Continuous sodium measurement system and uses thereof

Abstract

A continuous sodium measurement system for determining sodium levels in a user over time is provided. The system includes a continuous sodium sensor (CSS) positioned in interstitial fluid of the user and configured to determine data related to a sodium level in the user. The system also includes programmed circuitry comprising a processor and a memory communicatively coupled with the CSS. The programmed circuitry is programmed with logic and instructions for completion of the following steps by the programmed circuitry: (i) obtaining data related to the level of sodium in the user from the CSS; (ii) determining the level of sodium in the user from the data obtained in step (i); (iii) storing the level of sodium in the user determined in step (ii) in the memory; and (iv) repeating steps (i) to (iii) to determine and store in the memory sodium levels in a user over time.

Description

[0001] Title:

[0002] Continuous sodium measurement system and uses thereof

[0003] Cross-Reference to Related Applications:

[0004] The present application claims priority from US Prov. App. Ser. No. 63 / 651,839 filed on May 24, 2025, which is incorporated herein by reference for all purposes. This application can be used alone or in combination with any of the compositions, devices and / or methods as described in: PCT / US2022 / 037198 (PROT.P-OOl-WO); PCT / US2022 / 052927 (PROT.P-002-WO);

[0005] PCT / ffi2023 / 061417(PROT.P-003-WG); US Prov. Pat. App. Ser. No. US 63 / 523,060 (PROT.P- 004-PV); US Prov. Pat. App. Ser. No. US 63 / 605,425 (PROT.P-005-PV); and US Prov. Pat.

[0006] App. Ser. No. US 63 / 556,008 (PROT.P-006-PV) which are all incorporated by reference for all purposes.

[0007] Background of the Invention:

[0008] Sodium level is a critical indicator of a person’s health and well-being, which impacts or is indicative of various bodily functionalities including neurological, renal, and / or cardiac functions. Existing methods for monitoring sodium levels are intermittent and can require periodic invasive procedures and / or periodic manual testing in a professional healthcare setting. Prior art methods for determining sodium levels prevent real-time monitoring of the analyte and hence limits visibility into a person’s bodily functions and overall health. Furthermore, prior art invasive methods for determining sodium levels determine such levels in the blood which does not provide a complete understanding on physiological conditions of a patient. There is a need for different sodium level measurement systems and methods that can monitor sodium levels in a user over time, along with other functionalities, and a need for use of such systems in providing accurate and timely data for better health management and insights into bodily functions.

[0009] Summary of the Invention:

[0010] The continuous sodium measurement systems and methods herein described provide continuous, and / or semi-continuous, monitoring of a user's sodium levels over time. The system and methods integrate and communicatively couple a continuous sodium sensor (CSS) positioned in the interstitial fluid of a user and programmed circuitry equipped with a processor, memory, and a suite of functionalities, facilitating data collection, analysis, storage, and provision of alerts based on the collected and / or determined data. The systems and methods aim to improve healthcare management by providing accurate and timely information about an individual's sodium levels over time, allowing for proactive health measures and interventions.

[0011] In a first embodiment the present invention provides a continuous sodium measurement system for determining sodium levels in a user over time. The system includes a continuous sodium sensor (CSS) positioned in interstitial fluid of the user and configured to determine data related to a sodium level in the user. The system also includes programmed circuitry comprising a processor and a memory communicatively coupled with the CSS. The programmed circuitry is programmed with logic and instructions for completion of the following steps by the programmed circuitry: (i) obtaining data related to the level of sodium in the user from the CSS;

[0012] (ii) determining the level of sodium in the user from the data obtained in step (i); (iii) storing the level of sodium in the user determined in step (ii) in the memory; and (iv) repeating steps (i) to

[0013] (iii) to determine and store in the memory sodium levels in a user over time.

[0014] In additional embodiments, the present invention provides an audible and / or visual display including an alert produced by a sodium measurement system described anywhere herein and / or a data file (such as an aggregated data file), a data storage system containing such file (e.g. those including sodium levels obtained by sodium measurement systems herein described). The display is preferably part of the user computing device and / or the CSS electronics In yet further embodiments, the present invention provides a method for determining sodium levels in a user over time, the method can include the steps of providing a continuous sodium measurement system as described anywhere herein; and the following steps by the programmed circuitry of (i) obtaining data related to the level of sodium in the user from the CSS; (ii) determining the level of sodium in the user from the data obtained in step (i); (iii) storing the level of sodium in the user determined in step (ii) in the memory; and (iv) repeating steps (i) to (iii) to determine and store in the memory sodium levels in a user over time, thereby determining sodium levels in the user over time.

[0015] Employing this system and / or other related systems and / or other embodiments as a base continuous sodium measurement system, the present invention can provide a host of other functionalities, systems, and methods which provide insights into patient health, treatment protocols, and related concerns. These additional embodiments are described further within the following text.

[0016] Brief Description of the Figures:

[0017] FIG 1 shows an exemplary system according to the present invention.

[0018] FIG 2 shows interstitial fluid (ISF) measurement system for sodium. A) System placed on skin and measuring sodium in the ISF. B) List of product features in an exemplary system. C) Transmission of data to receiver (mobile device) to cloud to portal.

[0019] FIG 3 provides Sensor Overview: Diagram of sensing unit.

[0020] FIG 4 demonstrates reference electrode (RE) Stability via testing of 6 RE ability to maintain stable response over 72 hours with variation around 2 mV.

[0021] FIG 5 demonstrates Na+ sensing sensitivity and selectivity: A) Demonstration of Na+ sensing at different sodium concentrations (1 mM-300 mM). B) Selectivity to Na+ when adding Li+, Mg2+, and K+. Response to interfering ions is insignificant. C) Linear plot of log(Na+) versus EMF (potential) signal. Theoretical maximum sensitivity (slope): 59 mV / decade. Obtained: 49.8 ± 0.8 mV / decade. D) EMF signal changes with interfering ions showing variation of less than 5%.

[0022] FIG 6 depicts an example workflow for providing decision support and risk stratification around natremia status for a user, in which specific alerts and actions are instigated based on whether the user is in a state of hypernatremia, hyponatremia or normonatremia according to certain embodiments of the present disclosure.

[0023] FIG 7 depicts an example method for providing recommendations of / or modifying vaptan treatment for a user determined to be at risk of hyponatremia and / or other conditions, according to certain embodiments of the present disclosure.

[0024] FIG 8 depicts an example workflow for providing decision support based on the difference calculated between ISF Na+ and blood or dialysate Na+ concentration detected via varying sensor probe depths according to certain embodiments of the present disclosure. This depicts a specific use case where signals between a shallow sensor and deeper filament are compared to quantify the skin Na+ reservoir.

[0025] FIG 9 depicts an example workflow for providing decision support based on the difference calculated between ISF Na+ and blood or dialysate Na+ concentration detected via varying sensor probe depths according to certain embodiments of the present disclosure. This depicts a specific use case in which the user is experiencing interstitial water build-up in dermis and hypodermis during edema.

[0026] FIG 10 depicts an example workflow for providing decision support based on the difference calculated between ISF Na+ and blood or dialysate Na+ concentration detected via varying sensor probe depths according to certain embodiments of the present disclosure. This depicts a specific use case in which the user is undergoing dialysis and the difference between ISF Na+ and blood or dialysate Na+ concentration is compared.

