Methods for maintaining serum potassium homeostasis by subcutaneous monitoring

Abstract

Imbalances in potassium levels are the major cause of death of patients undergoing dialysis. Here, a method for maintaining serum potassium homeostasis by subcutaneous monitoring is provided. In one embodiment, an electrocardiographic (ECG) clinical manifestation is maintained for indicating the onset and presence of loss of serum potassium homeostasis in a dialysis patient, and in another embodiment, an arrhythmia signature is maintained for indicating the onset and presence of loss of serum potassium homeostasis in a dialysis patient. ECG signals of a heart of a patient are monitored subcutaneously continuously based on pacing heartbeat. The ECG signals are processed in real time into a set of ECG traces, where each ECG trace represents net electrical activity of the heart at a given moment in time. In one embodiment, each ECG trace is evaluated for this set of ECG representations, and in another embodiment, each ECG trace is evaluated over time for arrhythmia characteristics. An alert of the medical condition is generated when at least one of the ECG representations is identified in the ECG trace.

Description

Technical Field

[0001] The present application relates generally to the medical diagnosis and treatment of serum potassium imbalances and, in particular, to a method for maintaining serum potassium homeostasis by subcutaneously monitoring physiological parameters. Background Art

[0002] End-stage renal disease (ESRD) is a medical condition that affects more than 500,000 patients in the United States. ESRD, defined as a glomerular filtration rate of less than 15 mL / min, is the advanced stage of chronic kidney disease (CKD) when the kidneys permanently stop functioning. CKD and its sequelae, ESRD, remain a significant cause of reduced quality of life and premature death.

[0003] To stay alive, patients with ESRD must undergo regular dialysis or receive a kidney transplant. Dialysis removes waste and excess fluid from the blood through a combination of filtration and osmosis using a dialysis solution or dialysate. There are two types of dialysis, both of which take about four to six hours and are performed three times a week. Peritoneal dialysis (PD) uses tiny blood vessels in the lining of the abdomen (peritoneum) as a natural filter to clean the blood with the help of a dialysate. PD can be conveniently performed at home during sleep. Hemodialysis (HD) uses a semi-permeable dialyzer to filter waste from the blood, remove excess chemicals and fluid, and balance electrolytes using a dialysate. HD requires a specialized clinic with a dialysis machine and trained medical staff.

[0004] Although both HD and PD are life-sustaining for patients with ESRD, they are by no means without considerable risks to the patient's health. The risk lies in over- and under-removal of key blood components, including electrolytes, especially potassium, which is essential for normal cardiac function. Serum potassium homeostasis must always be kept strictly within a limited range to prevent the often tachycardic manifestation of a variety of lethal arrhythmias. It is well known that potassium deviations below or above the narrow range of about 3.5 to 5.5 mEq / L for days, hours, or even minutes can be fatal to patients with ESRD, depending on the extent of the low or high potassium levels and any underlying heart disease that is sensitive to such potassium abnormalities.

[0005] Patients with ESRD are at particularly high risk of sudden death if dialysis is not performed promptly and regularly to remove potassium that can no longer be excreted through the urine. Potassium levels above 6.0 mEq / L can easily be fatal if not addressed promptly. Such high potassium levels (called hyperkalemia) in patients with ESRD can occur in a very short period of time (frequently after dialysis) and have a variety of common causes, including delayed entry into a dialysis session, insufficient dialysis, or all those diseases or acute health conditions that may cause patients to suffer from dehydration and thus elevated potassium levels (such as infection with COVID-19 or lower gastrointestinal discomfort causing diarrhea). Fighting hyperkalemia requires urgent medical care. The opposing problem is that low potassium levels (called hypokalemia) in patients with ESRD are also common and can be fatal. Unfortunately, apart from routine pre-dialysis blood draws for HD patients, there is no real-time or even near-real-time testing method to proactively identify serum potassium imbalances in ESRD patients, which makes dialysis patients vulnerable and at risk.

[0006] Loss of serum potassium homeostasis is usually not noticed by an untrained observer until severe symptoms develop. However, there is a robust and well-known correlation between potassium imbalance and changes in electrocardiogram (ECG). Both high and low potassium levels show recognizable ECG changes. These ECG changes may be accompanied by specific heart rhythm dysfunction in the typical progression of arrhythmias, which in severe cases may indicate that the patient is at serious risk, including sudden cardiac death (SCD).

[0007] These characteristic ECG manifestations can be manifested within minutes. This typical ECG change seen in the case of low potassium levels begins when the potassium concentration drops to less than 2.5mEq / L and intensifies as the level further decreases. Similarly, for high potassium levels (usually above 6.0mEq / L), as the level rises and climbs to higher and higher levels, characteristic ECG changes will be shown. Since ESRD patients have limited ability to maintain potassium homeostasis in the case of metabolic deviations from the normal range caused by dialysis, the risks of serum potassium abnormalities causally related to HD or PD treatment are huge, especially because the survival rate of patients receiving dialysis in the United States is already the lowest in the world, and in particular, most patients start dialysis in the case of significant cardiovascular disease, which puts them at an increased risk of death due to unexpected arrhythmias or complications associated with potassium abnormalities. Cited from RNFoley et al., Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis, N.Engl.J.Med.365:1099-10,2011.

[0008] Conventional approaches focus on avoiding hypokalemia and hyperkalemia through preventive measures and periodic spot blood tests, but completely fail to address the significant and dynamic risks faced by ESRD patients, especially during the interdialytic period when serum potassium imbalances in these patients may go unnoticed. For example, one approach suggests applying dialysate potassium profile analysis during HD treatment, as discussed in P. P. Un and J. P. Middleton, Dialysate Potassium, Dialysate Magnesium, and Hemodialysis Risk, J. Am. Soc. Nephrol. 28:3441-3451, 2017. In the analysis, the optimal dialysate potassium level is selected to balance, achieve adequate potassium removal, thereby avoiding interdialytic hyperkalemia, while minimizing the potential risks caused by too rapid a reduction in potassium during dialysis. The analysis includes frequent serum potassium monitoring and flexible medical intervention when necessary. However, in practice, the analysis requires physically changing dialysate concentrations throughout HD treatment, thus making it impractical when applied to the general ESRD patient population who are at risk for potassium-triggered cardiac arrest that may occur within minutes or hours of dialysis.

[0009] A similar preventive approach applies dialysate potassium adjustment algorithms to HD therapy to avoid serum dialysate mismatches and achieve safe serum potassium concentrations. Adjustment algorithms are sometimes combined with nondialysis approaches that focus on patient analysis and management strategies through dietary counseling and the use of potassium-lowering medications. However, such algorithms are preventive at best and may even potentially increase risk by failing to distinguish isolated changes in predialysis serum potassium levels due to acute or transient conditions from chronic serum potassium trends, thereby inadvertently causing acute serum potassium imbalances.

[0010] The final approach involves using a higher concentration of dialysate potassium bath or lower blood and dialysate flow rates to extend the duration of HD treatment or increase the frequency. However, there are limited dialysis clinics available that can provide extended HD treatment or daily HD treatment, and this approach is generally less desirable for patients and dialysis providers. In addition, there is limited evidence that this approach has any real effect on preventing deaths caused by arrhythmias associated with potassium imbalances. The rapidity of the problem of severe potassium level changes, coupled with the complexity of each patient's disease, daily life, psychology, family situation, physical and mental abilities, etc., all combine to make efforts to predict and prevent who will die futile (especially those who live alone on PD and lack medical supervision from HD center staff). In addition, the human tendency to not strictly adhere to a strict course of medical action is a well-known weakness in the management of any chronic disease, and doubly so in a complex problem like ESRD. Any changes in routine arrangements will only increase the risk of potassium imbalance. Some simple examples include overeating, travel affected by traffic, flight cancellations, bad mood, interfering family diseases, power outages, etc. Thus, potassium levels in ESRD patients are highly dynamic, highlighting the relevance of cardiovascular mortality in those ESRD patients who have intermittent dialysis schedules and even changes in medications. Cited from RNFoley et al., in 1099.

[0011] Therefore, there remains a need for a proactive method for identifying, diagnosing, alerting, and promptly alleviating serum potassium imbalances, particularly when patients with ESRD are medically unattended and at risk for developing dangerously low or high potassium levels during the interdialytic period when these patients may develop dangerously low or high potassium levels in a very short period of time. Summary of the invention

[0012] Death caused by arrhythmias associated with serum potassium disorders is preventable. By actively monitoring the patient's ECG and proactively identifying specific ECG changes for indicating hypokalemia and hyperkalemia onset or presence, the significant and potentially fatal risk caused by the rapid development of hypokalemia or hyperkalemia in ESRD patients can be mitigated or even completely avoided. The ECG traces are analyzed in real time by an implantable cardiac monitor (ICM) to identify these specific ECG changes for indicating hyperkalemia and hypokalemia, which ECG changes are accompanied by or without arrhythmias. Ideally, the identification of ECG changes indicates the occurrence of arrhythmias. For optimal efficiency, this active monitoring should be carried out at any time during the interdialysis period, the dialysis period, and the post-dialysis period. In addition to the monitoring possibility exception during hemodialysis, the patient with ESRD tends to become an easily overlooked and unresolved serum potassium imbalance period in almost all periods.

[0013] One highly effective form of active ECG monitoring uses a continuous ICM that can exploit the correlation between changes in the electrocardiogram tracing and serum potassium imbalances. The ICM can wirelessly provide a continuous data stream of high-quality ECG signals and incorporate alarms when identifiable changes in the electrocardiogram tracing (ECG) occur, with or without specific arrhythmias that may indicate the onset or presence of hypokalemia or hyperkalemia. The continuous data stream enables the ICM to operate without memory limitations. Other forms of ECG monitors, either implantable or skin-mounted, are possible, but only ICMs with a continuous data stream are able to detect potassium imbalances. Depending on the severity of the abnormality, such data can be used to wirelessly alert one or more of the patient, family members, physicians, and emergency medical services (EMS) through algorithms on a 24 / 7 / 365 basis.

[0014] In one embodiment, the microcontroller in the ICM operates under microprogram control using firmware that can recognize in real time the ECG performance in the sensed ECG signal, which forms an ECG trace. If the ECG trace has a sunken ST segment and a prolonged QT interval (or QTU interval) (possibly accompanied by a significant U wave), hypokalemia is present and an emergency event is triggered. If the ECG trace has a peak T wave, moderate hyperkalemia is present and an emergency event is triggered. If the ECG trace has a wider QRS complex, a peak T wave, a longer PR interval, and a lower P wave amplitude than normal, severe hyperkalemia is present and an emergency event is triggered. Finally, if the ECG trace has a QRS complex and T wave similar to a "sine" wave without a P wave, severe hyperkalemia is present and an emergency event is triggered. Other ECG performances may result in different or complementary types of alarms.

