A method for treating an extremity by applying a combination of low pressure and heat to increase peripheral arterial blood flow

Abstract

The invention relates to a medical method for treating an extremity, e.g. a foot or hand, to increase arterial peripheral blood flow by applying a variable localized combination of low pressure and heat controlled by a heart rate variability module that adjusts negative pressure and heating in real-time in response to the HRV sensor data, and devices made for the same.

Description

[0001] APPLICATION FOR PATENT TITLE OF THE INVENTION A Method for Treating an Extremity by Applying a Combination of Low Pressure and Heat to Increase Peripheral Arterial Blood Flow FIELD OF THE INVENTION The invention relates to a medical method for treating an extremity, e.g. a foot or hand, to increase peripheral arterial blood flow by applying a localized combination of low pressure and heat, and devices made for the same. BACKGROUND Over half (53%) of adults in the United States have some form of diabetes. Traditional treatments have been inadequate in stopping this epidemic suggesting the need for novel therapies. U.S. patent 8,679,170 and 9,066,781 disclose an apparatus and method for treating a human condition by providing an appendage chamber having a thermal exchange member. A vacuum may be applied to the appendage chamber to maintain vasodilation of an appendage when placed within the appendage chamber. The appendage may be heated or cooled at the thermal exchange member for therapeutic application of thermal energy to treat a number of circulatory, neurological, lymphatic, or endocrinal maladies. U.S. patent 9,192,509 and 9,687,385 disclose an apparatus and methods are provided for treating a human condition by providing an appendage chamber having a thermal exchange member. Negative pressure may be applied to a human appendage when placed within the appendage chamber. Blood flowing through the arteriovenous anastomosis (AVA) of the appendage may be heated or cooled at the thermal exchange member for therapeutic application of thermal energy to adjust blood viscosity in the human to alleviate symptoms associated with a number of autoimmune, circulatory, neurological, lymphatic, and endocrinal maladies. A load sensor may be coupled to the thermal exchange member and configured to measure a force of the appendage applied to the thermal exchange member. In addition, a negative pressure sensor may measure pressure within the appendage chamber. SUMMARY OF THE INVENTION In one non-limiting preferred embodiment, the invention provides an apparatus, comprising a pressure and heating device includes a housing, a power supply, a negative pressure unit, a heat delivery unit, a control module, the housing having an extremity chamber with a water basin and a sealable cuff around an opening configured to accept the extremity, and the control module varies the settings of the negative pressure unit and the heating unit, wherein the heating unit heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure unit provides negative pressure at -20 mmHg and -150 mmHg. Any of the non-limiting embodiments may include wherein the negative pressure unit and heat delivery unit are coupled to a heart rate variability module and sensor, the control module receives HRV sensor input, and the heating unit and negative pressure unit vary the heat and pressure in response to the HRV sensor input. Any of the non-limiting embodiments may include wherein the heart rate variability module is coupled to the negative pressure unit and the heating unit and configured to measure the heart rate variability using a heart rate variability sensor, the heart rate variability module is electrically coupled to a programmable controller configured to: (a) determine a base heart rate variability measured using the heart rate variability sensor, (b) calculate and set a heart rate variability range using the base heart rate variability, (c) monitor whether the heart rate variability measured by the heart rate variability sensor falls within the heart rate variability range, (d) optionally send an alert if the heart rate variability is outside the heart rate variability range, and (e) adjust the heart rate variability range over time to modify pressure and temperature settings used by the negative pressure unit and the heating unit. Any of the non-limiting embodiments may include wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg . Any of the non-limiting embodiments may include wherein the negative pressure unit is disposed within the housing and includes a negative pressure gauge configured to measure a pressure within the foot and leg chamber, the negative pressure gauge is in communication with the control unit, and the control unit is programmably configured to monitor the negative pressure measured by the negative pressure gauge and to direct the negative pressure unit to adjust the pressure within the chamber, and the heating unit is disposed within the housing and includes a thermocouple configured to measure temperature within the foot and leg chamber, the thermocouple is in communication with the control unit, and the control unit is programmably configured to monitor the temperature measured by the thermocouple and to direct the heating unit to adjust the temperature within the chamber, e.g., to about 42°C. In another non-limiting preferred embodiment, the invention provides a method for treating an extremity to increase peripheral arterial blood flow by applying a localized variable combination of low pressure and heat in real-time response to heart rate variability sensor data, by providing an HRV negative pressure and heating apparatus having an extremity chamber with a water basin, the extremity chamber dimensioned to fit a foot, a leg, a leg and foot, a hand, an arm, and a hand and arm, applying negative pressure and heat in response to real-time HRV sensor data for a duration sufficient