'exercice simulé Withdrawn EP3727270A1 (fr)

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US7090648B2 (en) * 2000-09-28 2006-08-15 Non-Invasive Monitoring Systems, Inc. External addition of pulses to fluid channels of body to release or suppress endothelial mediators and to determine effectiveness of such intervention
EP1827348A2 (fr) * 2004-12-07 2007-09-05 Tylerton International Inc. Dispositif et procede d'entrainement, de readaptation et/ou de soutien
US8430796B1 (en) * 2012-05-29 2013-04-30 Mary Anne Tarkington Exercise devices and methods for exercising an ankle, foot, and/or leg
WO2014197385A1 (fr) * 2013-06-03 2014-12-11 Marvin Sackner Dispositif de jogging simulé passif

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