[0015] One embodiment provides a method for maintaining serum potassium homeostasis by subcutaneous monitoring. A set of ECG manifestations is maintained, the ECG manifestations being used to indicate at least one of the onset and presence of loss of serum potassium homeostasis in a dialysis patient. An electrocardiogram (ECG) signal of the patient's heart is continuously monitored subcutaneously on a beat-to-beat basis. The ECG signal is processed in real time into a set of ECG traces, each of which represents the net electrical activity of the heart at a given moment. Each ECG trace is evaluated for a set of ECG manifestations. Once at least one of the ECG manifestations is identified in one or more of the ECG traces, an alarm for a medical condition is generated.

[0016] Another embodiment provides an implantable cardiac monitor for maintaining potassium homeostasis. The implantable housing is formed as a cylinder with rounded hemispherical end caps and comprises a biocompatible material suitable for implantation in vivo. At least one pair of ECG sensing electrodes are disposed on a ventral surface and on opposite ends of the implantable housing, operably positioned about the end caps to facilitate proximal sensing of low amplitude, low frequency content cardiac action potentials generated during atrial and ventricular activation and atrial and ventricular repolarization. Electronic circuitry is disposed within the housing assembly and includes: a low-power microcontroller that is operable under modular microprogram control; an ECG front-end circuit that interfaces with the microcontroller and is configured to capture cardiac action potentials sensed by a pair of ECG sensing electrodes as an ECG signal, wherein the ECG signal includes a set of ECG traces, and each ECG trace represents the net electrical activity of the heart at a given moment; firmware that is provided as part of the microprogram, and the microprogram includes identifying ECG manifestations in one or more of the ECG traces based on a beat-to-beat basis; and a non-volatile memory that is electrically interfaced with the microcontroller and is operable to continuously store samples of the ECG signal, wherein the microcontroller generates an event trigger once the microcontroller identifies at least one of the ECG manifestations in one or more of the ECG traces.

[0017] Still other embodiments will become readily apparent to those skilled in the art through the following detailed description, wherein the embodiments are described by illustrating the best mode contemplated. As will be appreciated, other and different embodiments are possible, and the various details of the embodiments can be modified in various obvious respects, all without departing from their spirit and scope. Therefore, the drawings and detailed description should be regarded as illustrative rather than restrictive in nature. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a diagram illustrating, by way of example, a patient undergoing dialysis treatment with a hemodialysis (HD) machine according to one embodiment.

[0019] Figure 2 is a graph showing, by way of example, the relationship between long dialysis intervals and mortality in ESRD patients.

[0020] Figure 3 is a graph illustrating the relationship between hyperkalemia and the odds of death within a day for moderate and severe hyperkalemia events by way of example.

[0021] Figure 4A-4E is a graph showing, by way of example, the relationship between changes in electrocardiogram (ECG) tracings and serum potassium levels.

[0022] Figure 5is an external perspective view showing an implantable cardiac monitor (ICM) for maintaining potassium homeostasis according to one embodiment.

[0023] Figure 6 is an external perspective view showing an implantable cardiac monitor (ICM) for maintaining potassium homeostasis according to another embodiment.

[0024] Figure 7 It shows Figure 5 Block diagram of the ICM microarchitecture.

[0025] Figure 8 It is shown that Figure 5 Flow chart of a method for continuous electrocardiogram monitoring in an ICM.

[0026] Fig. 9 is a diagram showing a method for identifying a Figure 8 Flowchart of the procedure for ECG performance in the method.

[0027] Fig.10 is shown for evaluating the Figure 8 Flowchart of the procedure for the temporal nature of ECG performance in the method.

[0028] Fig.11 is a flow chart showing the patient workflow.

[0029] Fig.12 is a flow chart showing the workflow of doctors and staff.

[0030] Figures 13A-13C is a schematic diagram showing, by way of example, a patient case study presented in a tabular format indicating events with the patient's medical history and 31 day summary and comments reflecting significant morbidities relevant to the patient's condition. DETAILED DESCRIPTION

[0031] Serum potassium homeostasis

[0032] Electrolyte balance is essential to life, and serum potassium homeostasis must be maintained strictly within limited ranges to ensure normal cardiac function and to prevent the manifestation of various lethal arrhythmias. It is well known that potassium deviations below or above the narrow range of approximately 3.5 to 5.5 mEq / L, regardless of the cause, whether due to cardiovascular or renal disease or due to various medications, can be fatal within days, hours, or even minutes, depending on the degree of low or high potassium levels and underlying heart disease that is sensitive to such abnormalities. Potassium levels that rise above 7.0 mEq / L (hyperkalemia) can easily be fatal if not promptly addressed, and levels above 9.0 mEq / L almost certainly result in death. Hyperkalemia in patients with ESRD can develop over a short period of time and has a variety of common causes, including: delayed entry into dialysis sessions (such as delays in getting to an HD dialysis center), or due to inadequate dialysis (such as when patients shorten their PD for social or psychological reasons), or all those illnesses or acute health conditions that may cause patients to become dehydrated and thus have elevated potassium levels (such as contracting COVID-19, influenza, or having lower gastrointestinal complaints that cause diarrhea). COVID-19 is of particular concern given its ability to rapidly mutate, making containment of its spread futile, and its high contagiousness as an airborne virus. Frail and immunosuppressed people, many of whom are on dialysis, are at high risk for contracting COVID-19. Furthermore, despite the attention COVID-19 receives as a public health emergency, in reality, the diagnosis and treatment of COVID-19 often takes days, during which time changes in a patient's potassium level go undetected or even ignored because other symptoms, such as those affecting the respiratory system, such as cough, shortness of breath, and sore throat, receive the most attention.

[0033] Additionally, changes in dialysate prescriptions or changes in medications used for other conditions, such as heart failure, can affect potassium metabolism and raise potassium levels to dangerous levels. Potassium levels that drop below 2.5 mEq / L (hypokalemia) are also common in patients with ESRD and can be fatal. Levels below 1.5 mEq / L often result in sudden death. Often, dangerously low potassium levels are caused by prolonged dialysis, such as from extended sleep during PD, or by the use of a newly prescribed, overly concentrated dialysate that removes potassium too aggressively in an attempt to ameliorate a previously identified problem of hyperkalemia.

[0034] Because of the rapid lethal potassium shifts in patients with ESRD, continuous potassium monitoring is necessary to prevent disaster. There is a well-known robust correlation between decreasing and increasing potassium levels and specific electrocardiographic (ECG) changes, and this correlation can be effectively exploited to quickly identify serum potassium imbalances and save the patient's life. The typical ECG changes seen in the case of low potassium levels begin when the potassium concentration drops below 2.5 mEq / L and gradually increase in severity as the level decreases further. Similarly, for high potassium levels (usually above 6.0 mEq / L), the characteristic ECG appearance changes as the level increases and climbs to higher and higher levels.

[0035] Dialysis

[0036] There are two types of dialysis, both of which take about four to six hours and are performed three times a week. Dialysis approximates the normal state of the human body when the kidneys are healthy, although the kidneys are not constantly focused on removing toxins from the blood. Peritoneal dialysis (PD) uses the tiny blood vessels in the peritoneum as a natural filter to filter the blood with the help of a dialysis solution, or dialysate, that is passed into the abdominal space through an abdominal tube. PD is more popular than hemodialysis (HD) because it can be more conveniently performed at home during sleep. In the case of PD, a dialysate using glucose and other elements removes toxins by osmosis to extract toxins from the blood circulation in the peritoneal lining and abdominal organs, including excess potassium produced from food and normal cell metabolism. The dialysate is then drained from the abdomen at the end of the session.

[0037] Hemodialysis (HD) is a form of dialysis that goes directly into the patient's blood vessels and uses a semi-permeable dialyzer to filter waste products from the blood, remove excess chemicals and fluid, and balance electrolytes (potassium, sodium, bicarbonate, chloride, calcium, magnesium, and phosphate). Figure 1 is a diagram illustrating, by way of example, a patient 11 undergoing dialysis treatment 10 using an HD machine 12 according to one embodiment. The patient 11 is a recipient of an implantable cardiac monitor (ICM) 20, such as described in U.S. patent application Ser. No. 16 / 929,390, filed Jul. 15, 2020, pending, the disclosure of which is incorporated herein by reference and will be self-referenced below. Figure 5Further discussion begins). ICM 20 is capable of proactively identifying, diagnosing, alarming, and timely alleviating serum potassium imbalances. ICM 20 relies on the correlation between identifiable electrocardiographic (ECG) changes associated with specific arrhythmias and serum potassium imbalances. Therefore, ICM 20 proactively protects patient 11 from the fatal sequelae of hypokalemia and hyperkalemia at all times, including between dialysis periods when patients with ESRD are medically unattended and are at risk when these patients may develop dangerously high potassium levels in a very short period of time. Other forms of ECG monitors (whether implantable or skin-mounted) are also possible.

[0038] Dialysis treatments typically take about four to six hours. During HD treatment, a blood pump 16 draws blood from a patient 11 into a dialysis machine 12 via an arterial channel 13 and through a dialyzer 15, which removes excess waste and fluid from the blood. The cleaned blood is then returned to the patient 11 via a vascular channel 14. The dialyzer 15 is constructed of a thin fiber material used to form a semipermeable membrane that allows smaller particles and fluids to pass through. Fresh dialysate 17 passes in the opposite direction of the blood without actually contacting the blood, while spent dialysate 18 containing waste products leaves the dialyzer 17.

[0039] In both PD and HD, during the first hour of dialysis, the rate of potassium decline is rapid because the serum-dialysate gradient is greatest. Over the next two hours or so, the rate of potassium decline decreases, and during the last hour, serum potassium levels remain relatively stable.

[0040] Correlation between dialysis interval and patient death

[0041] The timing aspect of regular dialysis is critical to the patient's health, and failure to strictly adhere to a three-day dialysis schedule while on dialysis can have fatal consequences for ESRD patients. This fatal risk has been statistically validated. Patients typically undergo three dialysis treatments per week, with two 1-day intervals and one 2-day interval between sessions, followed by subacute postdialytic rebalancing and slow interdialytic accumulation of the same fluids and electrolytes during two 1-day intervals and one 2-day interval between sessions. In particular, a 2-day interval has been found to reflect an increased risk of cardiovascular complications and death. Note that dialysis performed on day 1 after a 2-day interval, which is usually performed on Monday, may be performed later in the day, as is the case with peritoneal dialysis. Figure 2is a graph showing by way of example the relationship 30 between long dialysis intervals 31 and mortality 32 in ESRD patients. The x-axis 31 reflects the dialysis intervals, where HD1 represents the day of the first dialysis session of the week, HD1+1 represents the day after the first dialysis session, and so on. The y-axis 32 reflects the mortality of ESRD patients attributable to all causes 33, cardiac causes 34, infectious causes 35, and vascular causes 36, respectively. One study found that on the day after a long dialysis interval, when HD1 was performed, the all-cause mortality rate was 22.1 deaths per 100 people per year (compared to 18.0 per 100 people per year), the mortality rate from cardiac causes was 10.2 deaths (compared to 7.5), the infection-related mortality rate was 2.5 deaths (compared to 2.1), the mortality rate from cardiac arrest was 1.3 (compared to 1.0), and the mortality rate from myocardial infarction was 6.3 (compared to 4.4). Cited from RN Foley et al., Long Interdialytic Interval and Mortality among Patients Receiving Hemodialysis, N. Engl. J. Med. 365:1099-10, 2011. The increased risk of adverse complications due to serum potassium imbalance after a 2-day interval may be ameliorated by proactive interventions provided by the use of ICM 20.