to effect treatment of the extremity. Any of the non-limiting embodiments may include wherein the heating device heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure is -20 mmHg and -150 mmHg . Any of the non-limiting embodiments may include wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg . Any of the non-limiting embodiments may include wherein treatment comprises increasing blood flow rate (time averaged mean velocity (TAMV) in a peripheral artery by 22.3% to 24.7%, and / or by increasing CSA by 9.7% to 10.4%, and / or by increasing blood flow by 29.5% to 32.3%. Any of the non-limiting embodiments may include wherein the heating unit is configured to deliver heating for approximately five to sixty minutes. Any of the non-limiting embodiments may include wherein the negative pressure is applied at negative pressure between -20 mmHg and -150 mmHg or between -100 mmHg and -150 mmHg, or is greater than -150 mmHg, or is between -150 mmHg and -200 mmHg. In another non-limiting preferred embodiment, the invention provides a method for treating an extremity of a patient in need thereof, comprising: (i) providing a heating and negative pressure apparatus; (ii) placing the patient's extremity in need of treatment in the heating and negative pressure apparatus; and using the heating and negative pressure apparatus to apply heat and negative pressure to increase peripheral blood flow. Any of the non-limiting embodiments may include wherein the heating and negative pressure apparatus includes an extremity chamber dimensioned to fit a foot, a leg, a leg and foot, a hand, an arm, and a hand and arm, the extremity chamber having a water basin. Any of the non-limiting embodiments may include wherein the heating device heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure is -20 mmHg and -150 mmHg . Any of the non-limiting embodiments may include wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg . BRIEF DESCRIPTION OF THE FIGURES FIGURE 1 is a graphic illustration showing participants seated during the 2-hr oral glucose tolerance test, according to the invention. Condition A was a thermoneutral control. Hot water (40°C) was applied to the feet (Condition B) or calves (Condition C) for 2 hours. Measurements were taken at baseline and every 30 minutes. FIGURE 2 is a line graph showing Blood glucose, and that there was a significant interaction between blood glucose and time (F (4.6, 72.6) = 2.6, p=.O36). Blood glucose was higher during calf-heating at minute 90 than during control (+12 (95%CI: +3 to +21) mg / dL, p=.O13) and feet heating (+19 (95% Cl: +5 to +34) mg / dL, p=.011 ). FIGURE 3 is a bar graph and shows Incremental area under the curve for glucose, and that there was no main effect for condition (F (1 .4, 25.4) = 0.3, p=.67). FIGURE 4 is a line graph and shows Heart rate, and that there was a significant interaction between condition and time (F (3.4, 54.5) = 3.5, p=.O17). Heart rate was higher during calf heating than control condition at minutes 60, 90, and 120 (mean A +11 to +13 BPM, p=.010-.029). FIGURE 5 is a line graph and shows HRV, and that there was a significant interaction between condition and time (F (4.3, 63.2) = 7.5, p<.0001). HRV during calf heating at minutes 30, 60, 90, and 120 was lower than the control condition (mean A - 13 to -7 , p<.007) and feet-heating (mean A - 13 to -11 , p<.009). FIGURE 6 is a line graph and shows Tympanic temperature, and that there was a significant interaction between condition and time (F (8,268) = 2.4, p=.O143). Differences between conditions were <0.2°C (p=.0657-.99) throughout. FIGURE 7 is a line graph and shows Thermal Comfort Score, and that there was a significant interaction between condition and time (F (8,248) = 22.1 , p<.0001). Scores were higher during calf- heating (mean A +1.0 to +2.5, p<.0001) and feet-heating (mean A +0.7 to +1.0, p<.001) than control at minutes 30- 120. Scores were higher than calf-heating than feet- heating (mean A +0.8 to +1 .3, p<.002) at minutes 60-120. FIGURE 8 is a line graph and shows Blood pressure, and that there was no significant nteraction between condition and time for systolic (F (8,256) = 0.73, p=.66) or diastolic (F (8,256) = 0.46, p=.88) blood pressure. FIGURE 9 is a line graph and shows Mean arterial pressure, and that there was no significant interaction between condition and time (F (8,256) = 0.47, p=.88). FIGURE 10 is a series of three bar graphs, and shows Blood flow data while using the device at the feet, shows a 64%, 22%, and 29% (p=.005-.022) increase in blood flow at the popliteal / superficial femoral, brachial, and carotid arteries. This difference is a result of increases in both blood flow velocity (TAMV) (35%, 15%, and 29% increase (p=.007-.087) respectively) and vessel cross-sectional area (CSA) (8%, 6%, and 8% (p=.015-.042) respectively). This is from 12 subjects. These changes are comparable to changes in blood flow experienced during exercise. Because blood flow is proportional to muscle glucose uptake, this is believed to be one of the primary mechanisms by which the device lowers blood glucose levels. These changes in blood flow are helpful for diabetic peripheral neuropathy. FIGURE 11 is an illustration of a non-limiting embodiment of the inventive device in use. FIGURE 12 is a graph of blood flow rate. FIGURE 13 is a graph of vessel area. FIGURE 14 is a graph of blood volume flow in mL / sec. FIGURE 15 is an image of representative ultrasound readings at baseline (top) and during intervention (bottom). FIGURE 16 is a flowchart showing one preferred example of a treatment process, according to the invention. FIGURE 17 is an illustration of internal components of an inventive device (circuit board for integrating HRV, not shown), according to the invention. FIGURE 18 is an illustration of a non-limiting embodiment of an external housing for the inventive device, according to the invention. FIGURE 19 is a graph showing heart rate variability (HRV).

