Thank you for the introduction, and thank you for being here today. I have nothing to disclose, and by the end of this talk, hopefully, you'll be able to recognize causes and risk factors associated with the development of euglacemic ketoacidosis and understanding design and management of euglacemic ketoacidosis. So diabetic ketoacidosis, or DKA, is a pretty well-established complication of a well-known complication of type 1 and type 2 diabetes defined by a clinical triad of hyperglycemia, metabolic acidosis, and ketosis. Hyperglycemia typically is the hallmark presentation of DKA, but in some patient population, the serum glucose levels are actually going to be normal despite the associated metabolic acidosis and ketosis, and that condition is deemed euglacemic ketoacidosis. Current American Diabetes Association guidelines define euglacemic ketoacidosis as blood glucose of less than 250 in presence of metabolic acidosis and ketosis. Euglacemic ketoacidosis was first described in 1973 when monitoring colleagues reported 37 cases of young adults with insulin-dependent diabetes presenting with DKA, but a blood glucose of less than 300, and 16 cases of blood glucose less than 200. All of those patients reported having vomiting and reduced carbohydrate intake in the preceding days. To this date, the true incidence of euglacemic ketoacidosis is unknown, largely due to varying definitions of the blood glucose cutoffs in the reported literature, as well as increasing use of medications that contribute to euglacemia and a high rate of misdiagnosis. The pathogenesis of diabetic ketoacidosis is pretty well established and is a result of absolute or relative insulin deficiency associated with increase in carter regulatory hormones, such as glucagon, cortisol, catecholamines, leading to increase in hepatic gluconeogenesis, accelerated glycogenolysis, and impaired use of glucose by the peripheral tissues, leading to lipolysis and increased mobilization of free fatty acids from the adipose tissue, resulting in ketone body formation, such as beta-hydroxybutyrate and acetoacetate, all leading to the well-known condition, which is the DKA. There are several predisposing factors that contribute to DKA that are listed on this slide, but ultimately, any condition that increases carter regulatory hormones paired with insulin deficiency will result in DKA. The underlying pathophysiology of euglacemic ketoacidosis has to do with reduced serum glucose availability, and that could be either due to reduced hepatic production, decreased caloric intake, or enhanced renal excretion of glucose, leading to, again, insulin deficiency, which then sets off the ketogenesis, increase in carter regulatory hormones, such as glucagon, which then further enhances renal excretion of glucose, leading to euglacemic ketoacidosis. There are many different conditions that have been described in the literature that trigger euglacemic ketoacidosis. Some of them are listed here, but the two that we'll focus on today are the use of sodium glucose transporter-2 inhibitors and CRRT, or continuous renal replacement therapy. Starting with the SGLT2 inhibitors, there are five SGLT2 inhibitors currently available on the market that are FDA-approved for management of type 2 diabetes, and also protective effects in patients with heart failure and carotid and kidney disease, with or without diabetes. It's also used as an adjunct for type 1 diabetic patients, although that is an off-label use. More recently, in May of 2023, a first SGLT1-2 inhibitor has been approved for management of type 2 diabetes as well. SGLT2 co-transporter basically inhibits or is responsible for reabsorption of nearly 90% of filtered glucose in the proximal convoluted tubule. So inhibiting this transporter will greatly enhance the renal excretion of glucose. And that's the mechanism behind correcting blood glucose with these agents. For the SGLT1 and 2 inhibitors, in addition to renal excretion of glucose, they also inhibit SGLT1 in the gut, and therefore decreasing absorption of glucose in the small intestine. There are several benefits of SGLT2 inhibitors that have been well-documented in the literature and the studies. In addition to decreasing A1c and blood glucose in general, they contribute to healthy weight loss, lowering blood pressure, lower requirements for insulin, lower risk of hypoglycemia, and favorable protective cardiovascular effects. There have also been a number of safety concerns associated with these agents that are listed here, and the one that we'll discuss is the DKA, or mucosemic ketoacidosis. So SGLT2 inhibitors will contribute to the reduced serum glucose availability, basically due to enhanced renal excretion of glucose. And because of that, many patients will end up reducing their insulin use as well, leading to the same pathogenesis we already described or discussed for the ketoacidosis. SGLT2 inhibitors also increase glucagon production, which can enhance further urinary glucose loss. About two years after the first drug was approved, the first SGLT2 inhibitor was approved, FDA published a warning saying that SGLT2 inhibitors can cause DKA and eudeka in patients with type 1 and type 2 diabetes, and that was based on a case report, a few case reports that were published. The analysis of the FDA adverse event reporting system reported 51 cases with a potentially seven-fold increase in risk of DKA, and 71 percent of those cases were deemed euglycemic, with a mean time to onset of about 43 days. With the popularity of these agents currently, the number of these case reports are increasing and will continue to increase since we, again, these drugs are being used quite widely. But overall incidence so far is still unknown, and reported to be pretty low, about 0.1 to 0.8 percent, which might be higher with type 1 diabetics compared to type 2. The data from these case reports is also supported by the data from the large randomized controlled landmark trials that these agents were studied in, and looking at the type 2 diabetic data showed almost over a two-fold increase in incidence of DKA compared to placebo, and with type 1 diabetics, nearly a three-and-a-half-fold increase in incidence of DKA. But again, the overall event rate seems to be pretty low, of less than one event per 1,000 patient years. And now that these agents are being used in patients who are not diabetic, and just as a cardio and renal protective agent, there have been already two case reports published recently of patients without diabetes experiencing euglycemic DKA and having challenges with management due to fluid load and such. So something to keep in mind that these patients do not have to have diabetes to experience euglycemic DKA. One of the most common presenting symptoms of euglycemic DKA has been reported to be