[0042] Although patients with ESRD are kept alive, HD and PD are by no means without considerable risk. The risk is over-removal and under-removal of key blood components, including electrolytes, especially potassium. After dialysis, a subacute rebound of serum potassium occurs, and these acute changes in serum potassium levels present a risk of first altering the electrocardiogram and then possibly inducing serious arrhythmias. In addition, dialysis patients remain at significant risk for serum potassium imbalance during the interdialytic period when various factors, such as diet and potassium-lowering medications, may affect the patient's serum potassium balance. The interdialytic period is critical because potassium levels are not actively monitored, and potentially fatal excursions above or below the safe range may go unnoticed and unaddressed. Note that 7 days a week and the practical impossibility of continuous or even daily dialysis make fluctuations in potassium balance an ongoing reality.

[0043] Regardless of the interdialytic interval, both forms of dialysis have the potential to disrupt serum potassium balance in ESRD patients because dialysis removes potassium that has accumulated in the blood during the interdialytic interval, creating a risk that serum potassium may be too low or not low enough during or immediately after treatment. The normal range of serum potassium in the general population is 3.5 to 5.0 mEq / L, while the optimal potassium concentration range is slightly higher in HD patients. Recent studies have shown that patients with predialysis serum potassium levels of 5.1 mEq / L exhibit the lowest risk of peridialytic sudden cardiac death (SCD), while serum potassium levels above and below 5.1 mEqg / L are associated with an increased risk due to the equally fatal problem of hyperkalemia, as discussed in P Phun and J P Middleton, Dialysate Potassium, Dialysate Magnesium, and Hemodialysis Risk, J. Am. Soc. Nephrol. 28: 3441-3451, 2017.

[0044] While predialysis risks associated with serum potassium levels can generally be modified, the potential impact of potassium drop during and after dialysis treatment remains a concern. The rate and amount of potassium removal is largely a function of the serum potassium-dialysate potassium gradient. When compared with a smaller serum dialysate gradient, a higher serum dialysate gradient results in a more rapid decline in serum potassium levels during treatment and a rapid rebound in potassium levels after dialysis. The rapid decline and rebound in serum potassium result in acute changes in serum potassium levels, which in turn can trigger hypokalemia or hyperkalemia, which may result in palpitations, shortness of breath, chest pain, nausea, vomiting, or worse, including stroke, dysrhythmia, myocardial infarction, and peridialytic SCD.

[0045] Hyperkalemia

[0046] In particular, sudden onset or severe hyperkalemia is a life-threatening condition requiring immediate medical attention, with a statistically demonstrated link between abnormal serum potassium levels and death. Figure 3It is a graph showing the relationship 40 between hyperkalemia 41 and the probability of death 42 by example. The x-axis 41 reflects the severity of chronic kidney disease (CKD), progressing from stage 3 to stage 5 (i.e. ESRD), plus a control group marked as "none". The y-axis 42 reflects the probability of death within one day of moderate and severe hyperkalemia events, respectively. A study found that patients with CKD were more likely to have hyperkalemia events at all stages of kidney disease than patients without CKD, where the probability of death in one day of hyperkalemia patients was greater than that of normal potassium events. Cited from LMEinhorn et al., The Frequency of Hyperkalemia and Its Significance in Chronic Kidney Disease, Arch. Intern. Med. 169 (12): 1156-1162 2009. Interestingly, hyperkalemic events in patients without CKD were associated with a higher odds of 1-day mortality compared with hyperkalemic events in patients with CKD, with an inverse correlation between the severity of CKD (by stage 43, 44, 45, 46) and the odds of 1-day mortality from hyperkalemic events, and more severe hyperkalemia was associated with a higher odds of mortality. When patients with CKD were repeatedly exposed to higher potassium levels, they sometimes modestly mounted less defensive mechanisms to higher potassium levels than those exposed twice. Nevertheless, this modest defensive response was extremely insufficient to offset the significant risk of hyperkalemia, regardless of the duration of exposure.

[0047] Correlation between ECG findings and serum potassium imbalance

[0048] The onset or presence of hypokalemia and hyperkalemia during the interdialytic and peridialytic periods can be detected by using the ICM 20. The ICM 20 is capable of detecting potassium imbalances and triggering text, email, and phone alerts to varying degrees based on algorithms wirelessly to patients, families, physicians, and emergency medical services 24 hours a day / 7 days a week / 365 days a year, 24 / 7 / 365. The correlation between ECG changes (which may but not always be accompanied by an accompanying specific arrhythmia ("ECG manifestation")) and serum potassium imbalances (such as discussed in DB Diercks et al., Electrocardiographic Manifestations: Electrolyte Abnormalities, J. Emerg. Med. 27: 153-160 2004) is known, and these characteristic ECG manifestations can be used to effectively trend toward diagnosis and treatment of hypokalemia and hyperkalemia in real time by using the ICM 20. Figure 4A-4EIt is a graph showing by way of example the relationship between changes in electrocardiogram (ECG) tracings and serum potassium levels. The x-axis represents time, while the y-axis represents the electrical signal strength, usually in millivolts. Figure 4A , shows an ECG trace 50 for an individual with normal serum potassium levels between 2.5-5.5 mEq / L; the ECG trace has three major components: the P wave, which represents depolarization of the atria; the QRS complex, which represents depolarization of the ventricles; and the T wave, which represents repolarization of the ventricles. (Note that the repolarization of the atria is too small to be seen on the ECG and is hidden by the large amplitude QRS.)

[0049] Low serum potassium, indicative of hypokalemia, is associated with ventricular tachycardia (VT) and ventricular fibrillation (VF). Figure 4B , shows an ECG trace 55 of an individual with a serum potassium level below 2.5 mEq / L and in a hypokalemic condition. The ECG trace 55 has a depressed ST segment 56 and a prolonged QT interval 57 (or a prolonged QTU interval), possibly with a prominent U wave 58. Note that the U wave is not always visible in the patient's ECG; the U wave occurs after the T wave of ventricular repolarization and, due to its small size, may not always be observed. Thus, a prominent U wave 58 may not be present. That is, the U wave can become very prominent in the setting of hypokalemia. These changes in the ST segment and QTU interval increase as the hypokalemia becomes more severe; a trend that can be detected by ICM. As serum potassium drops, rapid death due to VT and VF becomes increasingly likely. The observed concomitant presence of ventricular arrhythmias, combined with the low potassium levels detectable by ICM, adds a higher level of urgency for rising intervention.

[0050] High serum potassium, indicative of hyperkalemia, has been associated with bradycardia, heart block, asystole, and congestive heart failure (CHF). Figure 4C , shows an ECG trace 60 of an individual with elevated serum potassium levels in the range of 7.0-8.0 mEq / L. The ECG trace 60 has a "peaked" T wave 61, where the amplitude of the T wave gradually increases. Figure 4D , in the case of moderate potassium elevations in the range of 8.0-9.0 mEq / L, ECG trace 65 has a broadened QRS complex in addition to a specific peaked T wave, coupled with a longer PR interval and lower P wave amplitude. Figure 4EThe most severe hyperkalemia exists when the potassium level exceeds 9.0 mEq / L, and the ECG trace 70 has a broadened QRS complex and a broadened T wave (which together resemble a "sine" wave without a P wave). Such an event portends death (in minutes). As serum potassium continues to rise, death due to cardiac arrest, myocardial paralysis, and rhabdomyolysis becomes very likely.

[0051] ICM for identifying ECG findings

[0052] The risks posed by abnormal serum potassium causally related to HD or PD therapy are serious but can be greatly mitigated or avoided altogether by using an ICM, which can identify, diagnose, and trigger treatment of hypokalemia and hyperkalemia by alerting appropriate individuals through real-time monitoring of the patient's ECG. The ICM wirelessly provides a continuous data stream of high-quality ECG signals combined with alarms when identifiable electrocardiographic (ECG) changes and specific arrhythmias are detected, both of which together indicate the onset or presence of hypokalemia or hyperkalemia. The continuous data stream enables the ICM to operate without memory limitations. Figure 5 8 is an external perspective view of an implantable cardiac monitor (ICM) 80 for maintaining potassium homeostasis according to one embodiment. The ICM 80 continuously captures cardiac action potentials sensed by a pair of ECG sensing electrodes 82, 88 (or in another embodiment, three ECG sensing electrodes) as ECG signals. In another embodiment, the ICM 80 is combined with cloud-based diagnostics and monitoring, as described below with reference to Fig. 9 as discussed further.

[0053] The ECG signal forms an ECG trace that can be analyzed in real time by the ICM 80 to identify the above-mentioned ECG changes with or without arrhythmias indicative of hyperkalemia and hypokalemia. Ideally, the identification of ECG changes indicates the occurrence of arrhythmias. In some cases, they occur simultaneously. If a concerning medical condition is detected, the data center and the ICM 80 (if equipped for direct wireless communication) will contact the patient 11 and, if necessary, the medical care provider to take immediate intervention measures.

[0054] The ECG signal of the patient's heart is continuously monitored on a beat-to-beat basis, 24 / 7 / 365. The ECG trace is evaluated by the ICM 80 on a beat-to-beat basis and as a unity of the ECG and heart rhythm as they evolve over time. Each ECG trace represents the real-time net electrical activity of the heart at a given moment and is evaluated on a beat-to-beat basis for a set of ECG performances. The ECG trace is stored as a set of data representing the heart rhythm and is evaluated as a rhythm that evolves over time for arrhythmia characteristics. The ICM 80 captures the individual waveform components of each heartbeat and their characteristics (including their presence or absence, duration, and amplitude). In addition, as each heartbeat is captured, the ICM 80 is able to compare the heartbeats to identify any changes that may occur over time; for example, a gradual increase in the T wave amplitude will be detected and timed, which is noteworthy because a rapidly developing increase in the T wave amplitude is a key indicator of lethal hyperkalemia. With the heartbeats stored, the ICM 80 can also compare heartbeats from earlier recording time periods with heartbeats observed over the entire two-day interval between dialysis sessions, such that, for example, the occurrence of increased T wave amplitude can indicate a shift toward hyperkalemia, which, while not meeting the clinical definition of potassium levels rising above 6.0 mEq / L, may be sufficient to warrant a physician inquiry and patient follow-up. In addition, the ability to identify beat-to-beat variations in the heartbeat also enables the ICM 80 to identify a variety of possible arrhythmias. Thus, both beat-to-beat ECG variations and specific arrhythmias can be fully identified on a real-time, full-time basis by the ICM 80.