[0002] DETAILED DESCRIPTION Disclosed herein are embodiments directed to methods and devices for treating an extremity, e.g. a foot or hand, to increase peripheral arterial blood flow by applying a variable localized combination of negative pressure and heat, in real-time response to heart rate variability sensor information. In a preferred embodiment, the invention provides a device that provides constant and precise heat to the sole of the feet while pulling a vacuum (negative pressure) around the leg and foot. The combination of which ultimately increases blood flow allowing for greater glucose disposal and / or slowed glucose uptake. This could be coupled with heart rate measurements in order to calculate heart rate variability, a measure of sympathetic nervous system activation (SNS). Excessive heat elevates the SNS which reduces glucose disposal, decreases insulin sensitivity, and increases hepatic glucose. The addition of the HRV component would allow for maximizing heat and blood flow while minimizing the counter-regulatory effects of heat stress. The addition of a body temperature measurement could be used alongside the HRV measurement to further manage SNS activation and stress. Ultimately this device could be made portable and battery-powered, such as shoes or boots, in addition to the standard AC-powered unit. Improved use of the feet will allow for greater glucose disposal due to the larger attached musculature as well as more comfort for users. Furthermore, the addition of a heart rate measurement component and thus heart rate variability will allow for real-time adjustment of heat and vacuum to maximize the glucose-lowering benefits. In accordance with one aspect of the present invention, the apparatus may include a heart rate variability module coupled to the pressure and heating device and configured to measure the heart rate variability using a heart rate variability sensor. The heart rate variability module may be electrically coupled to a programmable controller configured to: (a) determine a base heart rate variability measured using the heart rate variability sensor, (b) calculate and set a heart rate variability range using the base heart rate variability, (c) monitor whether the heart rate variability measured by the heart rate variability sensor falls within the heart rate variability range, (d) optionally send an alert if the heart rate variability is outside the heart rate variability range, and (e) adjust the heart rate variability range over time to modify pressure and temperature settings used by the negative pressure unit and the heating unit. In accordance with another aspect of the present invention, the pressure and heating device includes a housing, a power supply, a negative pressure unit, a heat delivery unit, and a control module, the housing having a foot and leg chamber with a sealable cuff around an opening configured to accept the foot and leg. The negative pressure unit and heat delivery unit are coupled to the heart rate variability module and sensor. The control module receives HRV sensor input, and the control module varies the settings of the negative pressure unit and the heating unit in real time in response to the HRV sensor input. Any of the embodiments herein may include wherein the negative pressure unit is disposed within the housing and includes a negative pressure gauge configured to measure a pressure within the foot and leg chamber. The negative pressure gauge is in communication with the control unit, and the control unit is programmably configured to monitor the negative pressure measured by the negative pressure gauge and to direct the negative pressure unit to adjust the pressure within the chamber. In accordance with one aspect of the present invention, the heating unit is disposed within the housing and includes a thermocouple configured to measure temperature within the foot and leg chamber. The thermocouple is in communication with the control unit, and the control unit is programmably configured to monitor the temperature measured by the thermocouple and to direct the heating unit to adjust the temperature within the chamber, e.g., to about 42°C. Referring now to Figure 1 , a method of treatment having the following steps is provided: Applying Heat (42°C) to the sole of the feet of a patient, while the patient remains seated; Applying negative pressure (-75 mmHg) from the feet to the top of the calves of the patient; Calculating Blood flow using TAMV * CSA; Obtaining result that TAMV increased 22.3% to 24.7% ; Obtaining result that CSA increased 9.7% to 10.4%; and Obtaining increased blood flow 32.3% and 29.5%, in the left and right popliteal arteries respectively. In accordance with another aspect of the present invention, a method for treating an extremity, e.g. a foot or hand, to increase peripheral arterial blood flow by applying a localized variable combination of low pressure and heat in real-time response to heart rate variability sensor data, by providing an HRV negative pressure and heating apparatus having a foot and leg, or hand and arm chamber, applying negative pressure and heat in response to real-time HRV sensor data for a duration sufficient to effect treatment of the extremity. In a preferred embodiment, treatment comprises increasing blood flow rate (time averaged mean velocity (TAMV) in a peripheral artery by 22.3% to 24.7%, and / or by increasing CSA by 9.7% to 10.4%, and / or by increasing blood flow by 29.5% to 32.3%. Any of the embodiments herein may include wherein the heating unit may be configured to deliver heating for approximately five to sixty minutes. Any of the embodiments herein may include wherein the negative pressure is between -20 mmHg and -150 mmHg or between -100 mmHg and -150 mmHg, or is greater than -150 mmHg, or is between -150 mmHg and -200 mmHg. Any of the embodiments herein may include wherein the control unit may include one or more microprocessors, controllers, digital signal processors (DSPs), application specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), or equivalent discrete or integrated digital or analog logic circuitry, and the functions attributed to control unit herein may be embodied as software, firmware, hardware, or any combination thereof. Control unit may include a memory for storing data related to use of apparatus, such as user input, treatment times, treatment settings, detected errors, and the like. The memory may store program instructions that, when executed by the control unit, cause the control unit and apparatus to provide the functionality ascribed to them herein. The memory of the control unit also may store software downloaded thereon or implemented as a program product and stored on a tangible storage device such as machine-readable medium, e.g., tape, compact disk (CD), digital versatile disk (DVD), blu-ray disk (BD), external nonvolatile memory device, USB, cloud storage, or other tangible storage medium. The software may include computer executable instructions for controlling apparatus. Power source may be a port, e.g., power interface, to allow apparatus to be plugged into a conventional wall socket, e.g., via a cord with an AC to DC power converter, for powering components within the housing. Alternatively, power source may be a suitable battery such as a replaceable battery or rechargeable battery and apparatus may include circuitry for charging the rechargeable battery, and a detachable power cord. The heart rate variability module and sensor are configured to monitor heart rate variability of a user using components known in the art. In one embodiment, components may include a light emitter, e.g. a pair of LEDs, and a light receiver, e.g., a photodiode, are disposed on a connected HRV detector for monitoring heart rate variability during a treatment. The control unit / controller may direct a control panel to display HRV information, e.g., pulse rate, pulse rate variability, or may direct a communication module to transmit the pulse rate, pulse rate variability information to a remote location. Optionally, the invention may include a communication module configured to transmit information, such as user input, treatment times, treatment settings, detected errors, and the like, to a remote location such as a doctor workstation. Communication module is configured for wired and / or wireless communication over a network such as the Internet or a telephone network using techniques known in the art. Advantageously, communication module permits a doctor, caregiver, user, and the like to monitor use of apparatus. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the full scope of the claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing in this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. In general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” etc.). Similarly, the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers (or fractions thereof), steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers (or fractions thereof), steps, operations, elements, components, and / or groups thereof. As used in this document, the term “comprising” means “including, but not limited to.” As used herein the term “and / or” includes any and all combinations of one or more of the associated listed items. It should be understood that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” All ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof unless expressly stated otherwise. Any listed range should be recognized as sufficiently describing and enabling the same range being broken down into at least equal subparts unless expressly stated otherwise. As will be understood by one skilled in the art, a range includes each individual member. 0068. The embodiments herein, and / or the various features or advantageous details thereof, are explained more fully with reference to the non-limiting embodiments that are illustrated in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. Like numbers refer to like elements throughout.

