Checklist to Manage Hyperglycemia, DKA in Severe COVID-19

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With evidence mounting that hyperglycemia and diabetic ketoacidosis (DKA) are contributing to morbidity and mortality in COVID-19 — including among people without a prior diabetes diagnosis — experts are scrambling to share best practices for managing often-extreme glucose dysregulation in patients hospitalized with COVID-19.

The phenomenon has been documented thus far in several published articles and numerous anecdotal reports.

In one study, just reported by Medscape Medical News, persistent hyperglycemia (≥ 180 mg/dL) was associated with a fourfold greater risk for mortality in patients with COVID-19, rising to sevenfold among those without a pre-existing diabetes diagnosis.

And in an earlier pre-print report, investigators from Wuhan, China, found that fasting blood glucose independently predicted multiorgan injury, poor outcomes, and death among patients with COVID-19.

The American Diabetes Association has been posting a series of online webinars with experts discussing COVID-19 and diabetes-related topics, including three thus far specifically addressing aspects of inpatient glycemic management.

And "front-door" guidance, which is subject to revision, has been published online by Diabetes UK.

For its part, the US Food and Drug Administration (FDA) has issued guidance permitting home-use blood glucose meters in the hospital setting among patients with COVID-19.

The agency has also allowed two continuous glucose monitoring (CGM) devices — the Dexcom G6 and Abbott FreeStyle Libre — to be used in hospital during the pandemic, despite neither being officially approved for hospital use. Both CGM companies are also donating some of their supplies to hospitals on request and offering others at reduced prices.

Meanwhile, clinicians on the front lines have told Medscape Medical News that they're seeing extreme levels of insulin resistance, hyperglycemia, and DKA — both hyperglycemic and euglycemic — in COVID-19 patients with type 1 and type 2 diabetes, and far more than the usual numbers of new-onset cases of both types of diabetes.

And, as the Diabetes UK document notes, COVID-19 "precipitates atypical presentations of diabetes emergencies (eg, mixed DKA and hyperosmolar states)."

Shivani Agarwal, MD, director of the Supporting Emerging Adults with Diabetes Program at Albert Einstein College of Medicine, Bronx, New York City, participated in an ADA town hall on inpatient care of people with COVID-19 and diabetes that was posted online April 7.

Speaking with Medscape Medical News this week, she said: "At the time [of the town hall], I'd seen a lot of new-onset [diabetes], but not as much as I've seen now."

"In the Bronx, we have a large population of ketosis-prone type 2 diabetes. We're seeing a huge DKA spike with type 1 and type 2, in about equal amounts. It's really remarkable," Agarwal noted.

She said it's possible that the virus could be directly attacking the islets, which had been reported in the 2003 outbreak of severe acute respiratory syndrome (SARS).

Another theory, she said, is that "the cytokine storm associated with COVID-19 is just overwhelming the system in a way that other infections don't."

Given the rapidly evolving situation, what follows are some of the topics that experts have been grappling with, and some tentative current areas of consensus.

Before Hospital Admission

Physicians agree that if patients with diabetes are heading to the hospital with suspected COVID-19, they should bring everything they can — all the equipment they currently use, including glucose meters, test strips, and CGM, and insulin pump supplies.

And to keep things simple, this includes insulin, particularly if the patient is taking a type not typically available on hospital formularies, such as insulin degludec (Tresiba, Novo Nordisk) or faster insulin aspart (Fiasp, Novo Nordisk), said Irl Hirsch, MD, professor and diabetes treatment and teaching chair at the University of Washington, Seattle.

At his institution, "If the patient doesn't have to go on intravenous insulin and they bring their insulin with them, we keep them on it so we don't have to do any transitioning," he told Medscape Medical News.

"The big one is degludec — transitioning from that to glargine [Lantus, Sanofi] or detemir [Levemir, Novo Nordisk] is really ugly," he explained.

Stopping Meds, Particularly SGLT2 Inhibitors

Both Hirsch and Agarwal said they generally agree with much of the guidance outlined in the Diabetes UK "front door" algorithm.

One particular area of consensus is that sodium-glucose cotransporter 2 (SGLT2) inhibitors should be stopped in ALL patients admitted to hospital with COVID-19, due to the increased risk for euglycemic DKA with those agents.

There is also some agreement that other noninsulin glucose-lowering medications be stopped as well.

"I think there's just too much variation in their renal function, they're all getting imaging, I think it's too much of a risk with any of those," said Agarwal.

She noted there are now studies of dipeptidyl peptidase 4 (DPP-4) inhibitors in people with type 2 diabetes to see if they can help with diabetes control and reduce the severity of the COVID-19 infection.

"[This] could work, but honestly these patients are so insulin resistant when they come in, I don't think DPP-4 inhibitors would touch them. Insulin is literally the only option, and in very high doses," she said.

Don't Overlook Admission Glucose Testing

According to the UK guidance, blood glucose levels should be checked in ALL individuals admitted for COVID-19, ketones checked in anyone with an admission glucose level above 12 mmol/L (or 200 mg/dL), and pH and bicarbonate measured if the ketone level is 3 mmol/L or greater.

Although blood glucose is usually included in routine metabolic panels on admission in US hospitals, the results may be overlooked in people who don't already have a diabetes diagnosis, Hirsch noted.