[0055] Inadequacy of existing implantable devices

[0056] It is worth noting that existing implantable cardiac monitoring devices have traditionally been used to detect arrhythmias by sporadically using algorithms based on a limited amount of binned and stored data; such devices do not track cardiac activity on a beat-to-beat basis. Instead, these devices digitize ECG voltages and process these voltages to identify specific arrhythmia patterns (primarily atrial fibrillation and ventricular tachycardia), which represent only a very small subset of the range of known and potentially lethal arrhythmia patterns.

[0057] More specifically, existing implantable cardiac monitoring devices do not capture the characteristics of the individual waveform artifacts that make up the ECG, which is used to track potassium metabolism. Data that is critical to determining serum potassium homeostasis or its loss, such as the amplitude and polarity of the T wave or the presence or absence of the U wave, are not captured or even measured at all. In addition, these devices are unable to detect the equally important beat-to-beat changes that may occur with these artifacts, such as gradual increases and sharp increases in T wave amplitude. As a result, existing implantable cardiac monitoring devices are unable to identify ECG changes and, where applicable, are unable to identify specific arrhythmias that are indicative of hyperkalemia and hypokalemia, as described above. These types of monitoring devices are memory limited and are simply not built to continuously monitor trends in any key parameters on a beat-to-beat basis that are critical to detecting low or high serum potassium levels. Instead, such devices focus on identifying arrhythmia episodes by relying on a form of loop recorder that is forced to constantly re-record over earlier ECG observations to preserve memory, with ECG traces binned and averaged into summary "episodes," thereby losing critical beat-to-beat (heartbeat) data. Because beat-to-beat data is not stored, it cannot be used for beat-to-beat comparative analysis of ECG features that are not related to arrhythmias. This episodic approach means that because these devices effectively look for a "snapshot" of the ECG trace that matches an arrhythmia pattern, such as atrial fibrillation (AF), they are unable to capture evolving changes in the patient's ECG that occur over time as serum potassium levels drop or rise. Furthermore, when the device focuses on episodic ECG monitoring, individual ECG artifacts, such as T waves, have limited visibility at best, and the increase in T wave amplitude required to identify the onset of hyperkalemia is not discernible.

[0058] Continuous real-time monitoring

[0059] The ICM 80 is designed to be implanted in vivo and run full-time for extended periods of time, while monitoring different types of patient physiology, possibly in different ways at different times. The ICM 80 can record every heartbeat, performing real-time transmission or delayed transmission, which may occur, for example, two days or more after the recording or live monitoring. The ICM 80 is equipped with ECG sensing electrodes 82, 88, and in another embodiment, one or more physiological sensors, which non-exhaustively include temperature, pulse oximeter, oxygen saturation, respiration, blood sugar, blood pressure, and any appropriate measure of drug level or medical condition or disease.

[0060] The implications of making long-term continuous ICM data available through the use of ICM 80 are profound. Long-term disease management data will aid in home health care and web-based medical practices, and continuous data on key physiological parameters will provide new insights into disease progression and management of all health conditions, not just those related to CKD. As a result, continuous ICM data will be available to influence medical decisions for multiple chronic diseases, and medication, device, and procedural management can be optimized to ensure optimal medical care over many years of care. The long-term perspective provided by continuous ICM data will enable health care providers to begin to capture early signs of devastating diseases through large population studies, something that has not been possible until now.

[0061] When ECG changes with specific arrhythmias indicative of the onset or presence of hypokalemia or hyperkalemia are detected, the ICM 80 generates an emergency event trigger that is communicated to the data center for immediate real-time action and patient follow-up, as described below with reference to Fig.10 In another embodiment, the ICM 80 can alert the patient directly using a mobile phone or wirelessly connectable device (including a tablet or laptop computer or a wired desktop computer) through a wireless access point or other wireless communication interface.

[0062] In yet another embodiment, when equipped with the appropriate type of sensor, the ICM 80 may also monitor non-physiological data, such as posture derived from data measured by actigraph sensors, accelerometers, or inertial motion sensors. Other types of sensors and forms of physiological and non-physiological data capture are also possible, such as cardiac engagement levels, thoracic impedance, and audio recordings (including ultrasound and infrasonic recordings). In addition, medication history, diagnostic test reports, dialysate changes, surgical and therapeutic procedures may be entered into the ICM database in the form of a portable, personal medical record.

[0063] ICM Components

[0064] ICM 80 includes three main components. The main middle part of ICM 80 is center body 81, which can be formed by medical grade titanium or similar medical implant safety materials. Center body 81 has a tubular or cylindrical shape that defines an axial hole, and the axial hole provides a hollow tubular or cylindrical inner cavity that extends longitudinally on the length of center body 81 and opens on two end caps. It is also possible to have other shapes that are non-circular, non-tubular or non-spherical. Circular hemispherical end caps 82 and 83 are welded or fixed to center body 81 to form a hermetically sealed device housing. End caps 82 and 83 can be formed into other shapes, such as a tip or a semi-tip.

[0065] The shape of the ICM 80 is designed for long-term, comfortable, permanent implantation in a subcutaneous site located axially in the parasternal region of the chest and slightly to the left or right of the mid-sternal line. This location is ideal for the type of cardiac ECG monitoring that emphasizes the propagation of low-amplitude, relatively low-frequency content cardiac action potentials (particularly the P-waves produced during atrial and ventricular activation and repolarization of the atrial and ventricular), in contrast to existing implantable cardiac monitoring devices that are intended for short-term subcutaneous implantation in the left chest that sits diagonally relative to the heart.

[0066] The central body 81 houses a flexible circuit board, a low frequency resonant charging antenna to facilitate charging of the device, and an onboard power source including a rechargeable energy cell, battery or supercapacitor. The ICM 80 only needs to be charged about once a month, with a charging time of about 10 minutes. One of the hemispherical end caps, called the "protection electrode" 82, serves the dual purpose of serving as an electrode and housing patient protection components and device protection components. The other hemispherical end cap, called the "radar dome" 83, houses a high frequency antenna for transmitting data via an RF link, for example using Bluetooth or WiFi. In addition, the "radar dome" 83 can be used to house an inductive antenna and an inductive link. The RF link can also be used for device calibration and configuration. In another embodiment, the "radar dome" 83 can also house physiological sensors, such as a pulse oximeter and a sphygmomanometer. In yet another embodiment, the optically transparent "radar dome" 83 can allow light or other forms of radiation to be received and transmitted from it to passively facilitate the collection of other vital signs, such as pulse oximeter and blood pressure. In yet another embodiment, optical fibers or lenses implanted in the “radar dome” 83 may facilitate the collection of vital signs by sensors housed elsewhere within the ICM 80 .

[0067] In one embodiment, the ICM 80 has an overall length of approximately 5.5 cm to 8.5 cm, an outer diameter measured at the central body 81 of approximately 5-8 mm, and a wall thickness of approximately 0.3 mm; however, other dimensions (including overall length, wall thickness, and outer diameter) are possible depending on the type and number of electronic circuits and power supplies and physiological and non-physiological sensors that need to be accommodated therein.

[0068] In another embodiment, the ICM 80 can be filled with a gas, such as argon or other inert gas. In particular, argon is often used when welding titanium components, and is also used to protect electrical components and promote device life when oxygen that needs to be purged is blown into the interior of the ICM 80. In addition, support structures, such as acrylic rods, can be used as internal spacers to help hold the internal components in place.

[0069] In one embodiment, the central body 81 and the "guard electrode" 82 can be micro-bead blasted to increase the roughness of the central body 81 for improved silicone or parylene bonding and to increase the surface area of ​​the "guard electrode" 82 for better signal quality, respectively. A titanium nitride coating can also be applied to significantly increase the surface area of ​​the device.

[0070] The conductive surface 88 is formed by partially insulating the outer surface of the central body 81 using a non-conductive insulating surface treatment or coating ("insulating coating") 89. The insulating coating 89 is typically applied to the outer surface closest to the "guard electrode" 82, which maximizes the electrode dipole spacing. In one embodiment, the insulating coating 89 can be a chemical vapor deposited polymer, such as polyparaxylene C. In another embodiment, the insulating coating 89 can be a silicone polymer-based (polysiloxane) coating. Alternatively, two forms of coatings can be used, namely a polymer and a silicone polymer. Polypolymers exhibit excellent moisture resistance and insulation, but are susceptible to damage due to scratches and abrasions. The silicone polymer coating forms a durable protective layer and, when applied to a polymer coating (such as polyparaxylene C), can protect the underlying coating from scratches and abrasions when inserting, repositioning or removing the ICM 80.

[0071] The end 22 of the center body 81 closest to the conductive surface 88 interfaces with the "radar dome" 83. In one embodiment, the high frequency antenna is a discrete component contained within the "radar dome" 83. The high frequency antenna can be held in place by filling the cavity of the "radar dome" 83 with a filler material (such as acrylic, urethane, glass or similar material), and the high frequency antenna interfaces to the flexible circuit board via electrical contacts 20, which can be soldered or bonded to the high frequency antenna. In another embodiment, the high frequency antenna is formed on a foldable "ear" portion of the flexible circuit board and is routed into the "radar dome" 83 assembly.

[0072] In one embodiment, when configured to measure the signal of an electrocardiogram, the "guard electrode" 82 and the exposed conductive surface 88 of the central body 81 act as an electrode dipole. Other forms of electrode dipoles are also possible. The end cap 84 of the "guard electrode" 82 forms one electrode. The exposed conductive surface 88 of the central body 81 at the distal end of the "guard electrode" 82 forms another distal electrode 90. The metal housing of the power supply provides an electrical feed-through from the "guard electrode" 82 to the flexible circuit board, thereby simplifying the structure.

[0073] In another embodiment, a third electrode 91 is disposed on the ICM 80 as an additional exposed conductive surface on the central body 81. The third electrode 91 allows for the configuration of additional electrode dipole pairs, including pairs comprising a "guard electrode" 82 and a distal electrode 90, a "guard electrode d" 82 and a third electrode 91, and a distal electrode 90 and a third electrode 91. Multiple electrode dipoles improve the ability of the ICM 80 to distinguish the propagation of low-amplitude, relatively low-frequency content cardiac action potentials, particularly the P-wave produced during atrial and ventricular activation and atrial and ventricular repolarization. In yet other embodiments, the ICM 80 may have more than three electrodes.