[0003] 0069. The examples and / or embodiments described herein are intended merely to facilitate an understanding of structures, functions, and / or aspects of the embodiments, ways in which the embodiments may be practiced, and / or to further enable those skilled in the art to practice the embodiments herein. Similarly, methods and / or ways of using the embodiments described herein are provided by way of example only and not limitation. Specific uses described herein are not provided to the exclusion of other uses unless the context expressly states otherwise.

[0004] 0070. FIGURES

[0005] 0071 . Referring now to the figures, the invention provides that heat therapy can acutely increase or decrease glucose tolerance depending on the amount of body exposed. Postprandial glucose response is increased following whole-body heat exposure but lowered with heating of a single hand. The opposing effects of partial- and whole-body heat exposure are believed to be mediated in part from increased sympathetic nervous system (SNS). While heating the body increases muscular blood flow and glucose uptake, SNS activation via heat exposure increases catecholamines which worsen glucose tolerance.

[0006] 0072. To illustrate, postprandial blood glucose (PBG) was measured during partial heat exposure to either the feet only or up to the calves via hot water (40°C) to a thermoneutral control condition while monitoring SNS activity via heart rate variability (HRV) (Figure 1).

[0007] 0073. METHODS

[0008] 0074. Participants (N=31) without diabetes were included (Table 1).

[0009] #: data averaged from basetine values from each visit

[0010] 0075. 0076. Protocol

[0011] 0077. Participants consumed 75 grams of dextrose during a 2-hour oral glucose tolerance test during three conditions (Figure 1): A) Thermoneutral control, B) Feet heating via hot water (40°C) immersion, C) Calf heating via hot water (40°C) immersion.

[0012] 0078. Measurements INCLUDES: Capillary blood glucose (Contour Next); Ultra-short-term (60s) HRV (Polar chest strap & Elite HRVios); Tympanic temperature(Braun Thermoscan); Thermal Comfort (AHSRAE 7-point scale); Blood Pressure (Omron automated cuff).

[0013] 0079. Statistical Analyses

[0014] 0080. Data were analyzed using a mixed-effects model and follow-up paired t-tests (Graphpad Prism 8.0.1).

[0015] 0081. DISCUSSION

[0016] 0082. Calf-heating via hot water immersion worsens, while feet-heating may improve, glucose tolerance compared to control. Calf-heating decreases HRV suggesting increased SNS activity while HRV is similar during feet-heating compared to control. Changes in HRV preceding changes in glucose indicates. HRV may serve as a useful tool during heat therapy to monitor SNS activity and optimize heat therapy for acute glycemic benefits even when changes in body temperature are absent. Limitations include the lack of a condition in which body temperature increased, the use of non-diabetic apparently healthy participants, and an intervention duration which is unlikely to be readily adopted

[0017] 0083. As shown in FIGURE 1 , Participants remained seated during the 2-hr oral glucose tolerance test. Condition A was a thermoneutral control. Hot water (40°C) was applied to the feet (Condition B) or calves (Condition C) for 2 hours. Measurements were taken at baseline and every 30 minutes.

[0018] 0084. As shown in FIGURE 2, Blood glucose, there was a significant interaction between blood glucose and time (F (4.6, 72.6) = 2.6, p=.O36). Blood glucose was higher during calf-heating at minute 90 than during control (+12 (95%CI: +3 to +21) mg / dL, p=.O13) and feet heating (+19 (95% Cl: +5 to +34) mg / dL, p=.011 ). Figure 2. Panel A shows blood glucose measures at baseline and every 30 minutes thereafter. Panel B shows the incremental area under the curve (iAUC) for each condition. Letters (A,B,C) next to data points indicate a statistically significant (p<.05) difference from that condition. A: thermoneutral control; B: feet heating; C: calf heating.

[0019] 0085. As shown in FIGURE 3. Incremental area under the curve for glucose, there was no main effect for condition (F (1.4, 25.4) = 0.3, p=.67).

[0020] 0086. 0087. As shown in FIGURE 4, Heart rate, there was a significant interaction between condition and time (F (3.4, 54.5) = 3.5, p=.O17). Heart rate was higher during calf heating than control condition at minutes 60, 90, and 120 (mean A +11 to +13 BPM, p=.010-.029).

[0021] 0088. There was a main effect of time (F (2.3, 66.0) = 16.0, p<.0001) but not condition (F (1.7, 50.7) = 2.6, p= .087). There was a significant interaction between condition and time (F (3.4, 54.5) =

[0022] 3.5, p=.O17). There was no significant difference between control and feet heating conditions at any time point (range of mean difference: -9 to 0 BPM, p=.13-.96). There was not a significant difference in heart rate during feet heating compared to calf heating at any timepoint (range of mean difference: -10 to -14 BPM, p= .058 - .11). Heart rate was higher during calf heating compared to the control condition at minutes 60 (+12 (95%CI: +2 to +21) BPM, p=.019), 90 (+11 (95% Cl: +1 to +20) BPM, p=.029), and 120 (+13 (95% Cl: +4 to +23) BPM, p=.0100).