nausea and vomiting associated with abdominal pain, polyuria, polydipsia, and severe mental status changes are not as common with euglycemic DKA as it is with DKA. So any time patients present with GI symptoms and they are taking SGLT2 inhibitors, there should be a very high suspicion for DKA, euglycemic DKA, especially if the glucose is low. Some of the risk factors that have been reported as well for patients who are taking SGLT2 inhibitors listed here, among the high risk factors, again, is going to be decrease in insulin intake, decrease in carbohydrate intake. Any surgical or medical procedures that the patients are scheduled for, those patients are going to be very high risk for developing euglycemic DKA if they're continuing to take SGLT2 inhibitors. Vomiting, dehydration, and overall caloric decrease in caloric intake is going to be the highest contributors. Moving on to CRT as a potential cause of euglycemic ketoacidosis, CRT has become a pretty popular modality in the ICU for solute and toxin clearance and volume removal. There are several different modalities for CRT, with the most common one utilized, at least at our institution, being continuous vena-venous hemodial filtration, which utilizes both diffusion and convection, as well as ultrafiltration, using a semi-permeable membrane that effectively removes low and moderate size solutes and molecular size solutes, including glucose and various amino acids. There are several commercially valuable replacement fluids that are utilized during CRT to replace electrolytes and volume, but commonly what's utilized is a phosphate-containing CRT solution to mitigate the need to continue to replete phosphorus in these patients. However, that fluid does not contain any glucose and can significantly impact the net glucose loss in these patients who are also potentially probably being underfed or not fed due to hemodynamic instability. So it has been reported that patients who are receiving CRT with a glucose-free solution can lose up to 160 grams of glucose per day, which translates into over 600 calories per day. And as far as protein losses, on top of the CRT removing amino acids, critically ill patients, as you know, are in a protein calorie deficit and malnutrition due to critical illness and also underfeeding. So it's been reported that patients in the ICU can lose up to 17 grams of protein per day and have total nitrogen losses up to 25 grams. So all that will contribute to overall serum glucose levels being reduced. And then, again, coupling with hypo-insulinemia and insulin resistance, increasing counter-regulatory hormones leading to euglacemic ketoacidosis. There are very little published literature on CRT as a trigger for euglacemic ketoacidosis. In this prospective analysis of about 120 patients receiving CRT with glucose-free containing solution demonstrated that 15% of their patients developed euglacemic ketoacidosis during CRT therapy. Only half of those patients had diabetes or were diabetic. None of their patients were receiving enteral nutrition. And the average time to ketoacidosis identification was about 43 hours. In this slide, it shows that administration of glucose or enteral nutrition and insulin successfully resolved ketosis in these patients. And that brings us to the next section is management of euglacemic ketoacidosis. The diagnosis of euglacemic ketoacidosis is probably one of the most important factors just because most of the times it's delayed. There's not a marked increase in hyperglycemia or glucose. And there are so many different causes for why patients may be having metabolic acidosis, especially if they're critically ill. So obtaining a detailed history, especially medication use, off-label medication use, illicit medication use, as well as metabolic panels specifically looking for beta-hydroxybutyrate would be very important in order to differentiate the diagnosis of euglacemic DKA. As far as management, once the diagnosis is established, the management is quite simple and straightforward. Similar to DKA, first step is to restore fluid with balanced crystalloids. And it's imperative to go ahead and initiate IV insulin and concurrent IV dextrose administration in these patients as soon as possible, despite the normal glycemia or potentially even low blood glucose levels. So dextrose is used to increase the serum glucose levels in order to be able to administer insulin. But even though listed here as the last step, probably should be considered as an initial intervention is management of underlying etiology is trying to figure out why this patient is experiencing euglacemic ketosis and dealing with that, either whether it's nutrition or holding HGLT2 therapy. As far as holding the HGLT2 inhibitors, any patient, again, who is taking these agents and experiencing nausea and vomiting or any GI illness should be instructed to hold the medication. Any time patient are hospitalized due to acute illness and ordered NPO status, these agents should be held. If patients are not able to drink or eat consistently, these agents should be held. Patients who are scheduled for surgical or medical procedures, these agents should be FDA actually recommends holding these agents at least three to five days prior to the procedure. So it is extremely important to have these agents listed on medication list that are to be held prior to, you know, very operatively or prior to surgical procedures. And then any time patients are having, making modifications that are insulin pump or insulin doses or any malfunction of an insulin pump warrants holding HGLT2 inhibitors. Patients should also be instructed to follow the STITCH protocol that's listed here. Any time they're experiencing symptoms of ketosis or having acute illness, GI illness, and that involves stopping the agent, testing for ketones, injecting insulin, eating at least 30 grams of carbohydrates, hydrating, and seeking medical advice. So in summary, take-home points is that while it is an uncommon complication, it is a life-threatening emergency and early diagnosis and aggressive management can decrease morbidity and mortality from this condition. Any patient receiving CRT therapy with a glucose-free solution should be considered at risk for euglacemic ketosis, especially if they're a diabetic or not receiving adequate nutrition and not receiving any insulin therapy. Clinicians should be aware of possible triggers for euglacemic ketoacidosis, especially in patients taking HGLT2 inhibitors and holding these agents or instructing patients to hold these agents if they do exhibit any of the risk factors. And early diagnosis and aggressive management should reverse euglacemic ketosis relatively quickly. Thank you for your time.

euglycemic ketoacidosis

SGLT2 inhibitors

CRRT

insulin management

preventative steps