[0027] Detailed Description of the Invention:

[0028] The present invention provides solutions to the long-felt need and desire to continuously measure a user’ s / pati ent’s sodium levels in a discrete, user-friendly manner without the need and costs associated with healthcare office visits. Furthermore, the present invention provides solutions to prior art systems and methods for determining sodium concentrations and determination of physiological conditions in patients, for example edema and / or fluid status. Here, Applicant has determined that sodium concentration in a patient’s interstitial fluid is an independent biomarker relating to edema / fluid status of the patient, and it is not a simple proxy for sodium levels determined in other tissues / fluids (such as blood). Accordingly, employing the systems and methods as herein described provide unique solutions to problems and challenges encountered in the art and in the complex sodium regulation physiology of a patient. The systems and methods herein described provide quantifiable, remote, and accurate determination of sodium levels in a patient and provide a suite of useful related functionalities all providing significant advancements over the art.

[0029] As shown in Fig. 1, and described herein, the continuous sodium measurement system 101 includes multiple components and functionalities, each serving a specific role in the continuous monitoring and determination of sodium levels in a user 103. The system's 101 components include the continuous sodium sensor (CSS) 105, programmed circuitry 107 incorporating a processor 109 and memory 111. The programmed circuitry is programmed with logic and instructions for completion of the following steps by the programmed circuitry: (i) obtaining data related to the level of sodium in the user from the CSS; (ii) determining the level of sodium in the user from the data obtained in step (i); (iii) storing the level of sodium in the user determined in step (ii) in the memory; and (iv) repeating steps (i) to (iii) to determine and store in the memory sodium levels in a user over time. In additional embodiments programmed circuity and / or the system also includes any or all of a user computing device 113 (optionally running a user application), a remote server (shown in Fig. 1 as 107 (optionally running a server application)), and / or healthcare provider computing device 115 (optionally running a healthcare provider application). The user computing device 113, remote server and / or healthcare computing device 115 preferably include or are capable of accessing respective software applications (e.g. a user application, a remote server application and a healthcare provider application) running on resident programmed hardware or in the cloud (e.g. preferably to perform any or all of steps (i) to (iv)). These respective computing devices are preferably included, and in operative communication (as represented with dots), with the programmed circuitry of the presently contemplated systems and allow data transfer and communication between all of the user, the healthcare provider, processing, memory, and CSS. Furthermore, these respective devices can include user interface hardware for display of information of alerts and interaction therewith. In preferred embodiments, the respective computing devices are preferably selected from the group consisting of personal computers, desktops, laptops, cell phones, tablets, or other known computing devices. Data collection, processing, and memory storage preferably occur in the remote server 107, however can occur in part or entirety in any, or combination of the user computing device 113, remote server 107 (e.g. cloud server / storage / processing), and / or healthcare computing device 115.

[0030] The CSS 105 can be one described in any of the above-mentioned references which are incorporated herein by reference, or any other sensor configured for and capable of determining sodium level in a user. Part of the CSS 105 is positioned in the interstitial fluid of the user and is responsible for obtaining data related to the user's sodium levels. The CSS preferably includes sensor electronics (e.g. a power source such as a battery and a wireless transmitter for transmitting data all of which are optionally disposed within a housing on the skin of a user and being configured to maintain the CSS in interstitial fluid of a user) and measures and transmits data, typically in the form of voltage measurements, to the programmed circuitry 107, optionally through a user computing device 113 (as shown in dotted lines).

[0031] Programmed circuitry 107, including processor 109 and memory 111, is equipped with logic and instructions programmed to receive and perform specific tasks related to the data obtained by the CSS. These tasks include data acquisition from the CSS, processing of the obtained data to determine the user's sodium level and storing this information in memory 111. The programmed circuitry repeats these steps continuously, upon request (e.g. from the user computing device, healthcare provider application, and / or server application), or at regular intervals, ensuring continuous (or semi-continuous) monitoring and storage of sodium levels of the user over time. The term continuous and semi-continuous are used interchangeably herein and include: constant measurement of data relating sodium levels and / or determination of the level; and / or measurement of data and determination of sodium levels upon request or at predetermined (e.g. regular) time intervals, ranging from seconds to hours. In preferred embodiments, the steps are repeated at regular time intervals selected from the group consisting of 1 second, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours (preferably in 5-15 minute intervals). Programmed circuity 107 may be resident together with the CSS resident with the user (for example within the same housing as sensor electronics disposed on the skin of user) or may be resident within a separate device, or combination of separate devices, such as the user’s and / or health care provider’s computing devices, and / or remote server.

[0032] An exemplary preferred algorithm for determination of sodium levels in a user can be seen in Figs. 5. In a first step shown in Fig. 5 A, data relating to sodium level of a user is continuously determined / obtained by a sodium specific sensor, here CSS, positioned in interstitial fluid of a user. Here, the data is raw voltage data collected by the sensor in volts over time. This data is then converted, and / or correlated via use of a correlation or offset factor (e.g. via a lookup table, conversion chart, and / or recovery algorithm), into sodium levels of the user over time. Figure 5C shows the accuracy of the correlation / conversion / recovery application to the raw voltage data obtained from the CSS shown in Fig. 5A to achieve the determined sodium level (e.g. concentration of sodium mM in the user) over time. Other signal processing techniques can be applied to, or in lieu of, the above-described steps and do not depart from the scope of the present invention. Such techniques include but are not limited to: drift correction; fdtering algorithms; calibration techniques; signal conditioning and / or filtering; application of correction and / or offset factors; etc. The CSS data and / or determined sodium levels are stored in the memory of the programmed circuitry. The respective data can be time stamped (or otherwise associated with a timestamp) for chronological tracking of data and / or values over time and stored in memory (optionally in an aggregated data file) alone or with other data such as dietary input, activity levels, heart rate, interstitial pressure (e.g. from an interstitial pressure monitor associated with the systems and / or programmed circuitry) and / or timestamps, which can optionally be stored as secondary / tertiary level data such as metadata together with the sodium level data in a primary data level to provide rich contextual information regarding sodium levels determined and stored over time. The programmed circuity preferably further comprises logic and instructions for use of use of data stored in memory in predicting future health events of the user and / or determining current health of the user.

[0033] In preferred embodiments, the depth of the sodium sensor can be used to improve sodium level determinations and / or predictions. Without being bound by a particular mechanism, it is believed that sodium levels change relative to the depth and position of the sensor in the body. For example, it is believed that sodium concentration is higher closer to the skin surface and decreases the deeper the sensor is positioned. In certain embodiments, two or more sodium sensors, such as microneedles or filaments, may be employed that are configured, in combination, to determine and characterize the gradient of sodium in a user’s body. For example, as seen in Fig. 8, a first sensor can be positioned toward the skin surface and a second sensor can be positioned deeper. A corresponding sodium gradient can then be determined and used in further analysis of sodium level of a user. The sodium gradient can be impacted differently by different physiological states (e.g., edema, hypernatremia, hyponatremia, dialysis, vaptan treatment etc.). For example, during edema, interstitial water accumulates in dermis and hypodermis. Total tissue Na+rises and the Na+-rich epidermal / upper-dermal reservoir expands, widening the concentration gap between shallow and deep sensors. As congestion progresses and water dilutes the reservoir, that gap may later narrow. Tracking the A[Na+] between depths therefore provides an early, quantifiable indicator of evolving edema that can be monitored continuously and remotely. As described in Fig. 9, the system can identify and quantify whether the difference between Na+ concentration in the shallow and deep sensor is below, above or within a specific predetermined threshold. This value will indicate the risk of an edema occurrence, in which minimal differences in gradient indicate the user is at high risk of edema, and the system will provide the user with a specific recommendation and / or alert. Varying sensor depths can also be used to inform dialysis outcomes, as seen in Fig. 10. During dialysis, plasma fluid and Na+leave the patient by ultrafiltration and diffusion, while Na+simultaneously diffuses into or out of the blood depending on the dialysate sodium concentration (DNa). These opposing fluxes shift the Na+gradient between the dermal “reservoir” (shallow sensor), the subcutaneous / blood compartment (deep sensor), and the blood (or dialysate). Real-time trends in that A[Na+] can be used to individualize both DNA and ultrafiltration rate for each session. A large difference between ISF Na+ and blood or dialysate Na+ above a specific threshold would indicate the ability to safely alter or increase ultrafiltration or dialysate Na+ levels, while a moderate difference would indicate no action is required, and a minimal difference indicating the user may be at risk of hyponatrium where the system can recommend or enact treatment alterations such as slowing dialysis.