[0023] 0089. During the control condition, heart rate varied by <3% from baseline (p=.13-.7O). Heart rate during feet heating increased by 7-14% (p<.0001-.0155) from baseline. Compared to baseline, heart rate during feet heating was 7% higher at minute 30 (p=.O16) then increased by 12-14% (pc.0001 to p=.007) at 60, 90, and 120 minutes. Heart rate during calf heating increased by 8-17% (p=.0056 -.112) from baseline. Compared to baseline, heart rate during calf heating was 8% higher at minute 30 (p=.112) then increased by 15-17% (p=.0056-.0088) at 60, 90, and 120 minutes.

[0024] 0090.

[0025] 0091 . As shown in FIGURE 5, Heart Rate Variability (HRV), there was a significant interaction between condition and time (F (4.3, 63.2) = 7.5, p<.0001). HRV during calf heating at minutes 30, 60, 90, and 120 was lower than the control condition (mean A - 13 to -7 , p<.007) and feet-heating (mean A - 13 to -11 , p<.009).

[0026] 0092. There was a main effect for time (F (2.8, 79.1) = 5.0, p= .0039) and condition (F (1.7, 46.9) = 9.7, p=.0006). There was a significant interaction between condition and time (F (4.3, 63.2) =

[0027] 7.5, p<.0001). HRV was higher during feet heating than the control condition at minute 0 (+6 (95%CI: +2 to +9), p=.0062) but no other timepoints (p=.14-.99). HRV during calf heating was lower than the control condition at 30 minutes (-7 (95%CI: -12 to -2), p=.0060), 60 minutes (-10 (95%CI: -15 to -6), pc.0001), 90 minutes (95% Cl: -13 (-19 to -7), p=.0003), and 120 minutes (-12 (95%CI: -17 to -7), pc.0001). HRV during calf heating was lower than feet heating at 30 minutes (-11 (95%CI: -16 to -5), p=.0011), 60 minutes (-13 (95%CI: -20 to -6), p=.0012), 90 minutes (-12 (95%CI: -20 to -4), p=.0051), and 120 minutes (-12 (95%CI: -20 to -4), p=.0080). 0093. During the control condition, HRV increased by 2-6% from baseline at minutes 30, 60, and 90 (p=.081-.52) and by 7% (p=.O15) at minute 120. HRV decreased by 2-4% (p=.39-.7O) during feet heating and decreased by 13-19% (p<.0002) during calf heating.

[0028] 0094. As shown in FIGURE 6, Tympanic temperature, there was a significant interaction between condition and time (F (8,268) = 2.4, p=.O143). Differences between conditions were <0.2°C (p=.0657-.99) throughout.

[0029] 0095. There was a main effect for time (F (3.0, 197.8) = 4.0, p=.0065) but not condition (F (2, 67) = 0.18, p=.78). There was a significant interaction between condition and time (F (8,268) = 2.4, p=.O143). Differences between conditions were <0.2°C (p=.0657-.99) throughout.

[0030] 0096. Changes in tympanic temperature from baseline were <0.3°C at all timepoints for all conditions. Tympanic temperature differed from baseline by <0.1 °C (p=.58-.92) during the control condition, 0.1-0.3°C (p=.0169-.128) during feet heating, and 0.1-0.2°C (p=.0167-.44) during calf heating.

[0031] 0097. As shown in FIGURE 7, Thermal Comfort Score, there was a significant interaction between condition and time (F (8,248) = 22.1 , p<.0001). Scores were higher during calf- heating (mean A +1.0 to +2.5, p<.0001) and feet-heating (mean A +0.7 to +1.0, p<.001) than control at minutes 30- 120. Scores were higher than calf-heating than feet- heating (mean A +0.8 to +1 .3, p<.002) at minutes 60-120.

[0032] 0098. There was a main effect for time (F (2.9, 180.0) = 31.3, p<.0001) and condition (F (2, 62) = 35.9, p<.0001). There was a significant interaction between condition and time (F (8,248) = 22.1 , p<.0001). Compared to the control condition, thermal comfort score was higher during feet heating at 30 minutes (+0.7 (95% Cl: +0.3 to +1.1), p=.0004), 60 minutes (+1.0 (95% Cl: +0.5 to +1 .5), p<.0001), 90 minutes (+0.9 (95% CI:+0.5 to +1 .4), p<.0001), and 120 minutes (+0.9 (95% Cl: +0.4 to +1.3), p=.0002). Compared to the control condition, thermal comfort was higher during calf heating at 30 minutes (+1 .0 (95% CI:+0.6 to +1 .5), p<.0001), 60 minutes (+1.8 (95% Cl:+1 .3 to +2.3), p<.0001), 90 minutes (+2.1 (95% Cl: +1.6 to +2.5), p<.0001), and 120 minutes (+2.1 (95% Cl: +1.6 to +2.7), p<.0001). Thermal comfort scores were higher during calf heating than feet heating at 60 minutes (+0.8 (95% Cl: +0.3 to +1 .3), p=.0017, 90 minutes (+1.1 (95% Cl: +0.7 to +1.6), p<.0001) and 120 minutes (+1.3 (95% Cl: +0.7 to +1.8), p< 0001).

[0033] 0099. During the control condition, thermal comfort decreased by 0.2 to 0.3 points (p=.050-.134) from baseline. Thermal comfort increased by 0.4 to 0.6 points (p=.0006-.0150) during feet heating and increased by 0.9 to 2.1 points (p<.0001 to p=.0027) during calf heating. 00100. As shown in FIGURE 8, Blood pressure, there was no significant interaction between condition and time for systolic (F (8,256) = 0.73, p=.66) or diastolic (F (8,256) = 0.46, p=.88) blood pressure. Fig. 8 shows shows systolic blood pressure at baseline and every 30 minutes thereafter. Fig. 8 also shows diastolic blood pressure at baseline and every 30 minutes thereafter.