[0074] Informally, the non-conductive hemispherical end caps form a "radar dome" (radar dome) 83, which serves as a housing for a high-frequency antenna for RF data exchange. A high-frequency antenna for data exchange is housed within the "radar dome" 83. Note that more than one high-frequency antenna may be included. The "radar dome" 83 is a component that includes an electrically insulating hemispherical body 87 formed of a medical implant-safe grade material (such as acrylic, glass, crimson crystal, or ceramic), and a metal weld ring formed of medical-grade titanium or a similar medical implant-safe metal. These parts are joined together using press fit, brazing, laser welding, or electron beam welding. In another embodiment, the high-frequency antenna is defined as a portion of a flexible circuit board or folded metal shape, fold line, or other similar structure.

[0075] Informally, the conductive hemispherical end cap forms a "guard electrode" (feeder electrode) 82, which serves the dual purpose of serving as an electrode and for housing patient protection components and device protection components. The "guard electrode" 82 is an assembly that includes a conductive hemispherical body 84 formed of medical grade titanium or similar medical implant safe conductor, an insulating ring 85 formed of a medical implant safe grade material such as acrylic, glass, crimson crystal or ceramic, and a metal welding ring 86 that may include a chamfered edge to facilitate welding to a center body 81 formed of medical grade titanium or similar medical implant safe metal. These parts are joined together by shrink fit, crimping, brazing, epoxy adhesive, silicone adhesive or other similar bonding agent.

[0076] In certain circumstances, the proximity of the high frequency antenna to the conductive surface 88 exposed on the outer surface of the tubular body 81 may create a risk of degradation of the ECG signal. Figure 6is an external perspective view showing an ICM 100 for maintaining potassium homeostasis according to another embodiment. Electrode 101 formed as part of the "guard electrode" segment of the ICM 100 and electrode 102 formed on the outer surface of the tubular body 81 are formed with scalloped cuts on their respective inwardly facing aspects. The electrode configuration minimizes potential parasitic coupling of electrodes 101 and 102 with a ground strap for a high frequency antenna loop. In addition, the shape of electrode 101 of the "guard electrode" improves the performance and durability of the ceramic-titanium weld joint that connects the "guard electrode" 84 to the tubular body 81 when used.

[0077] Microarchitecture

[0078] The operation of ICM 80, including data capture, analysis and communications, is controlled by a programmable microcontroller. Figure 7 It shows Figure 5 80. The microcontroller is remotely interfaced via a wireless radio frequency (RF) data communications link using a high frequency antenna housed within a "guard electrode" 84, which enables the ICM 80 to provide continuous beat-to-beat heart monitoring and to be remotely reconfigured or reprogrammed to utilize one or more physiological sensors.

[0079] In one embodiment, a low power, high efficiency microcontroller 111 may be used, such as a microcontroller from the RL78 series of microcontrollers provided by Renesas Electronics Corporation of Tokyo, Japan. Architecturally, the microcontroller is built around a Harvard architecture that physically separates the signal paths and storage paths used for instructions and data storage. The microcontroller runs under a dedicated microprogram that is stored as firmware (rather than a general purpose operating system) as microcode in a non-volatile storage device, which helps in efficient operation and extended power life, but in another embodiment, an operating system including a real-time operating system may be used. Note that memory is placed both on and off the microcontroller, and program instructions are expected to be stored in the microcontroller's flash memory. The use of programmable firmware means that the ICM 80 is not dependent on on-board algorithms and can be field upgraded with enhanced functionality.

[0080] Microcontroller 111 interfaces with both integrated and off-chip components that provide continuous and scalable monitoring capabilities for ICM 80. Voltage regulation / charge control circuitry 118 interfaces with low frequency resonant charging antenna 117 and microcontroller 111, which together regulate and control charging of power source 119. Integrated Bluetooth system-on-chip (SoC) transceiver circuitry 112 similarly interfaces with high frequency antenna 34 and microcontroller 111 to provide data communications capabilities to ICM 80. Electrode dipoles are formed by electrodes 115 and 116 that interface with analog front end (AFE) 114 and microcontroller 111 to enable monitoring of electrocardiogram tracings. In one embodiment, temperature, actigraphy, and motion sensing are provided by temperature sensor 120, Hall effect switch 121, and accelerometer 122, respectively. Finally, the monitoring data including the continuous ECG data awaiting downloading is stored in the mass storage 123 in the form of random access memory or other volatile or non-volatile memory components.

[0081] Other possible signs of ICM

[0082] ICM 80 implements a configurable hardware platform based on a reprogrammable microcontroller. ICM 80 is independent of on-board algorithms and can be field upgraded with enhanced functionality. In one embodiment, the microcontroller is programmed with uploadable firmware that is capable of recognizing ECG findings indicative of potential hypokalemia and hyperkalemia in real time, as described above with reference to Figure 4B-Figure 4E As described above, and upon identifying such ECG findings indicative of the onset or presence of specific arrhythmias of hypokalemia and hyperkalemia, the ICM 80 generates an emergency event trigger that is transmitted to the data center for immediate real-time action and patient follow-up, as described below with reference to Fig.10 as further described.

[0083] The microcontroller-based design also provides the flexibility to select signal filtering and processing algorithm options that are appropriate for each patient. This microarchitecture allows for the best patient experience by eliminating designs that take a one-size-fits-all approach and are driven by considerations to accommodate the most difficult cases. The microarchitecture further adapts to changes in patient morphology; modifications to the filtering software can be dynamically selected and updated in the field as configuration updates pushed by the physician from the “cloud” (i.e., a server paradigm that virtualizes server-side functions as widely available services accessed through the Internet or other wide-area data communications networks).

[0084] In another embodiment, the transceiver 112 can be used in conjunction with a microcontroller to communicate with an ingestible sensor, such as that provided by Proteus Digital Health, Inc. (Redwood City, California). An ingestible sensor is a pellet made of biocompatible material that combines remote monitoring microelectronics with a medication or inert material that can be safely taken by the patient. Typically, the ingestible sensor is activated by dissolution or action of gastric fluid on its surface, after which the sensor begins to measure gastrointestinal physiology and, possibly, other types of physiology. Ingestible sensors that can communicate wirelessly, such as via Bluetooth, Medradio, or via WiFi, can be used as real-time functional alternatives to ingestible sensors that store recorded physiological information on-board the device. Such wirelessly enabled ingestible sensors allow for real-time capture of sensory data. In addition, these types of ingestible sensors can be coupled to the ICM 80; therefore, the patient's medication compliance can be monitored by providing accurate, time-related data that can be used to evaluate non-compliance and provide positive reinforcement. The patient's caregiver can be notified in real time about the patient's behavior in complying with the prescribed medication.

[0085] The described platform facilitates monitoring every heartbeat as compared to conventional non-rechargeable platforms which do not have sufficient power to store and transmit every heartbeat. In addition to monitoring every heartbeat, since the heartbeats can be offloaded, the heartbeats can be appropriately analyzed by intelligent algorithms not located in the ICM 80, which allows for better identification of arrhythmias and disease conditions than would otherwise be achieved using the computing resources of the ICM 80 alone, since the complexity of the algorithms is not limited by the processing, memory, storage, power and other resources available to the analysis device.

[0086] The microcontroller can be supplemented with additional physiological sensors, including SpO2 sensors, blood pressure sensors, temperature sensors, respiratory rate sensors, glucose sensors, airflow sensors, and volumetric pressure sensors, as well as non-physiological sensors, including accelerometers and inertial motion sensors. Sensors can be selectively activated over the implant life by the microcontroller 111, either in real time or during reprogramming, to customize patient monitoring for ongoing diagnostic needs. These additional sensors can be effectively used to manage other disease conditions and help doctors solve a range of problems, including: prioritizing kidney transplantation for stage 4 CKD patients with potassium issues, helping to protect stage 3-4 CKD patients, managing hyperkalemia in New York Heart Association (HYHA) stage 3-4 CHF patients who are using inhibitors of the renin-angiotensin-aldosterone system, managing hypokalemia in NYHA 1-4 CHF patients and hypertensive patients (i.e., patients who are using diuretics), and using a thermometer (i.e., temperature monitoring in the ICM, which is provided as a built-in diagnostic tool associated with battery charging) for infectious, neoplastic, and chronic lung diseases, etc.

[0087] Methods used to identify ECG findings

[0088] The ICM 80 continuously monitors the patient's heart rate on a beat-to-beat basis, and in another embodiment, monitors physiological and other non-physiological measurements of the patient, depending on the sensors with which the ICM 80 is equipped. Figure 8 It is shown for Figure 5 Flowchart of method 130 for continuous electrocardiogram monitoring of ICM 80 of FIG. 1. Initially, after successful implantation, microcontroller 111 performs a power-up sequence (step 131). During the power-up sequence, the voltage of power supply 119 is checked, the status of mass storage (flash memory) 123 is confirmed (both in terms of operability check and available capacity), and microcontroller operation is confirmed diagnostically.

[0089] Continuous real-time ECG monitoring

[0090] After the power-up sequence is satisfactorily completed, the microcontroller 111 continuously executes a set of iterative processing loops (steps 132-146). The various processing loops are executed simultaneously. The first processing loop handles continuous real-time monitoring of the ECG signal and, where applicable, also processes other data. During each iteration of this first processing loop, the AFE 114 continuously senses the signal of the electrocardiogram tracing through the electrode dipole created by the sensing electrodes 82, 88 (step 133); in addition, depending on the sampling frequency selected for the specific type of data being sensed, the patient's physiological and non-physiological measurements are sampled at appropriate intervals, where applicable. One or more physiological functions can be sensed at any given time. The type and sampling rate of physiological functions are selectively activated by program control via the microcontroller 111 throughout the life cycle of the ICM 80, which in turn determines the hardware devices used. For example, reading the patient's body temperature once a minute will require activation of the temperature sensor 120. After necessary modifications, a similar method is used to sense non-physiological data, such as position or posture.

[0091] By sampling the AFE 114 and appropriate physiological function sensing hardware, the microcontroller 111 reads samples of the ECG signal and reads physiological function and other data at appropriate intervals (step 134). Any ECG manifestations in the sensed ECG signal forming the ECG trace are identified, which ECG manifestations may indicate the onset or presence of hypokalemia or hyperkalemia (step 135), as described below with reference to Fig. 9 As discussed further herein, identification and evaluation of additional types of medical diagnostic artifacts may also be performed.

[0092] Each of the sampled ECG signals and physiological signals (in quantized and digitized form) is temporarily segmented in a buffer (step 136) in preparation for compression for storage in mass storage 123 (step 137). After compression, the compressed ECG digitized samples are buffered again (step 138) and then written to mass storage 123 using the communication bus (step 139). Processing continues (step 146) and terminates only when the ICM 80 is disabled or runs out of power. Still other operations and steps may be performed.