"Everybody will get a glucose test. The question is, at what glucose do you do routine point-of-care monitoring in a person without known diabetes? At the very least, if someone who was otherwise well comes in with a random blood glucose of 180-230 mg/dL, they should run an [A1c test] on that person," he said.

"I see this all the time — they go into the hospital for a different reason and have a random glucose of 300 mg/dL, but in many hospitals they only do routine point-of-care glucose testing if they come in with a diagnosis of diabetes," he added.

"That's a huge problem...What we don't know in this virus situation is how important inpatient glucose control is in reducing the morbidity and mortality of this infection."

Moreover, as Diabetes UK notes, shortness of breath is a COVID-19 symptom but also may be due to metabolic acidosis, as with DKA.

Therefore, they advise, "Ensure ALL newly admitted patients are evaluated for diabetes."

And, importantly: "NEVER stop basal insulin in persons with known type 1 diabetes or DKA may result."

Ways to Improve Inpatient Glycemic Monitoring

The loosening of regulations by the FDA on inpatient use of meters and CGMs may help a great deal in reducing the amount of time nurses need to spend in the patient's room, and the associated use of personal protective equipment (PPE), in situations where patients are able to perform glucose monitoring themselves and report the results to the nurses.

If the patient is using their own device from home, the nurse will need to manually enter the data into the patient's electronic health record.

At Agarwal's hospital, for some noncritical patients who are sleeping or otherwise unable to summon the nurse, the Dexcom G6 receiver has been taped to their door so the nurses can see the patient's blood glucose levels and hear any alarms of high or low levels.

"We put the patient close to the nursing station, turn the volume up, and train the RNs. The RNs were so excited. They understood the system...We obviously have to do it safely and train the right people, but there are ways to do this," she explained.

Of course, there are plenty of caveats. CGMs aren't advised for critical care settings where medications could interfere with their accuracy, and even on the floors, their accuracy should be verified with confirmatory fingersticks, at least for the first 24 hours after new sensor insertion.

Because the Libre requires manual scanning and does not have high and low alarms, Agarwal said that in her opinion, "the ideal situation for Libre…would be mild to moderate illness on the floor," whereas the Dexcom G6, with its alarms and share function, could be used in a broader range of patients.

Hirsch commented during one of the ADA webinars: "In my mind, that's a wonderful way to minimize nurses going into the room...having the ability to monitor the glucose, and having an alarm go off if it's critical on the high or low side...why did we have to wait for this crisis to have this? The added patient safety with this is just incredible."

Importantly, in the event of any magnetic imaging, all diabetes devices must be removed.

Intravenous vs Subcutaneous Insulin

It's becoming apparent that patients with COVID-19 and diabetes — and some without pre-existing diabetes — often require huge doses of insulin.

The UK guidance says, "IV insulin protocols may need amending (people seen requiring up to 20 units/hr)."

It's not clear why.

In many hospitals, use of intravenous insulin is difficult, in part because the equipment has been prioritized for other uses in patients with COVID-19.

Moreover, Agarwal said, "Insulin drips are a very efficient way to reduce inpatient hyperglycemia, but now with the limitations on PPE and the nursing ratios, it's getting harder for the nurses to manage insulin drips. It is something that really has to be weighed."

At her institution, they've been able to keep up with insulin drips, at least in the ICU, with fingersticks every 3 hours instead of the usual 1-2 hours. They've also been keeping patients on some subcutaneous basal insulin while on the drip, "because it allows you to wean them off the drip faster."

While IV insulin is usually preferred for patients with DKA, they have developed subcutaneous protocols, although "all the pre-existing ones require fingersticks every 2 hours," Agarwal said.

"That's just not going to happen. Ours is every 4 hours, and we advise patients [who are able] to check in-between."

Of course, the picture is quite different for patients who are critically ill, intubated, on tube feeds, with acute kidney injury, and on high-dose steroids.

As Agarwal said, "This is almost every patient we see in the ICU right now. It's very complicated. We want to minimize contact and use of PPE. We're not using insulin drips as much, and we're trying to use NPH and Regular [insulin] to match the pharmacokinetics of the steroids."

The Fluid Management Conundrum in DKA

Fluid management in critically ill patients with COVID-19 and DKA presents a dilemma: most have acute kidney injury, resulting in fluid overload.

The critical care medicine response is to withhold fluids to avoid cardiopulmonary compromise but this is the exact opposite of what's needed to treat DKA.

Agarwal says that the DKA is the priority.

"My personal feeling is people will die from DKA before they die from cardiopulmonary compromise. If they're very dehydrated, you can't even get the insulin to circulate. They need a certain amount of fluid to just get past the ketosis-forming stage," she explained.

"So I think in those cases it's extremely important to give fluids up front. Maybe you can dose reduce them later but I don't think you can do that as much as you would for other COVID-19 patients."

And, she added, there's yet another concern in this patient group and another good reason to use CGM if at all possible: "Our experience is that these patients are glucotoxic in the beginning, but as soon as you catch up, all of a sudden you have horrible hypoglycemia."

Overall, she said, the situation of severe COVID-19 in people with dysglycemia is "very tough…we really need data to guide us, and we just don't have it yet."

Agarwal has reported no relevant financial relationships. Hirsch has reported consulting for Abbott Diabetes Care, Roche, and Bigfoot Biomedical, conducting research for Medtronic, and is a diabetes editor on for UpToDate.

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