[0034] 00101. As shown in FIGURE 9, Mean arterial pressure, there was no significant interaction between condition and time (F (8,256) = 0.47, p=.88). Fig. 9 shows mean arterial blood pressure at baseline and every 30 minutes thereafter. Letters (A,B,C) next to data points indicate a statistically significant (p<.05) difference from that condition at that time point. A: thermoneutral control; B: feet heating; C: calf heating.

[0035] 00102. Referring now to FIGURE 10, Peripheral application of heat with negative pressure to the extremities reduces blood glucose in diabetics. To determine the effect of applying HNP to the feet and calves on glucose tolerance during an oral glucose tolerance test (OGTT) in apparently healthy young adults.

[0036] 00103. METHODS: Participants (N=20; 45% male; 23 (5) yrs; 26.7 (5.0)kg / m2) a fasted OGTT (75g dextrose) with and without HNP (42°C and -75 mmHg) on separate visits. Measurements were obtained every 15 minutes of the OGTT.

[0037] 00104. RESULTS: For blood glucose there was a main effect for time (F(4,20)=49.599, p<.001) but not for condition (F(1 ,20)=0.511 , p=0.483) nor an interaction between condition and time (F(4,20)=0.503, p=0.734). There was no interaction between condition and time for heart rate (F(4,20)=0.732, p=0.573), systolic blood pressure (F(4,19)=0.892, p=0.473), diastolic blood pressure (F(4,6)=0.239, p=0.913), tympanic temperature (F(4,3)=1 .431 , p=0.283), or overall thermal comfort (F(4,19)=2.072, p=0.093). Feet thermal sensation displayed a main effect in condition (F(1 ,19)=20.658, p<0.001), time (F(4,19)=9.596, p<0.001) and an interaction between condition and time (F(4,19)=7.387, p<0.001).

[0038] 00105. More specific to the invention, blood flow data while using the device at the feet, shows a 64%, 22%, and 29% (p=.005-.022) increase in blood flow at the popliteal / superficial femoral, brachial, and carotid arteries. This difference is a result of increases in both blood flow velocity (TAMV) (35%, 15%, and 29% increase (p=.007-.087) respectively) and vessel cross-sectional area (CSA) (8%, 6%, and 8% (p=.015-.042) respectively). This is from 12 subjects.

[0039] 00106. These changes are comparable to changes in blood flow experienced during exercise. Because blood flow is proportional to muscle glucose uptake, this is believed to be one of the primary mechanisms by which the device lowers blood glucose levels. These changes illustrate that blood flow is helpful for treating diabetic peripheral neuropathy. 00107. Referring now to FIGURE 11 , is an illustration of one non-limiting embodiment of the device in use, according to the invention.

[0040] 00108. Referring now to FIGURE 12, Fig. 12 shows Time Average Mean Velocity (TAMV). Left Limb: TAMV increased 22.3% from 13.0 (13.4) to 16.0 (16.5) cm / sec, p=.O59. Right Limb: TAMV increased 24.7% from 10.5 (10.7) to 13.0 (13.3) cm / sec, p=.O67.

[0041] 00109. Referring now to FIGURE 13, Fig. 13 shows Cross-sectional Area (CSA). Left Limb: CSA increased 9.7% from 0.42 (0.34) to 0.46 (0.39) cm2, p=.247. Right Limb: CSA increased 10.4% from 0.65 (0.62) to 0.72 (0.70) cm2, p=.122.

[0042] 00110. Referring now to FIGURE 14, Fig. 14 shows Blood Volume Flow. Left Limb: Blood volume flow increased 32.3% from 5.2 (3.1) to 7.0 (4.0) mL / sec, p=.115. Right Limb: Blood volume flow increased 29.5% from 7.2 (7.3) to 9.3 (7.4) mL / sec, p=.O32.

[0043] 00111. FIGURE 15 is an image of representative ultrasound readings at baseline (top) and during intervention (bottom), according to the invention.

[0044] 00112. FIGURE 16 is a flowchart showing one preferred example of a treatment process, according to the invention.

[0045] 00113. FIGURE 17 is an illustration of internal components of an inventive device (circuit board for integrating HRV, not shown), according to the invention.

[0046] 00114. FIGURE 18 is an illustration of a non-limiting embodiment of an external housing for the inventive device, according to the invention.

[0047] 00115. FIGURE 19 is a graph showing HRV.

[0048] 00116. EXAMPLE - METHOD

[0049] 00117. Referring now to FIGURE 16, the present invention was tested in a use case and provided the following results.

[0050] 00118. The invention changed the flow rate (time averaged mean velocity (TAMV)), vessel cross-sectional area (CSA), and blood flow in the popliteal artery during peripheral heating with negative pressure applied to the feet.

[0051] 00119. In this non-limiting example, measurements of TAMV, CSA, and blood flow were obtained from the left and right popliteal artery of participants using an ultrasound doppler (Philips CX50, General Electric, USA) during peripheral heating with negative pressure.

[0052] 00120. Heat (42°C) was applied to the sole of the feet and negative pressure (-75 mmHg) applied from the feet to the top of the calves while participants remained seated.

[0053] 00121 . Vessels were matched for pre and post measures using anatomical landmarks and vessel diameter. Blood flow was calculated as TAMV * CSA. Data are presented as mean (SD) and were analyzed with paired two-sided t-tests. 00122. In this non-limiting example, participants’ (N=8, 4 men and 4 women) demographics are as follows: age: 26.5 (6.1) years; height: 177.7 (9.0) cm; BMI: 25.5 (3.9) kg / m2; body fat: 18.9 (5.7) %.