[0093] Alerts and data downloads

[0094] The second processing loop deals with continuous real-time processing of the ECG signal and, if applicable, other data. The ICM 80 generates alarms and downloads stored monitoring data to a data center or other external device. Whenever any ECG manifestation in the sensed ECG signal is identified that may indicate the onset or presence of hypokalemia or hyperkalemia, the time and type of dialysis are critical to the type of alert to be executed, so the timeliness of the occurrence of the ECG manifestation is evaluated (step 140), as described below with reference to Fig. 9 In addition to or in lieu of the timing and type of dialysis, other considerations may factor into the temporal assessment.

[0095] Based on the evaluation of the severity and timing of hypokalemia or hyperkalemia, if the occurrence is considered urgent (step 141), a doctor and his staff (for clarity and convenience, the pronoun "his" will be used herein, but it should be understood that both genders are treated equally) are notified using, for example, a mobile phone executing a software application, a cellular enabled tablet computer, a network-connected laptop or desktop computer, or other portable or fixed computing device (step 142). The ICM 80 can contact the doctor and his staff directly through wireless communication or indirectly through a data center. In addition, if the occurrence is considered serious (step 143), such as in the case where fatal hyperkalemia has developed, the patient directly participates using, for example, a bedside monitor executing a software application, a mobile phone, a cellular enabled tablet computer, a network-connected laptop or desktop computer, or other portable or fixed computing device. The ICM 80 can contact the patient directly through wireless communication or indirectly through a data center. In extremely serious situations, especially when death due to cardiovascular causes is imminent, emergency medical services can also be used to automatically dispatch medical assistance to the patient.

[0096] Finally, as part of this processing cycle, data is downloaded from the ICM 80 (step 145). To download the stored data from the mass storage, the ICM 80 typically connects to the bedside monitor using Bluetooth or other forms of short-range wireless communication and sends the stored samples from the mass storage 123 to the bedside monitor. Alternatively, the ICM 80 can be connected to a computing device that executes a software application to communicate with the ICM 80, such as a mobile phone, a cellular-enabled tablet, a network-connected laptop or desktop computer, or other portable or fixed computing device, or can be directly connected to the data center itself. In turn, the bedside monitor or other device relays the uploaded ECG and physiological function samples to the data center. After the data download is completed, the ICM 80 may or may not be disconnected from the bedside monitor depending on the ECG results. Processing continues (step 144) and terminates only when the ICM 80 is disabled or runs out of power. Other operations and steps may also be performed.

[0097] ECG manifestation recognition

[0098] As mentioned above Figure 4B-Figure 4E As described above, identifiable ECG changes and specific arrhythmias that indicate the onset or presence of hypokalemia or hyperkalemia are known and can be identified in real time using the ICM 80 . Fig. 9 is a diagram showing a method for identifying a Figure 8 Although described with reference to ECG signals sensed using ICM 80, other types of cutaneous and subcutaneous cardiac and physiological monitoring devices may be used, provided that sufficient signal fidelity is available to distinguish the propagation of low amplitude, relatively low frequency content cardiac action potentials (particularly, the P wave generated during atrial and ventricular activation and atrial and ventricular repolarization).

[0099] At high levels, the ICM 80 can detect high and low serum potassium in real time by:

[0100] 1) Continuous measurement of the QT interval or QTU interval with or without VT in response to hypokalemia.

[0101] 2) Continuously measure the T wave amplitude for hyperkalemia.

[0102] 3) Continuously measure the widening of the QRS interval in response to hyperkalemia.

[0103] 4) Track the above ECG measurements and correlate them with any onset or frequency changes of all arrhythmias, especially VT and bradycardia.

[0104] Other methods are possible in addition to or in lieu of the methods described above.The details of ECG manifestation identification performed by the ICM 80 will now be discussed in detail.

[0105] First, the onset or presence of hypokalemia is evaluated. Hypokalemia, where the potassium level is less than 2.5 mEq / L, is flagged (step 151) based on the ECG characteristics of hypokalemia, including a depressed ST segment 56 and a prolonged QT interval 57 (or QTU interval), possibly with a prominent U wave 58 (step 152). Hypokalemia is often caused by dialysis, diuretics, and CHF medications, and can be alleviated by increasing the alarm by the ICM 80 when the QT interval increases, as well as by the physician changing the dialysate concentration and administering potassium supplements during dialysis.

[0106] Then, the onset or presence of hyperkalemia is evaluated. Note that the order of evaluation for hypokalemia and hyperkalemia is interchangeable. The evaluation begins by considering the onset of hyperkalemia. Hyperkalemia, where potassium is greater than 6.0 mEq / L, is flagged (step 153) based on early ECG features, including a peak T wave 61 with a widened or flattened P wave and a prolonged PR interval (step 154).

[0107] As serum potassium levels rise, ECG manifestations become more pronounced as hyperkalemia progresses from early to moderate severity. ICM 80 detects sustained changes in ECG trace 50 by identifying ongoing ECG changes and the occurrence of specific arrhythmia patterns. As potassium rises, hyperkalemia in which potassium is greater than 7.0 mEq / L is marked (step 155) based on mid-term ECG features, including widened QRS complexes, peak T waves, longer PR intervals, and lower P waves (step 156). These ECG manifestations are associated with specific arrhythmias, including sinus bradycardia, atrioventricular block, slow junctional or ventricular escape rhythms, and slower AF.

[0108] Finally, it is well known that potassium excursions above a narrow range of safe potassium levels can be potentially fatal to ESRD patients within days, hours, or even minutes, depending on high or low potassium levels and any underlying heart disease that is sensitive to such potassium abnormalities. Therefore, the ICM 80 continues to detect progressive hyperkalemia when early or intermediate ECG features have been identified, and hyperkalemia in which potassium is greater than 9.0 mEq / L is flagged (step 157) based on ECG features that indicate impending fatal hyperkalemia, including development of QRS complexes and T waves that resemble a "sinusoidal" wave without a P wave, i.e., a pre-death rhythm. ECG features may include pulseless electrical activity (PEA) with bizarre, wide-complex rhythms. These ECG manifestations are associated with specific arrhythmias, including cardiac arrest, bradyarrhythmic VF, and ultimately patient death.

[0109] Emergency Notification

[0110] The timing of dialysis sessions is related to the recognition of ECG findings that may indicate the onset or presence of hypokalemia or hyperkalemia, which is critical in determining the urgency of medical assistance. Patients with ESRD may develop dangerously low or high potassium levels in a very short period of time. Fig.10 is shown for evaluating the Figure 8 Flow chart of a procedure for the timing of ECG presentation in the method of . The timing of dialysis is factored in to determine the urgency of the intensity of hypokalemia and hyperkalemia, as identified by the ICM 80 via the ECG trace. In addition, the type of dialysis (whether HD or PD) is factored into the form of medical assistance provided, since patients on HD will more often have ready access to a physician and his or her staff during the interdialytic and peridialytic periods, while patients on PD may be at home and may fall asleep during dialysis sessions. In another embodiment, medical devices used to perform HD and PD dialysis are interfaced with a data center, and if appropriately configured for direct wireless communication, are interfaced with the ICM 80 so that data center personnel (and the ICM 80) are aware of the start and stop of dialysis, which will enable notifications to better adapt to the patient's real-time situation (particularly for the interdialytic and peridialytic periods).

[0111] At higher levels, once a preset threshold is crossed, notifications are sent to physicians and their patients via various methods, including phone calls, text messages, emails, or EMS dispatches:

[0112] 1) For hypokalemia, an early alert is generated upon detection of an elevated QT interval (with or without sudden VT).

[0113] 2) For hyperkalemia, an early warning is generated once an increase in T wave amplitude is detected.

[0114] 3) For hyperkalemia, an emergency alert is generated once an increase in QRS interval width is detected.

[0115] 4) For hyperkalemia, upon detection of a significant increase in QRS width (with or without associated heart block and significant bradycardia), an emergency notification is generated.

[0116] 5) For both high and low potassium, an emergency notification is generated upon detection of more than 20 beats or long VT traces exceeding 180 bpm and heart rate pauses exceeding 5 seconds (regardless of the degree of ECG changes).

[0117] Other thresholds are possible in addition to or instead of the thresholds described above.

[0118] Once notified, the physician or healthcare provider may impose interventions that include:

[0119] 1) Directly use potassium supplements for low potassium or potassium absorbers for high potassium.

[0120] 2) Increase or decrease the dialysate concentration or type as indicated by the ECG, for example, increase or decrease the glucose concentration, or switch from glucose to icodextrin.

[0121] 3) Change the dialysate schedule and consider dynamic scheduling based on ECG data.

[0122] 4) Prompt a medical call to a physician or healthcare provider, schedule an ER visit, or dispatch emergency medical services (EMS), as directed by the severity of the ECG data.

[0123] Other interventions are possible.

[0124] The data center securely maintains patient medical information in an electronic medical record (EMR) that serves as a historical and persistent resource for medical diagnosis, prognosis, and treatment. Each EMR can include specific details about the type of dialysis treatment being performed, including the type of dialysate and other medications used or administered, their amounts, concentrations or doses, and timing and frequency. These specific details can be factored into specific recommendations to medical personnel.

[0125] Importantly, the data center and ICM 80 can advantageously utilize the patient's EMR to quickly conduct a historical review of the patient's medical history to identify early events involving hypokalemia or hyperkalemia, arrhythmias, or any other medical problem, and can automatically make a medical diagnosis where applicable, or generate recommendations that can be provided to the physician, his staff, the patient, or his caregiver. As an example, as the patient recovers from HD, his T wave may begin to rise. Knowing that he previously suffered from an increase in T wave amplitude that subsequently became a VT complication has important implications for how the physician will provide care in the current event. This ability to access, process, and factor in the patient's complete medical history (implemented as an EMR), especially those factors related to dialysis treatment and serum potassium homeostasis, can be critical to ensuring appropriate patient care, because external factors, such as the patient being traveling and receiving care at a dialysis center far from home, may deprive the existing medical service provider of necessary information, which may result in a completely different outcome, i.e., a positive solution or bad news for the patient. The details of physician and patient notification will now be discussed in detail.

[0126] Hyperkalemia can develop over a short period of time, usually after dialysis, and has a variety of common causes. Some factors are known to the patient, such as delayed entry into a dialysis session, rescheduling a dialysis session, or experiencing insufficient dialysis due to shortened treatment or complications from fistula entry. Other factors may not be as obvious to the patient, including sudden but aggressive illness or acute health conditions. Such illnesses include infection with COVID-19, influenza, or other infections, even minor ones. Acute health conditions include lower gastrointestinal distress leading to diarrhea. In each of these examples, COVID-19, influenza, and lower gastrointestinal distress can cause the patient to become dehydrated, which can lead to elevated potassium levels.

