by George Taniwaki

Your smartphone is more than an addictive toy. With simple modifications, it can become a lifesaving medical device. The phone can already receive and send data to medical sensors and controllers wirelessly. By adding the right software, a smartphone can do a better job than a more expensive standalone hospital-grade machine.

In addition, smartphones are portable and patients can be trained to use them outside a clinical setting. The spread of smartphones has the potential to revolutionize the treatment of chronic conditions like diabetes. This can enhance the quality of life of the patient and significantly increase survival.

Monitoring blood sugar

Type 1 diabetes mellitus is an autoimmune disease in which the body attacks the pancreas and interrupts the production of insulin. Insulin is a hormone that causes the cells in the body to absorb glucose (a type of sugar) from the blood and metabolize it. Blood sugar must be controlled to a very tight range to stay healthy.

A lack of insulin after meals can lead to persistent and repeated episodes of high blood sugar, called hyperglycemia. This in turn can lead to complications such as damage to nerves, blood vessels, and organs, including the kidneys. Too much insulin can deplete glucose from the blood, a situation called hypoglycemia. This can cause dizziness, seizures, unconsciousness, cardiac arrhythmias, and even brain damage or death.

Back when I was growing up (the 1970s), patients with type 1 diabetes had to prick their finger several times a day to get a blood sample and determine if their glucose level was too low or too high. If it was too low, they had to eat a snack or meal. (But not one containing sugar.)

They would also test themselves about an hour after each meal. Often, their glucose level was too high, and they had to calculate the correct does of insulin to self-inject into their abdomen, arm, or leg to reduce it. If they  were noncompliant (forgetful, busy, unable to afford the medication, fearful or distrustful of medical institutions or personnel, etc.), they would eventually undergo diabetic ketoacidosis, which often would require a hospital stay to treat.

BloodGlucoseTestStrip

Figure 1a. Example of blood glucose test strip. Photo from Mistry Medical

InsulinShot

Figure 1b. Boy demonstrating how to inject insulin in his leg. Photo from Science Photo Library

If all these needle pricks and shots sound painful and tedious, they were and still are. There are better test devices available now and better insulin injectors, but they still rely on a patient being diligent and awake.

Yes, being awake is a problem. It is not realistic to ask a patient to wake up several times a night to monitoring her glucose level and inject herself with insulin. So most patients give themselves an injection just before going to bed and hope they don’t give themselves too much and that it will last all night.

Continuous glucose monitoring

Taking a blood sample seven or eight times a day is a hassle. But even then, it doesn’t provide information about how quickly or how much a patient’s glucose level changes after a meal, after exercise, or while sleeping.

More frequent measurements would be needed to estimate the rate at which a patient’s glucose level would likely rise or fall after a meal, exercise, or sleeping. Knowing the rate would allow the patient to inject insulin before the glucose level was outside the safe range or reduce the background dosage if it is too high.

In the 1980s, the first continuous glucose meters were developed to help estimate the correct background dosage of insulin and the correct additional amounts to inject after snacks and meals.

The early devices  were bulky and hard to use. They consisted of a sensor that was inserted under the skin (usually in the abdomen) during a doctor visit and had wires that connected it to a monitoring device that the patient carried around her waist. The sensor reported the glucose level every five to ten seconds and the monitor had enough memory to store the average reading every five to ten minutes over the course of a week.

The devices were not very accurate and had to be calibrated using the blood prick method several times a day. The patient would also have to keep a paper diary of the times of meals, medication, snacks, exercise, and sleep. After a week, the patient would return to the doctor to have the sensor removed.

The doctor would then have to interpret the results and calculate an estimated required background dose of insulin during the day and during the night and the correct amount of additional injections after snacks and meals. The patient would repeat the process every year or so to ensure the insulin dosages were keeping the glucose levels within the desired range.

Today, continuous glucose monitors can measure glucose levels using a disposable sensor patch on the skin that will stay in place for a week. It transmits data to the monitor wirelessly. Using a keypad, the monitor can also record eating, medication, exercise, and sleeping. The monitor can store months of personal data and calculate the amount of insulin needed in real-time. Alerts remind the patient when to inject insulin and how much. They are cheap enough and portable enough that the patient never stops wearing it.