[0054] 00123. From baseline to during the intervention, TAMV increased 22.3% from 13.0 (13.4) to 16.0 (16.5) cm / sec, p=.O59 and 24.7% from 10.5 (10.7) to 13.0 (13.3) cm / sec, p=.O67; CSA increased 9.7% from 0.42 (0.34) to 0.46 (0.39) cm2, p=.247, and 10.4% from 0.65 (0.62) to 0.72 (0.70) cm2, p=.122; and blood flow increased 32.3% from 5.2 (3.1) to 7.0 (4.0) mL / sec, p=.115 and 29.5% from 7.2 (7.3) to 9.3 (7.4) mL / sec, p=.O32, in the left and right popliteal arteries respectively.

[0055] 00124. Accordingly, the inventive method illustrates that applying heat and negative pressure to the feet increased arterial blood flow by increasing flow rate with lesser changes to vessel CSA.

[0056] 00125. EXAMPLE - DEVICE

[0057] 00126. The invention is unique in that it incorporates a novel method of monitoring sympathetic nervous system activity via heart rate variability (HRV) in order to apply the optimal amount of heat and avoid the counter-regulatory effect of excess heat.

[0058] 00127. Heat will be applied to the soles of the feet using heating pads, heating wires, or heating tape. The temperatures should range from body temperature 37 to 45° (97°F to 113°F). In a preferred example, the temperature is 42°C (110°F).

[0059] 00128. Negative pressure or vacuum will be attained using a vacuum pump. The negative pressure should be able to reach -150 mmHg.

[0060] 00129. HRV will be measured using a heart rate monitor (chest strap, wristband, ring, ankle band). When HRV changes by X% the heat and vacuum will be modulated to prevent counterregulatory effects.

[0061] 00130. The device will have a two piece outer plastic shell with a control panel and two openings for the feet on top. The openings will be made of stretchable material. Inside the plastic shell there will be two receptacles for the foot chambers. The electronic components will be housed between the foot chambers.

[0062] 00131. EXAMPLE -

[0063] 00132. To examine changes in flow rate (time averaged mean velocity (TAMV), vessel cross-sectional area (CSA), and blood volume flow in the popliteal artery before and during peripheral heating with negative pressure applied to the feet.

[0064] 00133. Test: Peripheral heating with negative pressure applied to the feet will increase blood volume flow in the popliteal artery

[0065] 00134. Participants: A total of eight participants (4 men and 4 women) were included (Table 1). 00135. Protocol: Blood flow in the popliteal arteries were measured before and during the intervention.

[0066] 00136. Intervention: Heat (42°C) was applied to the sole of the feet and negative pressure (-75 mmHg) applied from the feet to the top of the calves while participants remained seated (Figure 1).

[0067] 00137. Measurement: An Ultrasound Doppler - (Philips CX50, General Electric, USA) was used to measure the following variables at the left and right popliteal arteries:

[0068] 00138. •Time average velocity (TAMV)

[0069] 00139. •Cross-sectional Area (CSA)

[0070] 00140. ‘Blood volume flow (mL / sec)

[0071] 00141 . ‘Vessels were matched for pre and post measures using anatomical landmarks and vessel diameter.

[0072] 00142. Statistical Analyses: Blood volume flow was calculated as TAMV * CSA .

[0073] 00143. Data are presented as mean (SD) and analyzed with paired two-sided t-tests.

[0074] 00144. TABLE 1

[0075] 00145. Table 1 : Participants were young males and females in apparent good health

[0076] Table 1: Subject Demographics

[0077] All 26.5 (6.1) 25.3 (3.9) 80.9 (16.9) 18.9 (5.7) (N-8)

[0078] Male 26 (5.6) 27.6 (2.7) 88.0 (10.8) 18.7 (7.1)

[0079] (n=4)

[0080] Female 25.6 (9.1) 21.3 (3.6) 62.4 (16.6) 21.4 (2.6) (n=4)

[0081] 00146.

[0082] 00147. EXAMPLE

[0083] 00148. The acute effects of heat therapy on glycemic markers oppose those of the chronic effects.

[0084] While the postprandial glucose response is exaggerated and fasting glucose increased during whole body heat exposure e.g. during use of a sauna, chronic heat exposure via hot water immersion lowers HbA1c. Additionally, the acute effects of heat therapy differ depending on the amount of body exposed to heat. Heating a single hand does not increase fasting glucose and lowers postprandial glucose. The opposing effects of partial and whole body heat exposure could be mediated in part from increased sympathetic nervous system (SNS) activity following heat stress. While heating the body increases muscular blood flow and glucose uptake, SNS activation via heat exposure increases catecholamines which inhibit insulin-mediated glycogenesis, increase glycogenolysis, and increase gluconeogenesis elevating blood glucose.

[0085] 00149. In a recent experiment we compare glucose tolerance during partial heat exposure to either the feet only or up to the calves via hot water (40°C) to a thermoneutral control condition while monitoring SNS activation via heart rate variability (HRV) in healthy subjects (N=28).

[0086] 00150. Participants consumed 75 grams of dextrose with glucose measurements at baseline and every 30 minutes for 2 hours with heat exposure throughout. There was an expectation of decreased PBG with no change in HRV following feet heating and increased PBG with an increase in HRV following calf heating compared to the thermoneutral control condition.

[0087] 00151 . From the results, there was no interaction between time or condition for blood glucose (F(8, 252) = 1.567, p=.135). There was an interaction between time and condition for HRV (F(8, 239) = 6.760, p<.0001). HRV was lower during calf heating versus control at 30 (-12%, p=0.014), 60 (-17%, p=.0009), 90 (-21 %,p< 0001) and 120 min (-20%,p< 0001). There was no change in body temperature (<0.1 °C).

[0088] 00152. Partial heat exposure to the feet or calves did not affect blood glucose but calf heating did decrease HRV. HRV appears to be more sensitive to heat exposure than the glycemic response. Thus HRV can be used to predict and prevent overt changes in the glycemic response.