[0127] Ideally, the patient's physician should be informed of any acute health condition that affects his or her health. Therefore, when possible, patients are usually monitored by a bedside monitor (see below). Fig.11Further described) or a mobile device (such as a cell phone, tablet, etc.). In turn, the bedside monitor or mobile device will connect to the data center and alert the patient's physician of the presence of an acute health condition. In situations where the condition is known to have an impact on potassium levels (such as reports of patients suffering from COVID-19, influenza, and lower gastrointestinal discomfort), the ICM and the data center can automatically take action on the acute health condition (step 171) by increasing the urgency to seek medical assistance (step 172), or the physician or his staff can increase the urgency to seek medical assistance after reviewing the acute medical condition and any relevant factors. If the acute condition occurs with alarming rapidity through the data available through the ICM (including ECG), the urgency to seek medical assistance will also be automatically increased, as a severe onset of diarrhea can quickly dehydrate the patient, increase potassium levels, and cause T-wave amplitudes to rise rapidly.

[0128] During the interdialytic period, patients undergoing dialysis are often medically unattended and are therefore at significant risk of suffering adverse consequences because their hypokalemia or hyperkalemia is often not discovered and resolved. The two-day interval between dialysis courses is extremely critical and sometimes fatal for ESRD patients undergoing dialysis (step 173). In practice, "two days" may be misleading. Generally speaking, the two-day interval is from the end of dialysis treatment on Friday to the start of dialysis treatment on Monday. The amount of time between the start and end of dialysis may actually exceed two days; for example, a patient who completes dialysis at noon on Friday may be scheduled to start dialysis at 6 pm on Monday, which is a 78-hour pause. During a week, a patient may have up to 36 hours between dialysis courses, and the 78-hour pause in this example is more than twice the time he spends between his Monday to Wednesday and Wednesday to Friday dialysis courses, so his serum potassium imbalance may be serious and even fatal. In order to help deal with the serious problems caused by the two-day interval (as described above in reference Figure 2As discussed in detail, the statistically high mortality rate of dialysis patients after a two-day interval is highlighted), and special attention is paid to monitoring potassium levels during the two-day interval. In the event that a low or high serum potassium level is identified during the two-day interval, the urgency of seeking medical assistance (step 174) is increased, which can be achieved by notifying the physician and his staff, especially notifying the patient on HD, and notifying the patient that medical assistance should be sought. In the case of a patient on PD, a partner, such as a spouse or other individual who is usually at home with the patient, can be notified. The severity and rapid onset of hypokalemia or hyperkalemia can highlight the urgency of the notification; if the patient's condition deteriorates rapidly, medical assistance can be dispatched to the patient immediately if necessary. The one-day interval between dialysis treatments is still very critical for ESRD patients undergoing dialysis (step 175), but due to the shorter period of time, the urgency of seeking medical assistance (step 176) may be less, and the urgency of concern may be reduced because if the patient is on HD, he will be under medical supervision the next day.

[0129] Patients undergoing HD may be at the lowest risk during the interdialytic and peridialytic periods due to the presence of trained medical personnel, but HD patients are at risk during longer dialysis intervals. However, patients undergoing PD are always at high risk during these same periods, especially when PD patients undergo dialysis at home while sleeping and may need weeks or even longer before receiving medical attention. Whether the patient is undergoing HD or PD, the ICM 80 continuously monitors the ECG signal and analyzes these ECG findings indicating hypokalemia and hyperkalemia and the accompanying arrhythmias. In another embodiment, if the device used to perform dialysis is equipped with direct wireless communication, and the precise start and stop of dialysis is known and factored into the notification process, the device used to perform dialysis is connected to the data center in a communicative manner, and may also be connected to the ICM 80 in a communicative manner. Otherwise, medical personnel, patients or their caregivers may need to inform the data center (or ICM 80) when to start and end dialysis.

[0130] During the interdialytic period (step 177), the medical staff and possibly the patient are notified of the potassium imbalance, and for patients on HD, the medical staff can address the potassium imbalance by possibly adjusting the dialysate concentration and administering potassium supplements or ongoing dialysis treatment (step 178). In another embodiment, based on stored details maintained in the patient's EMR, the notification can include specific recommendations for changes in dialysate concentration and medication dosages, rather than awaiting intervention by the attending physician or nurse.

[0131] For patients undergoing PD, the patient will be asked to contact his physician or medical care provider for assistance, and if the patient is unable to be away, for example because he is sleeping, the patient's caregiver may be contacted instead. During the peri-dialysis period (or pre-dialysis and recovery period) (step 179), the medical staff or patient is notified of the potassium imbalance and appropriate remedial steps are taken (step 180). Although a blood draw is typically performed before starting a course of HD, serum potassium levels are not typically measured after dialysis, and the benefit of the ICM 80 providing an alert to the medical staff and patient is that it enables them to address the potassium imbalance immediately before the condition worsens. Several other temporal considerations may also be made.

[0132] Patient Workflow

[0133] The ICM 80 facilitates the identification and diagnosis of hypokalemia and hyperkalemia and provides appropriate medical advice or attention when necessary. The ICM 80 works in conjunction with a data center or other cloud-based computing infrastructure to interact with the patient or their caregiver, medical personnel, and EMS when necessary.

[0134] A real-time and proactive approach to diagnosing and addressing serum potassium imbalance begins with providing the patient with an ICM 192, such as the one referenced above. Figure 5 Other forms of ECG monitors (whether implantable or skin-mounted) may also be used, provided sufficient signal fidelity can be obtained. Fig. 9 is a flow chart illustrating a patient workflow 190. Initially, a physician 191 implants an ICM 80 into a patient 11 (step 192). To optimize monitoring of the electrocardiographic tracing of the heart (with emphasis on propagation of low amplitude, relatively low frequency content cardiac action potentials, particularly propagation of P waves produced during atrial and ventricular activation and repolarization of the atrial and ventricular chambers), the ICM 192 is preferably implanted in a subcutaneous site located axially in the parasternal region of the chest and slightly to the left or right of the midline of the sternum. Subcutaneous implantation may be performed as an outpatient procedure, such as in a physician's office, using a specialized implantation instrument that includes a trocar for cutting the skin and forming a subcutaneous tunnel, and a cannula through which the ICM 192 may be guided into position, and then the implantation instrument may be removed and the surgical incision closed. Other implantation sites within the body are possible, depending at least in part on the desired range of physiological functions to be monitored.

[0135] Patient 11 returns home 193 and is equipped with a bedside monitor and an ICM charging station (step 194). Alternatively, in place of a bedside monitor, the ICM 80 can be connected to a computing device that can execute a software application to communicate with the ICM 80, such as a cell phone, a cellular-enabled tablet, a network-connected laptop or desktop computer, or other portable or fixed computing device. For example, in response to the ICM 80 identifying ECG changes indicating the onset or presence of hypokalemia or hyperkalemia and specific arrhythmias, the bedside monitor or other device provides patient 11 with access to immediate care via automatic data transmission and generated alarms. The bedside monitor and charging station also allow the ICM 192 to download stored monitoring data for relay to a data center or other external device and recharge the onboard power supply approximately once a month (step 195). The bedside monitor can also be used to download new programming to the ICM 192. The data center saves the uploaded monitoring data (including continuous ECG and physiological data) to the patient's electronic medical record (EMR). Finally, the patient records the symptoms in a diary using a software application executed by a cell phone or computer, as desired (step 196).

[0136] Physician and staff workflow

[0137] Behind the scenes for Patient 11, the physician and his staff were involved in supporting the workflow to ensure that Patient 11 was able to maintain serum potassium homeostasis. Fig.10 200 is a flowchart showing a doctor 191 and staff workflow 200. Based on the patient's EMR maintained by the data center, the doctor 191 and staff receive notifications of patient events and monthly summary reports on a daily or regular basis (step 201). The notifications and reports are generated by the data center based on the uploaded ECG and physiological function samples sent by the ICM 80, and the patient EMR portal can be expanded to accommodate other medical records, test results, and patient medical history, and the doctor 191 can obtain a simple, long-term review and comparison. Therefore, the doctor 191 can view all ECG and other patient data and navigate to any previous time period through the data (step 202). Typically, the staff will be responsible for departmental tasks related to patient billing and insurance reimbursement. Therefore, the staff issues a bill for the implant surgery to the patient or insurance company (step 203) and a monthly bill for the generated summary report (step 204).

[0138] Real-time and proactive diagnosis and resolution of serum potassium imbalance is provided as a special sub-example of the physician 191 and staff workflow 200. If the ICM 80 triggers the occurrence of an emergency event indicating hyperkalemia or hypokalemia, the physician 191 and staff may receive an emergency notification generated by the data center (step 205). In another embodiment, the data center generates an emergency event indicating hyperkalemia or hypokalemia based on the downlink data received from the ICM 80.

[0139] Receiving an emergency notification can trigger two parallel tasks. First, the physician 191 and staff can establish immediate contact with the patient 11 (step 206) to provide guidance, such as in the case of flagging hypokalemia or hyperkalemia, or to provide remedial measures to be taken, including instructions to report to a hospital, such as in the case of flagging moderate hyperkalemia. Likewise, emergency care assistance can be dispatched directly to the patient 11, such as in the case of flagging severe hyperkalemia, in appropriate circumstances (step 207). Other steps for identifying, diagnosing, and treating hypokalemia and hyperkalemia are also possible, including relaying instructions to the dialysis center or to a bedside monitor or the patient's mobile device, where appropriate.

[0140] Example Case Study

[0141] To illustrate the above-described method of real-time monitoring of a patient's ECG with the aid of an ICM to identify, diagnose, and trigger treatment of hypokalemia and hyperkalemia, a set of illustrative case studies will now be discussed. Figure 13A-13C is a schematic diagram showing, by way of example, patient case studies 210, 220, 230 presented in tabular form with events 211, 221, 231 indicated by the tables, accompanied by patient histories 212, 222, 232 and 31-day summaries 213, 223, 233, and comments reflecting significant morbidities associated with the patient's condition. In each case study, the ICM wirelessly provides a continuous data stream of high-quality ECG signals, combined with alarms when identifiable ECG changes and specific arrhythmias indicative of the onset or presence of hypokalemia or hyperkalemia are detected, and appropriate remedial actions are then taken.

[0142] 63-year-old female patient with dialysis fluid change

[0143] First reference Fig.13A, shows an illustrative case study of a 63-year-old female patient undergoing PD. The patient had not lost enough weight due to water retention (edema). Around mid-month, her physician changed her dialysate to one with higher glucose (214) to increase diuresis or remove water. However, the change in dialysate was too drastic, resulting in excessive potassium removal, which in turn led to significant QT interval prolongation due to hypokalemia. This change was followed by intense, more dangerous episodes of VT.