[0034] In other embodiments, a sodium gradient can be provided and / or obtained from a user input, a healthcare professional, or from the internet (e.g. for example a lookup chart containing variables such as a user’s age, race, physiology, medical condition, dietary inputs, and / or activity levels). In other embodiments, the sodium gradient can be estimated based upon other related variables.

[0035] In preferred embodiments, the systems and methods of the present include determination and use of the sodium sensor’s depth position within the user in combination with the determined, estimated, and / or received sodium gradient. In some embodiments, the sensor is configured with electronics to determine sensor depth (for example relative to the surface of the skin) and provide this information to the processor. In other embodiments, markings are provided on the sensor surface (see FIG 2B) for a user to determine sensor depth and subsequently provide this information to the processor for use in later determinations of sodium levels. In most preferred embodiments, the programmed circuitry employs the sensor depth (in a correlation, offset, and / or correction factor) in the determination of current and / or prediction of future sodium levels in the user. Additionally, the system further comprises one or more correlation modules for performing the sodium level determination and / or predictions may be improved based on sensor placement in different compartments or tissues such as muscle, dermal, or adipose as interstitial sodium fluctuates differently in different compartments / tissues. Accordingly in certain embodiments the methods and / or programmed circuitry (e.g. logic and instructions stored in the memory) of the apparatuses and / or systems of the present invention include the further supplemental steps of: determining a correction factor for any determined value based upon the elevation and / or depth of the sensor below the surface of the skin and / or the type of tissue; and / or the optional step of correcting or adjusting any determined value based upon the elevation and / or depth of the sensor below the surface of the skin and / or type of tissue. In other embodiments, the present invention provides a method of determining disease state (or determining a sensor calibration state, etc.) comprising the steps of: employing one or more sodium sensors described herein and determined Na levels at different elevation within a user’s body and / or a Na gradient within a user’s body; correlating said determined levels and / or gradient with a lookup value or chart; determining from the correlation the disease state of the user; and determining a correction factor for any determined value based upon the elevation and / or depth of the sensor below the surface of the skin. In other embodiments, the present invention provides a sodium sensor and electronics wherein a sodium sensor insertion tool comprises a sensor depth insertion setting feature that allows the sensor to be positioned within the users body at a certain elevation from the skin surface optionally combined and / or coupled with sensor electronics for measuring or determining the sensor depth, providing the information to the processor, and employing said depth in further calculations within electronics (e.g. depth set on insertion tool which communicates with electronics so that the electronics can understand how deep sensor is from depth set on insertion tool; and / or a scroll depth set on insertion to allows user to select depth of sensor insertion; and / or insertion tool having insertion depth confirmation algorithm that confirms sensor inserted properly to set depth and communicates to sensor electronics).

[0036] In addition to sodium level monitoring, the programmed circuitry preferably integrates hardware and / or other functionalities for obtaining, receiving, analyzing, and / or handling dietary other analyte information, activity inputs, activity tracking, medication regimen information, health tracking and time stamp association. This integration involves modules comprising logic and instructions and / or hardware for receiving, storing, analyzing, and associating this information (e g. dietary and activity input) with the stored sodium levels. The system can further comprise hardware commonly available including hardware for such functionalities such as an accelerometer, an activity tracker, blood pressure monitor, interstitial fluid monitor, PulseOx, and / or a heart rate monitor etc. The timestamps dietary input, activity tracking and / or input, and health tracking etc. can be stored together with the sodium level data, for example as metadata, optionally in an aggregated data file, providing context for interpreting the sodium level data, and / or making determinations and / or predictions regarding current and / or future analyte levels and / or physiological / health and / or disease states.

[0037] In additional embodiments, the system can include one or more correlation modules programmed with logic and instructions to: provide instantaneous and / or future alerts regarding current and / or future sodium levels and / or physiological conditions; predict future sodium levels; to compare sodium level data obtained over time; compare activity and dietary data; compare medication intake data and protocols; analyze trends and other stored data; determine rate of changes in levels; predict from the rate of change the timeframe for reaching a particular state of natremia, and / or detect correlations indicating changes in sodium levels and / or overall health of a user and / or overall functionality of a user’s organs including the heart, kidneys, and liver etc. Based on the determined correlation(s), the system can generate alerts for users and / or healthcare providers, offer alerts and / or instructions and / or recommendations tailored to an observed correlation, sodium levels and / or changes thereof over time. The alerts vary according to the determined correlation, such as the current or approaching predicted conditions of normonatremia, hypernatremia, severe hypernatremia, hyponatremia and / or severe hyponatremia, and to provide actionable guidance to the user or their health care provider to better manage the user's health effectively.

[0038] Sodium levels for each of the outlined conditions are known in the art and are not particularly limited herein. For example, hyponatremia is often associated with a user having a serum sodium level of less than 135 mEq / L, severe hyponatremia is often associated with a user having a serum sodium level of less than 120 mEq / L, normonatremia is often associated with a user having a serum sodium level of between 135-145 mEq / L, hypernatremia is often associated with a user having a serum sodium level of greater than 145 mEq / L, while extreme hypernatremia is often associated with a user having a serum sodium level of 160 mEq / L or greater. As shown in Fig. 6, the programmed circuitry can be programmed with logic and instructions to provide several different alerts, messages and / or recommendations depending on the determined correlation and / or current or future predicted sodium level. Contemplated alerts, messages, and / or recommendations include providing an indication or alert of the rate of change in or current sodium level and / or health condition of the user (e.g. user is in or approaching a specific state of natremia); a recommendation to maintain or change diet (e.g. maintain, increase / decrease ingestion of sodium containing foods / beverages, or fluid restriction), activity (take a walk or sweat-inducing activity), medication protocol (dosage and / or type of sodium lowering or raising medication for example those selected from the group consisting of: vaptans, vasopressin agonists, antagonists or other modifiers, hypertonic saline infusion, isotonic saline infusion, diuretics, urea, potassium salt, sodium salt, glucocorticoid, thyroid hormone, and IV electrolyte administration); initiate dialysis; seek emergency medical attention and / or optionally directions to the closest emergency facility; contact the user and / or health care provider; and combinations thereof or similar optional alerts.

[0039] In other embodiments the correlation module can be programmed to determine and act upon longer term trends or specific daily trends regarding observed correlations surrounding particular events such as meals, sleep, wakefulness, and / or activities. For example, the correlation module can be employed in further management of chronic disease states wherein the correlation module can be programmed to determine longer term trends or changes in sodium levels to determine disease progression and to provide related alerts to the user or healthcare provider regarding longer term or timing of suggested changes in diet, activity levels, and / or medication protocols etc.