[0089] 00153. LEGAL EQUIVALENTS

[0090] 00154. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited, unless so stated, to particular methods, order of processing steps, components, materials, systems, partial aspects of processes, components or systems, uses, compounds, compositions, standards, routines, modes, computers, hardware, firmware, and software programming which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting unless specifically stated. 00155. While various embodiments have been described above, it should be understood that they have been presented by way of example only, and not limitation. Where methods described above indicate events occurring in specific order, the ordering of events is sequential, but the invention contemplated herein may also include modifications that do not depart from the scope and spirit of the invention. Additionally, certain of the events may be performed concurrently in a parallel process when possible, as well as performed sequentially as described above.

[0091] 00156. Where schematics and / or embodiments described above indicate certain components arranged in certain orientations or positions, the arrangement of components is specified, but the invention contemplated herein may also include modifications that do not depart from the scope and spirit of the invention.

[0092] 00157. While the embodiments have been particularly shown and described, it will be understood that various changes in form and details may be made. Any portion of the apparatus and / or methods described herein may be combined in any combination, except mutually exclusive combinations. The embodiments described herein can include various combinations and / or sub-combinations of the functions, components, and / or features of the different embodiments described that do not depart from the scope and spirit of the invention. Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications that do not depart from the scope and spirit of the invention.

[0093] 00158. Various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments. It is therefore to be understood that within the novel, unobvious, enabled, and described scope of the broadest reasonable interpretation of the appended claims, the invention may be practiced otherwise than as narrowly described. Accordingly, all such modifications are intended to be included within the novel, unobvious, enabled, and described scope of this invention as defined in the broadest reasonable interpretation of the following claims.

Claims

CLAIMS1. An apparatus, comprising a pressure and heating device includes a housing, a power supply, a negative pressure unit, a heat delivery unit, a control module, the housing having an extremity chamber with a water basin and a sealable cuff around an opening configured to accept the extremity, and the control module varies the settings of the negative pressure unit and the heating unit, wherein the heating unit heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure unit provides negative pressure at -20 mmHg and -150 mmHg.

2. The apparatus according to claim 1 , wherein the negative pressure unit and heat delivery unit are coupled to a heart rate variability module and sensor, the control module receives HRV sensor input, and the heating unit and negative pressure unit vary the heat and pressure in response to the HRV sensor input.

3. The apparatus according to claim 2, wherein the heart rate variability module is coupled to the negative pressure unit and the heating unit and configured to measure the heart rate variability using a heart rate variability sensor, the heart rate variability module is electrically coupled to a programmable controller configured to: (a) determine a base heart rate variability measured using the heart rate variability sensor, (b) calculate and set a heart rate variability range using the base heart rate variability, (c) monitor whether the heart rate variability measured by the heart rate variability sensor falls within the heart rate variability range, (d) optionally send an alert if the heart rate variability is outside the heart rate variability range, and (e) adjust the heart rate variability range over time to modify pressure and temperature settings used by the negative pressure unit and the heating unit.

4. The apparatus according to claim 1 , wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg .

5. The apparatus according to claim 1 , wherein the negative pressure unit is disposed within the housing and includes a negative pressure gauge configured to measure a pressure within the foot and leg chamber, the negative pressure gauge is in communication with the control unit, and the control unit is programmably configured to monitor the negative pressure measured by the negative pressure gauge and to direct the negative pressure unit to adjust the pressure within the chamber, and the heating unit is disposed within the housing and includes athermocouple configured to measure temperature within the foot and leg chamber, the thermocouple is in communication with the control unit, and the control unit is programmably configured to monitor the temperature measured by the thermocouple and to direct the heating unit to adjust the temperature within the chamber, e.g., to about 42°C.

6. A method for treating an extremity to increase peripheral arterial blood flow by applying a localized variable combination of low pressure and heat in real-time response to heart rate variability sensor data, by providing an HRV negative pressure and heating apparatus having an extremity chamber with a water basin, the extremity chamber dimensioned to fit a foot, a leg, a leg and foot, a hand, an arm, and a hand and arm, applying negative pressure and heat in response to real-time HRV sensor data for a duration sufficient to effect treatment of the extremity.

7. The method according to claim 6, wherein the heating device heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure is -20 mmHg and -150 mmHg .

8. The method according to claim 6, wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg .

9. The method according to claim 6, wherein treatment comprises increasing blood flow rate (time averaged mean velocity (TAMV) in a peripheral artery by 22.3% to 24.7%, and / or by increasing CSA by 9.7% to 10.4%, and / or by increasing blood flow by 29.5% to 32.3%.

10. The method according to claim 6, wherein the heating unit is configured to deliver heating for approximately five to sixty minutes.

11. The method according to claim 6, wherein the negative pressure is applied at negative pressure between -20 mmHg and -150 mmHg or between -100 mmHg and -150 mmHg, or is greater than -150 mmHg, or is between -150 mmHg and -200 mmHg.

12. A method for treating an extremity of a patient in need thereof, comprising: (i) providing a heating and negative pressure apparatus; (ii) placing the patient's extremity in need of treatment in the heating and negative pressure apparatus; and using the heating and negative pressure apparatus to apply heat and negative pressure to increase peripheral blood flow.

13. The method according to claim 12, wherein the heating and negative pressure apparatus includes an extremity chamber dimensioned to fit a foot, a leg, a leg and foot, a hand, an arm, and a hand and arm, the extremity chamber having a water basin.

14. The method according to claim 13, wherein the heating device heats the water to 37 to 45 °C (97 °F to 113 °F), and wherein the negative pressure is -20 mmHg and -150 mmHg .

15. The method according to claim 13, wherein the heating device heats the water to 42 °C (110 °F), and wherein the negative pressure is -75 mmHg .

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