[0144] The use of the ICM enables changes in her QT interval to be observed on a beat-to-beat basis. In addition, the frequency of her VT episodes may be associated with increases in her QT interval, indicating a subsequent dangerous and potentially fatal trend toward impending cardiac arrest. In this example, when her QT interval prolongs and the frequency of her VT episodes begins to increase, her physician is called based on an alarm generated through the use of the ICM (215). Further, when her heart rate continues to rise above 180 bpm, the EMS is called again based on an alarm generated through the use of the ICM (216).

[0145] A 73-year-old male patient undergoing a change in heart failure (HF) medication

[0146] Next reference Fig. 13B , shows an illustrative case study of a 73-year-old male patient with PD. The patient had heart failure and was taking medication. Around mid-month, his physician changed his heart failure medication, which caused his serum potassium level to rise. As potassium rose, his T wave amplitude increased, followed by a widening of his QRS interval. Shortly after, cardiac arrest developed.

[0147] Note that, contrary to what is observed in hypokalemia, the QT interval also shortens as potassium levels increase. Typically, as potassium levels increase, the P wave increases first, followed by a widening of the QRS interval. These changes are accompanied by sinus bradycardia, with a pause of 5 to 10 seconds. When continuous occurrences of sinus bradycardia are involved and a pause of at least five seconds is detected, the EMS is called (224) based on an alarm generated through the use of the ICM.

[0148] A 63-year-old male patient with mild COVID-19

[0149] Final Reference Fig. 13C , shows an illustrative case study of a 63-year-old male patient on PD. Around mid-month, the patient contracted a mild case of COVID-19, which caused the patient to become dehydrated. In turn, his dehydration led to an increase in potassium levels with typical ECG changes and subsequent arrhythmias as shown in previous case studies of patients with heart failure.

[0150] Note that any cause of dehydration may result in higher potassium levels, including COVID-19, influenza, anorexia, lower gastrointestinal distress, other infections, and fever. When an occurrence of sinus bradycardia is detected, EMS is called (234) based on an alarm generated through use of the ICM.

[0151] Still other examples are possible regarding the efficacy of real-time monitoring of a patient's ECG with the aid of an ICM to identify, diagnose, and trigger hypokalemia and hyperkalemia.

[0152] While the invention has been particularly shown and described with reference to embodiments thereof, it will be understood by those skilled in the art that the foregoing and other changes in form and details may be made therein without departing from the spirit and scope.

Claims

1. A method for maintaining serum potassium homeostasis by subcutaneous monitoring, comprising the following steps: maintaining a set of ECG findings for indicating at least one of the onset and presence of loss of serum potassium homeostasis in a dialysis patient; continuously and subcutaneously monitoring an electrocardiogram (ECG) signal of the patient's heart on a beat-to-beat basis; processing the ECG signal in real time into a set of ECG traces, wherein each ECG trace represents the net electrical activity of the heart at a given moment; evaluating each ECG trace for the set of ECG manifestations; and When at least one of the ECG manifestations is identified in one or more of the ECG traces, an alert of a medical condition is generated.

2. The method according to claim 1, further comprising: The steps include: maintaining an arrhythmia signature for further indicating at least one of the onset and presence of a loss of serum potassium homeostasis in a dialysis patient; evaluating the ECG trace over time for characteristics of the arrhythmia; and A medical condition alert is generated when at least one of the ECG findings is identified in one or more of the ECG traces and at least one of the arrhythmias is identified in the ECG traces over time.

3. The method according to claim 1, further comprising the steps of: For hypokalemia, defining a set of ECG findings that includes at least one of a prolonged QT interval and a prolonged QTU interval and one or more of a depressed ST segment; and The QT interval and the QTU interval in each ECG trace are monitored.

4. The method according to claim 3, further comprising the steps of: For hypokalemia, the definition included the presence of arrhythmic features of ventricular tachycardia; evaluating the ECG trace over time for characteristics of the arrhythmia; and A medical condition alert is generated when at least one of the ECG findings is identified in one or more of the ECG traces and ventricular tachycardia is identified in the ECG traces over time.

5. The method according to claim 1, further comprising the steps of: For early hyperkalemia, a group of ECG findings is defined, which includes the presence of P waves One or more of a broadened or flattened peak T wave and a prolonged PR interval; and The T wave in each ECG trace is monitored.

6. The method according to claim 3, further comprising the steps of: For intermediate hyperkalemia, defining a set of ECG findings that includes one or more of a widened QRS complex, a peaked T wave, a longer PR interval, and a lower P wave; and The QRS interval in each ECG trace was monitored.

7. The method according to claim 6, further comprising the steps of: For fatal hyperkalemia, defining a set of ECG findings that include one or more of a QRS complex that resembles a "sinusoidal" wave and a developmental wave of a T wave; and The QRST interval in each ECG trace was monitored.

8. The method according to claim 7, further comprising the steps of: For the fatal hyperkalemia, a group of ECG manifestations is defined, wherein the group of ECG manifestations includes one or more of pre-death rhythm, pulseless electrical activity PEA and wide complex rhythm; and evaluating the ECG trace over time for the arrhythmia; and A medical condition alert is generated when at least one of the ECG findings is identified in one or more of the ECG traces and one or more of a pre-mortem rhythm, a PEA, and a wide complex rhythm are identified in the ECG traces over time.

9. The method according to claim 7, further comprising the steps of: ECG findings were further defined as those that included a pause greater than 5 seconds; and Upon one or more substantially continuous pauses of greater than 5 seconds occurring in one or more of the ECG traces, EMS is dispatched.

10. The method according to claim 1, further comprising the steps of: receiving an indication of an acute medical condition affecting said patient; and Increases the urgency of the alert.

11. The method of claim 10, wherein the acute medical condition comprises a health condition selected from the group consisting of COVID-19, influenza, anorexia, lower gastrointestinal discomfort, other infections, and fever.

12. The method according to claim 1, further comprising the steps of: maintaining said dialysis schedule; and If the alarm occurs during a two-day interval between the dialysis sessions, the urgency of the alarm is increased.

13. The method according to claim 1, further comprising the steps of: maintaining said dialysis schedule; and If the alarm occurs during an interdialytic period of a dialysis session, one or more of medical personnel, the patient, and the patient's caregiver are immediately notified of a recommendation to adjust the dialysis treatment.

14. The method of claim 1 further comprising the step of communicatively interfacing with a device used to perform the dialysis on the patient.

15. The method according to claim 14, further comprising the steps of: maintaining an electronic medical record for the patient, the electronic medical record for the patient including details regarding the type of dialysis treatment being performed, the type of dialysis fluid being administered and the amount, concentration, frequency, and dosage, other medications being administered and one or more of the amount, concentration, frequency, and dosage; and Based on the type of dialysis treatment being performed and the medical condition behind the alert, adjustments to one or more of the dialysate and other medications are recommended.

16. The method according to claim 1, further comprising the steps of: maintaining said dialysis schedule; and If the alarm occurs during the peri-dialysis period of a dialysis session, one or more of medical personnel, the patient, and the patient's caregiver are immediately notified of a recommendation to seek medical help.

17. An implantable cardiac monitor for maintaining potassium homeostasis, comprising: an implantable housing formed in a cylindrical shape with rounded hemispherical end caps and comprising a biocompatible material suitable for implantation in a living body; at least one pair of ECG sensing electrodes disposed on the ventral surface and on opposite ends of the implantable housing, operably positioned about the end caps to facilitate proximal sensing of low amplitude, low frequency content cardiac action potentials generated during atrial and ventricular activation and atrial and ventricular repolarization; and An electronic circuit disposed within the housing assembly comprises: a low-power microcontroller operable under modular microprogram control; an ECG front-end circuit interfaced with the microcontroller and configured to capture cardiac action potentials sensed by the pair of ECG sensing electrodes as an ECG signal, the ECG signal comprising a set of ECG traces, wherein each ECG trace represents the net electrical activity of the heart at a given moment; firmware configured as part of the microprogram, the microprogram comprising identifying ECG manifestations in one or more of the ECG traces based on a beat-to-beat basis; and a non-volatile memory electrically interfaced with the microcontroller and operable to continuously store samples of the ECG signal, wherein the microcontroller generates an event trigger when the microcontroller identifies at least one of the ECG manifestations in one or more of the ECG traces.

18. The subcutaneously insertable cardiac monitor of claim 17, further comprising: The firmware also includes arrhythmia characteristics identified in the ECG trace over time, Wherein, the microcontroller generates an event trigger when the microcontroller identifies at least one of the ECG manifestations in one or more of the ECG traces and identifies at least one of the arrhythmias in the ECG traces over time.

19. The subcutaneously insertable cardiac monitor of claim 17, further comprising: For hypokalemia, the firmware includes ECG findings including at least one of a prolonged QT interval and a prolonged QTU interval and one or more of a depressed ST segment.

20. The subcutaneously insertable cardiac monitor of claim 17, further comprising: For hypokalemia, the firmware also includes an arrhythmia signature including ventricular tachycardia, Wherein, the microcontroller generates an event trigger when the microcontroller identifies at least one of the ECG manifestations in one or more of the ECG traces and identifies ventricular tachycardia in the ECG traces over time.

21. The subcutaneously insertable cardiac monitor of claim 17, further comprising: For early hyperkalemia, the firmware includes ECG findings including one or more of a peaked T wave with a widened or flattened P wave and a prolonged PR interval.

22. The subcutaneously insertable cardiac monitor of claim 17, further comprising: For moderate hyperkalemia, the firmware includes ECG findings including one or more of a widened QRS complex, a peaked T wave, a longer PR interval, and a lower P wave.

23. The subcutaneously insertable cardiac monitor of claim 17, further comprising: For fatal hyperkalemia, the firmware includes an ECG presentation that includes one or more of a QRS complex similar to a "sinusoidal" wave and a developing wave of a T wave.

24. The subcutaneously insertable cardiac monitor of claim 23, further comprising: For the fatal hyperkalemia, the firmware also includes the following arrhythmia features: It includes one or more of pre-death rhythm, pulseless electrical activity (PEA) and wide-complex rhythm. Wherein, when the microcontroller identifies at least one of the ECG manifestations in one or more of the ECG traces, and identifies one or more of pre-mortem rhythms, PEA and wide-complex rhythms in the ECG traces over time, the microcontroller generates an event trigger.

25. The subcutaneously insertable cardiac monitor of claim 17, further comprising: at least one additional ECG sensing electrode additionally disposed on the ventral surface of the implantable housing assembly, Therein, the firmware includes programmatically selecting one or more pairs of the ECG sensing electrodes.

26. The subcutaneously insertable cardiac monitor of claim 17, wherein: The ECG front-end circuit is optimized to sense P-wave signals and T-wave signals in the cardiac action potential.

27. The subcutaneously insertable cardiac monitor of claim 17, further comprising: An interface is provided, which is suitable for communicatively interfacing the microcontroller with a device for performing dialysis on a patient.

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