[0040] In another embodiment, the CSM system based upon interstitial fluid (ISF) measurements is in communication with a dialysis system such that based on the sodium determination, correlation, and / or prediction, the system is programmed with logic to provide instruction to the dialysis system to initiate, modify, or stop dialysis, flow rate, dialysate sodium concentration, and / or other dialysate electrolyte levels. The present Inventors have discovered inter alia that ISF measurement can be preferable to other types of sodium measurements (e.g. such as that from the dialysate itself, serum levels, or fistula levels, etc.) because ISF measurements measure flow out (or into) of Na+ reserves in the dermal to the serum (FIG 10). This is a rate of change that can identify several key elements about Na+ dynamics, especially since one would know the Na+ concentration in the dialysate. Accordingly, if dialysate has low Na+, but Na+ remains high in the ISF, this implies that reserves were built up high and likely more Na+ removal is desired via dialysis, and an according instruction can be sent by the processor to the dialysis system to continue dialysis or increase the rates. Moreover, if it is low it implies low Na+ reserves, thus indicating likely less or slower Na+ removal is desired by dialysis with corresponding instructions sent. Alternatively, if a user has high Na+ dialysate, but ISF remains low, this can imply reserves were depleted. Furthermore, similar conclusions can be derived about Na+ dynamics via monitoring the correlation calculated between the Na+ concentration in the blood plasma of the patient and in the ISF, which would signify and send instruction to the system to adjust treatment accordingly. Moreover, comparative calculations which monitor the flow of Na+ levels into and out of the patient through the dialysis lines to the dialyzer also act to provide useful insights about the gradient of Na+ which would in turn signify treatment alterations based on information garnered about patient Na+ kinetics. In view of these discoveries and in such embodiments, the system can uniquely monitor and send instructions to modify and / or make adjustments in real-time to maintain desired sodium levels and fluid levels based on but not limited to these varying sources of input to the CSM system.

[0041] In further embodiments, the system includes a variety of correlation modules programmed to identify changing and / or predict changing sodium levels before, during, and / or after sodium- modifying stimulus or events including, but not limited to, administration of vaptans, chemotherapy, syndrome of inappropriate antidiuretic hormone secretion (SIADH), tumor lysis syndrome, sweat-inducing exercise, dialysis, kidney transplant, and IV fluid administration all based upon, or in concert with measurements from the CSM and systems of the present invention, optionally in view of baseline serum levels to calculate rate of changes of sodium. Furthermore, the system can also use other analyte levels which may include but are not limited to K+, glucose, and / or other common components of the dialysate. In these cases, change or predicted change of sodium levels can trigger alerts to providers or users to modify treatment (e.g., stop vaptans) and / or suggest further management (e.g., increase fluid intake). Algorithms for identifying rates of change, dialysis rate, warning messages etc. are within and do not depart from the scope of this embodiment. In certain embodiments, the correlation module is programmed with logic to determine a correlation selected from the group consisting of: user has or may have edema, fluid overload, dehydration, overhydration, electrolyte imbalances, hypertension, tumor lysis syndrome, SIADH, and cardiovascular events based on current and predicted sodium levels. If a correlation is determined an alert is provided selected from the group consisting of: user has or may have edema, fluid overload, dehydration, overhydration, electrolyte imbalances, hypertension, tumor lysis syndrome, SIADH, and cardiovascular events based on current and predicted sodium levels.

[0042] Vaptans as generally discussed herein refer to any active agents that downregulates or blocks the vasopressin pathway, such as vasopressin antagonists. Modulators of vasopressin (even if not a formal or exclusive Vasopressin antagonist), and / or any other active therapeutic that works upstream of vasopressin to block such pathway are included within the definition of such active agents. Vasopressin antagonist include: vasopressin (V2) receptor antagonists such as Tolvaptan (Selective V2 receptor antagonist), Lixivaptan, Mozavaptan, Satavaptan; Vla / V2 Dual Receptor Antagonists including Conivaptan, dual antagonists including OPC-131461; Selective Via Receptor Antagonists including Relcovaptan (RWJ-351647); Selective Vlb Receptor Antagonists such as Nelivaptan (SSR149415) (investigational); and Modulators of the Vasopressin Receptors including Allosteric Modulators, and synthetic intrabody (Ib30), VRQ397; Biased Ligands including TRV120027: P-arrestin biased ligand of the angiotensin II type 1 receptor; Partial Agonists such as OPC-51803: Partial agonist to V2-receptors . Upstream Modifiers of the Vasopressin system which are also considered within the scope of the active agents of the present invention include actives that reduce the amount of vasopressin thereby reducing vasopressin receptor activation such as Renin-Angiotensin-Aldosterone System (RAAS) Modulators including: ACE Inhibitors such as Benazepril (Lotensin), Captopril (Capoten), Enalapril / Enalaprilat (Vasotec), Fosinopril (Monopril), Lisinopril (Zestril and

[0043] Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik); Angiotensin II Receptor Blockers: Azilsartan (Edarbi). Candesartan (Atacand). Irbesartan (Avapro). Losartan (Cozaar).Olmesartan (Benicar). Telmisartan (Micardis). Valsartan (Diovan); and Mineralocorticoid receptor antagonists (MRAs): Spironolactone, Eplerenone, Finerenone. The present Inventors have discovered that employing the methods and CSM systems of the present invention allows for significant advancement over the prior art. Such advancements include inter alia:

[0044] A method of obtaining a vaptan active ingredient over the counter (e g. without prescription) by a user and administering said therapeutic agent to a user using the CSM systems of the present invention, monitoring sodium levels using the CSM systems herein described before, during, and / or after administration, and providing an instruction relative the the medication protocol to the user based at least in part upon the sodium levels determined using the CSM systems and optionally the current vaptan medication protocol. In the present embodiment, it is envisioned that the methods and systems of the present invention provide the ability to switch prescriptionbased vaptan therapies to over-the-counter therapies (e.g. switching vaptan active from available only by prescription to be available over the counter as a non-prescription agent in combination with use of the systems and methods herein described);

[0045] Allowing initiation / re-initiation outside of the clinic / hospital by allowing at home Na monitoring;

[0046] Allowing initiation / re-initiation in the clinic, and then sending the patient home with remote Na monitoring;

[0047] Having real time monitoring to see "too rapid correction of hyponatremia" so a user can adjust / stop dose, add sodium, add fluid, slow down correction, ect.;

[0048] Replacing the Serum Na+ monitoring with ISF Na+ monitoring;

[0049] Companion diagnostic with device / vaptan. You can identify / diagnosis hyponatremia out of clinic and trigger vaptan usage out of clinic (or trigger to come in to clinic);

[0050] IV dosing, and immediate feedback loop with ISF Na+ (as ISF Na allows continuous vs serum); and

[0051] Closed loop system such that an automatic a vaptan, diuretic or other Na modulating agent is automatically adjusted based on CSM data.

[0052] It is herein further contemplated that ISF monitoring of sodium using the systems and methods herein described can provide several advantages over serum monitoring including: Decoupling of ISF to serum Na+ might indicate disease status (large differences between ISF and serum levels may indicate worsening disease progression) which may indicate how vaptans should be given (whether they should be given or not, timing, type, inpatient vs outpatient, dosing);

[0053] ISF Na+ may be beneficial (compared to serum) for telling output of Vaptan. Specifically, in edema formation, Na+ is likely rising rapidly in the ISF; and edema treating agents, like tolvaptan, should be decreasing this edema. ISF Na+ is a leading / early indicator of edema status (whereas serum Na+ is not). A rapid increase in ISF Na+ is likely a leading / early indicator of edema formation, and a decrease in ISF Na+ is signal edema treatment is working;