ContinuousGlucoseMonitor

Figure 2. Wireless continuous blood glucose monitor and display device. Image from Diabetes Healthy Solutions

Continuous insulin pump

Also in the 1980s, the first generation of subcutaneous insulin pumps were commercialized. These pumps could supply a low background dose of insulin rather than big spikes provided by manual injections. The first pumps were expensive, bulky, hard to use. By the early 2000s though, insulin pumps became widely available and were shown to reliably reduce the fluctuations in glucose levels seen in patients who relied on manual injections. By providing a low dose of insulin continuously during the day and at night with the ability of the patient to manually apply larger doses after meals, it lowered the average level of glucose while also reducing the incidence of hypoglycemia. Over longer periods it also reduced the incidence of complications commonly seen with diabetes.

InsulinPumpEarlyinsulinpump

Figure 3a and 3b. Early insulin pump (left) and modern version (right). Images from Medtronic

There is one drawback to the continuous insulin pump. It can provide too much insulin at night while the patient is asleep. While sleeping, the patient’s glucose level falls. Since she is not performing blood tests, she will not notice that the insulin pump is set too high. Further, since she is asleep she may not realize that she is in danger, a condition called nocturnal hypoglycemia.

Software to control the pump

Imagine combining the continuous glucose meter with the continuous insulin pump. Now you have a system the mimics the behavior of the human pancreas. Sensors constantly monitor the patient’s glucose level, and anticipate changes caused by activities like eating, sleeping, and exercise.

The key is to use a well-written algorithm to predict the amount of insulin needed to be injected by the pump to keep sugar levels within the acceptable range. Instead of a human, software controls the insulin pump. If the glucose level does not stay within the desired levels, the algorithm learns its mistake and corrects it.

The initial goal of the combined monitor and pump was to predict low glucose levels while a patient was sleeping and suspend the pumping of insulin to prevent nocturnal hypoglycemia. Ironically, the US FDA panel rejected the first application submitted for the device saying that the traditional uncontrolled continuous insulin pump was actually safer than a new device because of the new device’s lack of field experience.

After years of additional studies the combined device, manufactured by Medtronic, was approved for use in the US in 2013. Results of a study involving 25 patients in the UK was published in Lancet Jun 2014. Another trial, involving 95 patients in Australia was published in J. Amer. Med. Assoc. Sept 2013.

CombinedGlucoseMonitorInsulinPump

Figure 4. Combined glucose meter and insulin pump form a bionic pancreas. Image from Medtronic

Better software and smartphones

The Medtronic combined device is proprietary. But several groups are hacking it to make improvements. For instance, researchers led by Z. Mahmoudi and M. Jensen at Aalborg University in Denmark have published several papers (Diabetes Techn Ther Jun 2014Diabetes Sci Techn Apr 2014, Diabetes Techn Ther Oct 2013) on control algorithms that may be superior to the one currently used in the Medtronic device.

Another interesting paper appeared in the New Engl J Med Jun 2014. It reports a study by Dr. Steven Russell of Massachusetts General Hospital and his colleagues. They wrote an app for a smartphone (Apple’s iPhone 4S) that could receive the wireless data from the Medtronic glucose meter and wirelessly control the Medtronic insulin pump.

Smartphones are ideal platforms for use in developing medical devices because they can communicate wirelessly with other devices, have sufficient computing power and memory for even the most complex control tasks, are designed to be easy to program and easy to use, and many people already own one.

Dr. Russell and his colleagues used a machine learning algorithm they had previously developed (J Clin Endocrinol Metab May 2014) to couple the two.

Even though this is a research project, not a commercial product, the results are pretty impressive. The study lasted 5 days, with the first day used to calibrate the algorithm and days 2-5 as the test.

As can be seen in Figure 5, after a day of “training” patients using the bionic pancreas (solid black line) had lower average glucose levels than patients on the standard protocol (solid red line). Further, the variance of their glucose level (black shaded area) was smaller than for patients on the standard protocol (red shaded area). Notice how much better the control is using the bionic pancreas, especially at night.

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Figure 5. Variation in mean glucose level among adults during 5-day study. Image from New Engl J Med

Another measure of quality is the amount of time the patients’ glucose levels were within the desired level of 70 to 120 mg/dl (the green shaded region in Figure 6). Patients with the bionic pancreas (solid black line) spent about 55% of the time within the desired level. They also had fewer incidents of hypoglycemia (pink shaded region) or hyperglycemia (white region on right) than patients using the standard protocol (red line).

Note that even with the bionic pancreas, 15% of the time patients had a glucose level above 180, so there is still plenty of room to improve control.

InsulinNEJM

Figure 6. Cumulative glucose level in adults during day 1 where the bionic pancreas adapted to the patient (dashed line) and days 2-5 (solid black). Image from New Engl J Med

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