[0054] Vaptans, like tolvaptan, produce aquaresis without sodium loss. Specifically, and in certain embodiments, vaptans do not actually change the total Na+ amount, they cause decreased water reabsorption in the kidneys resulting in water loss, which can result in increased serum Na+ concentration where total Na+ is the same, but less water is present. Therefore, Napconcentration increases in serum, and increased Na+ should flow to ISF which acts as a buffer. This means that ISF could be a better indicator of actual body Na+ equilibrium (steady state) as it is further away from the mechanism of action for vaptans. ISF is especially advantageous when identifying Na+ concentration, around organs (e.g., in the ISF Na+ around the heart), in such events then dermal ISF would be a better indicator of fluid status. For example, dermal ISF Na+ might be a better proxy for heart ISF Na+ compared to serum Na+;

[0055] Interstitial fluid has a buffer / reserve of Na+ (specifically in the glycosaminoglycans (GAGs)). When released, that Na+ goes to the ISF, and then goes to the serum. Changes in the ISF Na+ levels demonstrate useful information in regards to Na+ reserve levels. This includes exhibiting the rate of movement of stored Na+ from reserves to the ISF and then plasma (or opposite direction; serum to ISF to GAGS), how quickly Na+ reserves are being depleted or increased, and additionally the amount of Na+ in reserves, etc. This is useful information related to the rate of change of Na+ in relation to vaptan dosing, which ensures hyponatremia is not corrected too fast and assists to avoid hypernatremia from overcorrection. For example, if GAGs are at Na+ storage capacity, and Na+ is rising in serum due to vaptan treatment, hypernatremia is more likely than if there was still Na+ storage capacity in the GAGs; and ISF Na+ can be measured continuously, serum cannot. This allows rate of Na+ change calculations which is useful for dosing, timing, type of vaptan (such as fast acting vs slow acting), administration route (IV vs oral), setting (inpatient vs outpatient), and other correction mechanism (fluid intake, sodium intake, diuretic usage, etc.). For example, as seen in FIG. 7, a user may initiate vaptan treatment for hyponatremia or another condition (e.g., SIADH, ADPKD), in which the CSM is used to monitor ISF Na+ levels. The rate of change of Na+ levels in the ISF can be calculated and if Na+ levels are increasing faster than a specific threshold or concentration is above a specific value, the system can indicate that the user as risk of hypernatremia and suggest an alert to alter or discontinue vaptan dosage; also if the user’s ISF Na+ concentration has been increasing within an optimal rate and below a specific concentration threshold then the system can indicate to the user that vaptan treatment is progressing normally and their fluctuating Na+ levels are not of concern.

[0056] In other embodiments, the systems, methods, and correlation modules herein described can be used to identify, diagnose, and / or predict medical events including edema, fluid overload, dehydration, overhydration, electrolyte imbalances, hypertension, tumor lysis syndrome, SIADH, and cardiovascular events based on current and predicted sodium levels. In these embodiments, prediction may be improved by measurement of sodium in the interstitial fluid (as opposed to blood levels) as sodium levels change in the ISF earlier than levels changing in the serum and therefore may be an independent leading indicator of fluid status or edema ( Na+ in serum is lagging and massively confounded). In such embodiments, the present invention provides a correlation algorithm between ISF and Serum sodium levels and a method of using such correlation. For example, the method can optionally include determining ISF Na levels using the system and / or methods herein described, correlating the determined ISF Na levels with a lookup value and / or chart to determine a predicted Serum Na level, if the determined ISF Na levels and / or predicted Serum Na level exceeds a threshold value taking further action.

[0057] In yet further embodiments, the system can further incorporate a continuous analyte sensor (CAS) also positioned in interstitial fluid to monitor and determine levels of sodium using a different method than the CSS and / or determine levels of other analytes or some other physiological measure. The “other analyte” as used herein, is a broad term, and can include naturally occurring substances, artificial substances, metabolites, or reaction products. In some embodiments, the other analyte of interest includes any single analyte, or any combination of two or more analytes where the sensor employed is configured for determination of one or more analytes (e.g. for example by using two or more electrodes, each configured, or in combination configured, for measuring the same or different analytes). Other analytes of interest include: acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine / urocanic acid, homocysteine, phenylalanine / tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bicarbonate; biotinidase; biopterin; c-reactive protein; carnitine; camosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-P hydroxy-cholic acid; cholorine (C1-); cortisol; creatine; creatinine; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d- penicillamine; de-cthylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcohol dehydrogenase, alpha 1 -antitrypsin, cystic fibrosis, Duchenne / Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, sexual differentiation, 21-deoxycortisol); desbutylhalofantrine; dihydropteridine reductase; diptheria / tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids / acylglycines; free P-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri -iodothyronine (FT3); fumarylacetoacetasc; galactose / gal-1 -phosphate; galactose- 1 -phosphate uridyltransferase; gentamicin; glucose; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B / A-l, P); lithium (Li+); lysozyme; magnesium (Mg++); mefloquine; netilmicin; phenobarbitonc; phenytoin; phytanic / pristanic acid; potassium (K+); progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri -iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; sodium (Na+); somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles / mumps / rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi / rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat, vitamins, and hormones naturally occurring in blood or interstitial fluids can also constitute analytes of interest in certain embodiments of the present invention. Analytes of interest can additionally, or alternatively, include those naturally present in the biological fluid or endogenous, for example, a metabolic product, a hormone, an antigen, an antibody, and the like. Alternatively, the other analyte of interest can be introduced into the body or exogenous, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or a drug or pharmaceutical composition, including but not limited to: insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons, nicotine); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. Metabolic products of drugs and pharmaceutical compositions are also contemplated analytes of interest. Analytes of interest also include neurochemicals and other chemicals generated within the body, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5 -hydroxy tryptamine (5HT), and 5- hydroxyindoleacetic acid (FHIAA). In some preferred embodiments, the other analyte of interest is selected from the group consisting of: K+, Li+, Mg++, CL, bicarbonate, glucose, lactate, urea, albumin, uric acid, and creatinine. In other preferred embodiments, the other analyte of interest is selected from the group consisting of: K+, glucose, creatinine, C1-, Ca++, urea nitrogen, uric acid, and bicarbonate. In some most preferred embodiments, the other analyte of interest is K+ where a preferred combination of other analytes of interest include K+ combined with any analyte listed above, for example K+ combined with another analyte selected from the group consisting of glucose, uric acid, and creatinine.

[0058] In other embodiments, the CAS is configured to also determine a physiological condition. For example, ISF pressure has been used to monitor heart failure due to fluid build up. Measuring sodium levels together with ISF pressure could provide supplemental information and guidance on warnings, messages and / or treatment. For example, if high fluid pressure is accompanied with elevated Na levels, Na levels need to be decreased. If there are high fluid levels, without elevated Na+ levels, a different treatment may be suggested and / or needed.

[0059] The programmed circuitry for the CAS can operate in a similar fashion to that for sodium monitoring by acquiring data, determining analyte levels or physiological measure, and storing this information for analysis, alerting and / or comprehensive health monitoring. The data received from the CAS and determined analyte levels or physiological measures can be used alone or together with the data regarding sodium levels determined by the CSS in a correlation module to determine particular health related events and determine and issue associated alerts. For example, the CAS can determine data related to glucose or sodium or potassium levels in the user and when combined and correlated with the sodium levels determinations provided by the system can provide an indication related to insulin levels and / or suggested insulin dosage of the user, provide an indication related to organ health, volume status and / or hydration levels in the user. Additionally, the level of one additional analyte (e.g., potassium) or physiological measure (e.g., ISF pressure) measured on the CAS could be used in the signal processing algorithm of sodium (and vice versa) including using techniques such as, but are not limited to: drift correction; filtering algorithms; calibration techniques; signal conditioning and / or filtering; application of correction and / or offset factors etc. Accordingly, the CAS as described herein can be any known analyte or physiological condition monitoring system.

[0060] In still a further embodiment, the present system can further include a prescription medication lockbox maintained by the user. The lockbox is communicatively coupled to the programmed circuitry and the programmed circuitry further comprises logic and instructions for unlocking the lockbox in response to one or more stimuli selected from the group consisting of an instruction from a health care provider; a determination of a correlation; and sodium levels determined in step (ii) and / or stored in step (iii). Where the system further comprises a heart rate monitor, the programmed circuitry preferably is configured to determine a cardiac event of a user and logic and instructions for unlocking the lockbox in response to a cardiac event determined by the heart rate monitor.

[0061] In further embodiments the present invention provides a data file, an aggregated data file, a data storage system optionally containing data and / or such data file, etc. comprising sodium levels obtained by a sodium measurement system or methods described herein. Furthermore, an audible and / or visual display comprising an alert produced by a sodium measurement system or methods described herein is provided in any claim above

[0062] The continuous sodium measurement systems and methods described herein offer an innovative approach to monitoring and determining sodium levels in a user over time. By combining the CSS with programmed circuitry equipped with the various described functionalities and modules, the system enables continuous, real-time monitoring, data analysis, and personalized alerts for effective management of sodium-related health concerns. The detailed description and accompanying drawings elucidate the structure, operation, and capabilities of this novel system, showcasing its potential in healthcare and personal health management.

[0063] Reference throughout the specification to “one embodiment,” “another embodiment,” “a preferred embodiment,” “some embodiments,” and so forth, means that a particular element (e g., feature, structure, property, and / or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described element(s) and / or feature(s) of any embodiment described herein may be combined in any suitable manner with any other described embodiments. For example, steps or elements from one embodiment may be combined with any other steps or elements of another embodiment. Furthermore, the following claims include dependent claims based upon a single parent independent or dependent claim. Any of the following dependent claims may be combined with any other dependent claim(s) such that the specific dependent claim is considered a multiple dependent claim which necessarily includes all features of multiple parent claims and such combinations are supported by and do not depart from the scope of the present disclosure.

Claims

Claims:

1. A continuous sodium measurement system for determining sodium levels in a user over time, the system comprising: a continuous sodium sensor (CSS) positioned in interstitial fluid of the user and configured to determine data related to a sodium level in the user; and programmed circuitry comprising a processor and a memory, wherein the CSS and programmed circuitry are communicatively coupled, and wherein the programmed circuitry is programmed with logic and instructions for completion of the following steps by the programmed circuitry:(i) obtaining data related to the level of sodium in the user from the CSS;(ii) determining the level of sodium in the user from the data obtained in step (i);(iii) storing the level of sodium in the user determined in step (ii) in the memory; and(iv) repeating steps (i) to (iii) to determine and store in the memory sodium levels in a user over time.

2. The system of claim 1, wherein the data related to the level of sodium in the user is a voltage measurement from the CSS, wherein step (i) is performed by obtaining a voltage measurement from the CSS and (ii) is performed by processing the voltage measurement from the CSS obtained in step (i) to determine the level of sodium in the user.

3. The system of claim 2, wherein processing step (ii) is performed by correlating the voltage measure from the CSS obtained in step (i) to a reference value (e g. lookup table) to determine the level of sodium in the user.

4. The system of claim 1, wherein the programmed circuitry further comprises: a user computing device; CSS electronics comprising a wireless transmitter and a power source; and a remote server, wherein the user computing device, CSS electronics and remote server are communicatively coupled.

5. The system of claim 4, wherein the CSS electronics are enclosed within a housing, wherein the housing is disposed on the skin of a user and configured to maintain the CSS in the interstitial fluid of the user.

6. The system of claim 4, wherein the user computing device and / or the remote server comprise logic and instructions for performing steps (i), (ii), (iii) and / or (iv).

7. The system of claims 4, wherein the programmed circuitry further comprises: a health care provider computing device, the health care provider computing device communicatively coupled with the remote server or both the remote server and the user computing device.

8. The system of claims 4, wherein the user computing device comprises a user display interface configured to display information to the user, wherein the information is received from the user computing device, the remote server, and / or the health care provider computing device.

9. The system of claim 1, wherein steps (i) to (iii) are repeated in step (iv) upon an instruction issued from the user computing device and / or the remote server.

10. The system of claim 1, wherein steps (i) to (iii) are repeated in step (iv) at regular time intervals.11 . The system of claim 10, wherein steps (i) to (iii) are repeated in step (iv) at regular time intervals selected from the group consisting of: 1 second, 5 seconds, 10 seconds, 15 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours (preferably in 5-15 minute intervals).

12. The system of claim 1, wherein the programmed circuitry comprises a food intake module configured to receive and store in the memory dietary input from a user or health care professional.

13. The system of claim 1, wherein the programmed circuitry comprises an activity intake module configured to receive and store in the memory activity input from a user or health care professional about a user’s activity level.

14. The system of claim 1, wherein step (iii) further comprises associating the level of sodium in the user determined in step (ii) with a time stamp and storing the associated sodium level and time stamp in the memory.

15. The system of claim 1, wherein the programmed circuitry is programmed with logic and instructions to store dietary input, activity input, and / or a time stamp in an aggregated data fde as metadata with the sodium level of the user, wherein the metadata provides context regarding the sodium levels stored over time in step (iv).

16. The system of claim 1, wherein: the programmed circuitry comprises an accelerometer, an activity tracker, interstitial pressure monitor, and / or a heart rate monitor; the memory comprises accelerometer data, activity tracker data, interstitial pressure, and / or heart rate monitor data; and the programmed circuitry is programmed with logic and instructions for use of use of data stored in memory in predicting future health events of the user and / or determining health of the user.

17. The system of system of claim 1, wherein: the programmed circuitry stores information about the depth of the sensor measurement and / or sensor location (e.g., dermal, muscle) from either the user or the system; and the programmed circuitry is programmed with logic and instructions for use of sensor depth and / or sensor location data stored in memory in determining sodium levels and / or in predicting future health events of the user and / or determining health of the user.

18. The system of claim 1, wherein: the programmed circuitry stores information from two or more sensors about the depth of the sensor measurement and / or sensor location (e.g., dermal, muscle) from either the user or the system; and the programmed circuitry is programmed with logic and instructions for use of sensor depth and / or sensor location data stored in memory in determining sodium levels and / or predicting future health events of the user and / or determining health of the user.

19. The system of claim 1, wherein the programmed circuitry receives or determines a sodium gradient of a user and a depth of sensor measurement; wherein the programmed circuitry employs the sodium gradient and the depth of sensor measurement in the determining sodium levels and / or predicting future health events of the user and / or determining health of the user.

20. The system of claim 1, wherein the programmed circuitry further comprises a correlation module programmed with logic and instructions for completion of the following steps by the programmed circuitry:(v) comparing the data relating to the sodium level obtained in step (i), the sodium level determined in step (ii), and / or the sodium level stored in step (iii) to a reference value to determine if a correlation exists; and(vi) if a correlation is determined to exist in step (v) providing an alert to the user and / or healthcare provider.

21. The system of claim 20, wherein the correlation is selected from the group consisting of: user is in normonatremia; user is in hypernatremia; user is in severe hypernatremia; and user is in hyponatremia, and user is in severe hyponatremia, and / or wherein the correlation is selected from the group consisting of: user has or may have edema, fluid overload, dehydration, overhydration, electrolyte imbalances, hypertension, tumor lysis syndrome, SIADH, and cardiovascular events based on current and predicted sodium levels.AND, wherein the alert contains information selected from the group consisting of: user is in normonatremia; user is in hypernatremia; user is in severe hypernatremia; and user is in hyponatremia, and user is in severe hyponatremia, and / or wherein the alert contains information selected from the group consisting of: user has or may have edema, fluid overload, dehydration, overhydration, electrolyte imbalances, hypertension, tumor lysis syndrome, SIADH, and cardiovascular events based on current and predicted sodium levels.

22. The system of claim 20, wherein the alert contains an instruction selected from the group consisting of: maintain diet; change diet; maintain activity level; change activity level; maintain medication protocol; change medication protocol; initiate dialysis; go to emergency room; and contact user and / or contact healthcare provider.

23. The system of claim 20, wherein the correlation is user is in normonatremia and the alert contains instructions selected from the group consisting of: maintain diet; maintain activity level; and maintain medication protocol.

24. The system of claim 20, wherein the correlation is user is in hypernatremia or severe hypernatremia and the alert contains instructions selected from the group consisting of: change diet; change activity level; change medication protocol; initiate dialysis; go to emergency room; contact user; and contact healthcare provider.

25. The system of claim 24, wherein the alert contains instructions selected from the group consisting of: decrease ingestion of sodium containing foods and beverages; increase activity level; take or increase dosage of sodium lowering medication.

26. The system of claim 24, wherein the alert contains instructions to go to emergency room and / or directions to nearest emergency room.

27. The system of any of claims 20, wherein the correlation is user is in hyponatremia and the alert contains instructions selected from the group consisting of: change diet; change activity level; change medication protocol; go to emergency room; contact user; and contact healthcare provider.

28. The system of claim 27, wherein the alert contains instructions selected from the group consisting of: increase ingestion of sodium containing foods and beverages; decrease activity level; and take and / or increase dosage of sodium raising medication.

29. The system of claim 27, wherein the alert contains instructions to go to an emergency room and / or directions to nearest emergency room.

30. The system of claim 1, wherein the programmed circuitry further comprises a correlation module programmed with logic and instructions for completion of the following steps by the programmed circuitry:(vii) comparing sodium levels in a user over time determined and stored in memory in step (iv) to determine a rate of change in sodium levels of the user;(viii) determining from the rate of change in sodium level of the user determined in step (vii) if a correlation exists; and(ix) if a correlation is determined to exist in step (viii) providing an alert to the user and / or healthcare provider.31 . The system of claim 30, wherein the correlation determined in step (viii) is selected from the group consisting of: user is in or approaching normokalaemia; user is in or approaching hypernatremia; user is in or approaching severe hypernatremia; and user is in or approaching hyponatremia, and user is in severe hyponatremia and wherein the alert contains information selected from the group consisting of: user is in or approaching normokalaemia; user is in or approaching hypernatremia; user is in or approaching severe hypernatremia; and user is in or approaching hyponatremia and user is in severe hyponatremia.

32. The system of claim 30, wherein the alert comprises a message selected from the group consisting of: maintain diet; change diet; maintain activity level; change activity level; maintain medication protocol; change medication protocol; initiate dialysis; go to emergency room; contact user or healthcare provider.

33. The system of claim 30, wherein the correlation is user is in or approaching normonatremia and the alert contains instructions selected from the group consisting of: maintain diet; maintain activity level; and maintain medication protocol.

34. The system of claim 30, wherein the correlation is user is in or approaching hypernatremia or severe hypernatremia and the alert contains instructions selected from the group consisting of: change diet; change fluid intake, change activity level; change medication protocol; initiate dialysis; go to emergency room; contact user; and contact healthcare provider.

35. The system of claim 34, wherein the alert contains instructions selected from the group consisting of: decrease ingestion of sodium containing foods and beverages; increase fluid intake, increase activity level; take or increase dosage of sodium lowering medication.

36. The system of claim 34, wherein the alert contains instructions to go to emergency room and / or directions to nearest emergency room.

37. The system of claim 30, wherein the correlation is user is in hyponatremia and the alert contains instructions selected from the group consisting of: change diet; change activity level;change medication protocol; go to emergency room; contact user; and contact healthcare provider, wherein the alert optionally contains instructions selected from the group consisting of: increase ingestion of sodium containing foods and beverages; change activity level; take or increase dosage of sodium raising medication, and wherein the alert optionally contains instructions to go to emergency room and / or directions to closest emergency room.

38. The system of claim 30, wherein the correlation module is programmed with logic and instructions for completion of the following further steps: (x) estimating from the rate of change determined in step (viii) a time of reaching hypernatremia (and / or cardiac event), normonatremia, or hyponatremia in the user and providing an alert to the user and / or healthcare provider.

39. The system of claim 38, wherein step (x) further comprises estimating a time of reaching hypernatremia or hyponatremia, from a data source selected from the group consisting of: activity data of the user, diet of the user; medicating protocol of the user; accelerometer data; activity tracker data; and heart rate monitor data.

40. The system of claim 1, wherein the programmed circuitry further comprises a correlation module programmed with logic and instructions for completion of the following steps by the programmed circuitry:(vii) comparing sodium levels in a user over time determined and stored in memory in step (iv) to determine a rate of change in sodium levels of the user;(viii) determining from the rate of change in sodium level of the user determined in step (vii) if a correlation exists; and(ix) if a correlation is determined to exist in step (viii) providing an alert to the user, a healthcare provider, and / or a dialysis system.

41. The system of claim 40, wherein the correlation determined in step (viii) is selected from the group consisting of:user is in or approaching normokalaemia; user is in or approaching hypernatremia; user is in or approaching severe hypernatremia; and user is in or approaching hyponatremia, and user is in severe hyponatremia and wherein the alert contains information selected from the group consisting of: user is in or approaching normokalaemia; user is in or approaching hypernatremia; user is in or approaching severe hypernatremia; and user is in or approaching hyponatremia and user is in severe hyponatremia.

42. The system of claim 40, wherein the alert comprises a message selected from the group consisting of: start dialysis, maintain dialysis, stop dialysis, slow down rate of dialysis, increase rate of dialysis, increase sodium in dialysate, decrease sodium in dialysate, increase other electrolyte, such as potassium, in dialysate, decreases other electrolyte, such as potassium, in dialysate, go to emergency room; contact user or healthcare provider.

43. The system of claim 40, wherein the correlation is user is in or approaching normonatremia and the alert contains instructions selected from the group consisting of: maintain dialysis.

44. The system of claim 40, wherein the correlation is user is in or approaching hypernatremia or severe hypernatremia and the alert contains instructions selected from the group consisting of: stop dialysis, slow down rate of dialysis, increase rate of dialysis, decrease sodium in dialysate, increase other electrolyte, such as potassium, in dialysate, decreases other electrolyte, such as potassium, in dialysate, go to emergency room; contact user or healthcare provider.

46. The system of claim 44, wherein the alert contains instructions to go to emergency room and / or directions to nearest emergency room.

47. The system of claim 40, wherein the correlation is user is in hyponatremia and the alert contains instructions selected from the group consisting of: stop dialysis, slow down rate of dialysis, increase rate of dialysis, increase sodium in dialysate, increase other electrolyte, such as potassium, in dialysate, decreases other electrolyte, such as potassium, in dialysate, go to emergency room; contact user or healthcare provider.

48. The system of claim 40, wherein the correlation module is programmed with logic and instructions for completion of the following further steps: (x) estimating from the rate of changedetermined in step (viii) a time of reaching hypernatremia (and / or cardiac event), normonatremia, or hyponatremia in the user and providing an alert to the user and / or healthcare provider.

49. The system of claim 48, wherein step (x) further comprises estimating a time of reaching hypernatremia or hyponatremia, from a data source selected from the group consisting of: two sodium sensors at different depths in the dermal, activity data of the user, diet of the user; medicating protocol of the user; accelerometer data; activity tracker data; interstitial pressure, other analytes or electrolytes in the serum or ISF, composition of current or future dialysate, and heart rate monitor data.

50. The system of claim 1, wherein the programmed circuitry further comprises a correlation module programmed with logic and instructions for completion of the following steps:(xi) comparing the sodium levels in a user over time determined and stored in memory in step (iv) to determine a trend in sodium levels in the user over time;(xii) determining from the trend in sodium levels in the user over time determined in step (xi) if a correlation exists, and(xiii) if a correlation is determined to exist in step (xii) providing an alert to the user and / or healthcare provider.

51. The system of claim 50, wherein the correlation determined in step (xii) is that the user is in or approaching hypernatremia and / or severe hypernatremia and the alert contains instructions selected from the group consisting of: go to emergency room; directions to closest emergency room; contact user; contact healthcare provider; and initiate a sodium level lowering therapy such as a sodium level lowering therapy selected from the group consisting of vasopressin agonists or other vasopressin-modifying agent, diuretics, IV electrolyte administration, IV fluids.

52. The system of claim 50, wherein the correlation determined in step (xii) is that the user is in chronic hypernatremia and the alert contains instructions selected from the group consisting of: contact user; contact healthcare provider; consider initiation of a sodium level lowering therapy selected from the group consisting dietary and activity consultation, diuretics, IV electrolyte administration, IV fluids, and increased fluid consumption.

53. The system of claim 50, wherein the correlation determined in step (xii) is that sodium level changes at a particular time of day (e.g. after a meal, after an activity, etc.) and the alert contains instructions selected from the group consisting of: change diet at the particular time per day; change activity level at the particular time per day; change medication protocol at the particular time per day.

54. The system of claim 50, wherein the correlation determined in step (xii) is that sodium level is changing after a particular sodium-modifying stimulus or events including, but not limited to, administration of vaptans or other vasopressin-modifying agent, chemotherapy, syndrome of inappropriate anti diuretic hormone secretion (SIADH), tumor lysis syndrome, sweat-inducing exercise, dialysis, kidney transplant, and IV fluid administration and the alert contains instructions based on the event selected from the group consisting of: stop, maintain, or modify vaptan treatment, chemotherapy, exercise level, or fluid administration; increase, decrease, or maintain dietary consumption of sodium containing drinks or food; ; increase, decrease, or maintain fluid consumption; start, stop, or modify hypertonic or isotonic saline infusion; stop, maintain, or modify diuretics, urea, potassium salt, sodium salt, glucocorticoid, or thyroid hormone treatments; or initiate dialysis,55. The system of claim 50, wherein the correlation determined in step (xii) is that the trend in sodium level in the user is increasing or decreasing over time and the alert contains instructions selected from the group consisting of: change medication; change diet; change activity level; user kidney function is decreasing; user heart function is decreasing; user fluid retention is increasing or decreasing, edema is increasing or decreasing, contact user; and contact health care provider.

56. The system of claim 1, further comprising: a continuous analyte sensor (CAS) positioned in interstitial fluid of the user and configured to provide data related to an analyte level (other than a sodium level) of the user; and programmed circuitry comprising a processor and a memory, wherein the CAS, memory, and processor are communicatively coupled and wherein the programmed circuitry is programmed with logic and instructions for performing the following steps performed:(a) obtaining the data related to the analyte level of the user from the CAS;(b) determining the analyte level in the user from the data obtained in step (a); and(c) storing the analyte level determined in step (b) in the memory.

57. The system of claim 56, wherein the analyte is selected from the group consisting of: potassium, calcium, magnesium, glucose, chloride, and creatine.

58. The system of claim 56, wherein the programmed circuitry further comprises a correlation module communicatively coupled with the processor, wherein the correlation module is programmed with logic and instructions for completion of the following steps by the processor:(d) comparing the data obtained in step (a), the analyte level determined in step (b), and / or the analyte level stored in step (c) to a reference value to determine if a correlation exists; and(e) if a correlation is determined to exist in step (d) providing an alert to the user and / or healthcare provider.

59. The system of claim 56, wherein the programmed circuitry further comprises a correlation module communicatively coupled with the processor, wherein the correlation module is programmed with logic and instructions for completion of the following steps by the processor:(d) comparing the sodium level determined in step (ii) and the analyte level determined in step (b) to determine if a correlation exists; and(e) if a correlation is determined to exist in step (d) providing an alert to the user and / or healthcare provider.

60. The system of claim 59, wherein the analyte is glucose and the correlation of sodium levels and glucose levels provides an estimation of insulin levels of a user and / or an estimation of insulin dosage.

61. The system of claim 59, wherein the analyte is potassium and the correlation of sodium levels and potassium levels provides an estimation: kidney health, heart health, volume status, or hydration levels.

62. The system of claim 59, wherein instead of an analyte, interstitial pressure is measured, and the correlation of sodium levels and interstitial pressure provides an estimation of edema, fluid levels, or hypertension of a user and / or an estimation of oral or IV fluid and / or electrolytes; or arecommendation to start, stop, or modify medications including diuretics, vaptans, or hypertensives.

63. The system of claim 59, wherein the other analyte is potassium and the correlation of sodium levels and potassium levels provides an estimation of hydration and / or fluid status of a user and / or an estimation of oral or IV fluid and / or electrolytes needed to return to normal.

64. The system of claim 63, wherein one analyte that is not sodium, and the correlation of sodium levels and the other analyte levels together provides improved signal processing to determine the true levels of sodium and / or the other analyte. Techniques include, but are not limited to: drift correction; filtering algorithms; calibration techniques; signal conditioning and / or filtering; application of correction and / or offset factors; etc.

65. The system of claim 59, wherein the other analyte is potassium, and the correlation of sodium levels and potassium levels together provides improved signal processing to determine the true levels of sodium and / or potassium. Techniques include, but are not limited to: drift correction; filtering algorithms; calibration techniques; signal conditioning and / or filtering; application of correction and / or offset factors; etc.

66. The system of claim 56, wherein the alert comprises a message selected from the group consisting of: maintain medication protocol; change medication protocol; initiate dialysis immediately; go to emergency room; contact user or healthcare provider.

67. The system of claim 1, further comprising a medication lockbox communicatively coupled to the programmed circuitry, wherein the programmed circuitry further comprises logic and instructions for unlocking the lockbox in response to: an instruction from a health care provider; a determination of a correlation; and / or sodium levels determined in step (ii) and / or stored in step (iii).

68. The system of claim 67, further comprising a heart rate monitor configured to determine a cardiac event, wherein the heart rate monitor is communicatively coupled to the programmedcircuitry, and wherein the programmed circuitry further comprises logic and instructions for unlocking the lockbox in response to a cardiac event determined by the heart rate monitor.

69. A method for determining sodium levels in a user over time, the method comprising the steps of: providing the continuous sodium measurement system of any claim above; and the following steps by the programmed circuitry:(i) obtaining data related to the level of sodium in the user from the CSS;(ii) determining the level of sodium in the user from the data obtained in step (i);(iii) storing the level of sodium in the user determined in step (ii) in the memory; and(iv) repeating steps (i) to (iii) to determine and store in the memory sodium levels in a user over time, thereby determining sodium levels in the user over time.

70. A data file, data storage system, etc. comprising sodium levels obtained by a sodium measurement system described in claim 1.

71. An audible and / or visual display comprising an alert produced by a sodium measurement system described claim 1.

72. An aggregated data file comprising: a. sodium level data received from the sodium measurement system of claim 56; and b. analyte sensor data received from the CAS, wherein the timestamps of the data received from the CSS and the timestamps of the CAS are aligned.

73. An aggregated data file comprising data from the system of claim 1.

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