Diabetic Emergencies: Part I
AUTHORS
Jessica Zhen, MD, Attending Emergency Medicine Physician USAF, MC, Wright Patterson AFB, OH; Core Faculty Member, Emergency Medicine Residency WPAFB/Wright State University Boonshoft School of Medicine, Dayton, OH
Jordan Hickey, MD, Resident Emergency Medicine Physician, Wright State University Boonshoft School of Medicine, Dayton, OH
PEER REVIEWER
Steven M. Winograd, MD, FACEP, Attending Emergency Physician, Keller Army Community Hospital, West Point, NY
I am old enough to have used bolus insulin therapy for diabetic ketoacidosis (DKA) during my training. Since the hospital laboratory was one floor away from the emergency department and three floors away from the intensive care unit, we monitored therapy using Dextrostix whole blood glucose test strips and Acetest urine ketone reagent tablets to provide more real-time information than the 30- to 45-minute laboratory turnaround. The development of accurate point-of-care testing for glucose and electrolytes has been the biggest game-changer in the management of diabetic emergencies during my practice career. So, as we have become much better at the diagnosis and management of diabetic emergencies, the incidence of diabetes has increased to where we are having to use this knowledge more often. This two-part series of Emergency Medicine Reports will discuss the latest concepts in diabetic emergencies. Part I will cover epidemiology, pathophysiology, and clinical features, and Part II will cover the diagnostic approach, management, and disposition.
— Joseph Stephan Stapczynski, MD, Editor
Introduction
According to the National Diabetes Statistics Report, 37.3 million people in the United States have diabetes, with adults accounting for 76.4% of the cases, and 23% of those are undiagnosed. One in three American adults, 38% of the total U.S. adult population, or 96 million more people are prediabetic.1 With such a high prevalence and rising incidence, patients with diabetes presenting to the emergency department (ED) for associated complications, as well as unrelated issues, are inevitably common.
Although diabetes affects various organ systems and complicates other disease processes, pure diabetic emergencies include diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic syndrome (HHS), euglycemic diabetic ketoacidosis (EDKA), and severe hypoglycemia. These emergencies often are precipitated in a patient with known diabetes but frequently can be the initial presentation in someone with undiagnosed diabetes. It is essential for ED providers to understand the pathophysiology, clinical features, workup, and management of these conditions, since they can be fatal, as they often were before the availability of insulin.
Although many institutions have treatment algorithms in place for DKA since it is the more common emergency, there are some key distinctions in the pathophysiology of HHS, making the treatment slightly, but importantly, different. Similarly, there often are separate protocols for pediatric vs. adult DKA. However, the two-bag system (discussed later) commonly used in pediatrics can be implemented in adults and may be more beneficial. During management of diabetic emergencies, close monitoring of hemodynamics and laboratory values is necessary, and adding end-tidal carbon dioxide (ETCO2)/capnography monitoring can be a simple and useful adjunct.
This article will discuss the epidemiology, etiology, pathophysiology, clinical features, differential diagnoses, workup, management principles, and disposition of these diabetic emergencies: DKA, HHS, EDKA, and hypoglycemia. A focus on distinguishing characteristics and nuances of each emergency will be discussed.
Epidemiology
Approximately 537 million adults worldwide are living with diabetes, and that number is expected to climb to 783 million by the year 2045.2 Three out of four people with diabetes are residents of low to middle income countries. Because of significant increase in incidence and prevalence in the past two decades, diabetes became the ninth leading cause of death globally in 2019 and resulted in the largest rise in male deaths among the top 10 causes of death.
These data mirror the impact that diabetes has in the United States, with diabetes currently the eighth leading cause of death. The number of youth and young adults with diabetes and prediabetes is particularly astonishing. From 2001 to 2017, the number of people younger than age 20 years living with type 1 diabetes (DM1) increased by 45%, and the number living with type 2 diabetes (DM2) grew by 95%.3 While DM1 remains more common in white youth, DM2 is more common and rising more rapidly in racial and ethnic minority groups, most notably Black, Hispanic, and American Indian. Similar rising numbers are seen with prediabetes: one in five adolescents (ages 12-18 years) and one in four young adults (ages 19-34 years) in the United States, with a higher prevalence in males and those with obesity.4
The seemingly unstoppable rise in diabetes and prediabetes, particularly in youth and young adults, means more long-term health consequences and, ultimately, more healthcare costs. Acute complications also will continue to increase, contributing to more ED visits. For both DM1 and DM2, those who experience DKA/HHS are more likely to be Black or Hispanic and of lower income.5 Interestingly, among inner city young adults, there have been parallels between hemoglobin A1c (HbA1c) and some of these demographics; young adults admitted for DKA/HHS had severely uncontrolled diabetes with HbA1c > 12% more associated with being Black and uninsured.6
Although DKA more commonly is associated with DM1, it can occur under extreme stress in DM2. It is more common in those younger than age 65 years, while HHS is seen more often in those older than 65 years. From 2000-2009, DKA hospitalization rates decreased, but this trend has reversed, with a steady increase in DKA hospitalization rates from 2009 to 2014 at an average annual rate of 6.3%.7 In a large commercially insured population with DM1, the incidence of DKA was 55.5 per 1,000 person-years between 2007-2019.8 Nationwide mortality rates for DKA decreased from 0.51% in 2003 to 0.33% in 2014 from analysis of the National Inpatient Sample.9 An analysis of the same data source for 2017 found a slight uptick in mortality to 0.38%, with higher rates in males, Blacks, and elderly patients.10
There is less population-based data for DKA and HHS in DM2; however, the rate of admissions for HHS is lower than that for DKA, but the mortality rate is significantly higher, ranging from 10% to 20%.7
EDKA is even more rare, with an incidence between 2.6% to 3.2% of DKA admissions.11 However, this likely is an underrepresentation of the disease process because of the lack of consensus for a definitive cutoff of serum glucose. The three most common situations associated with EDKA are pregnancy, prolonged fasting, and the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for treating diabetes.11,12 Analysis of the Food and Drug Administration’s (FDA) adverse event reporting system on DKA incidence with SGLT-2 inhibitors found a seven-fold increased risk for DKA, and around two-thirds of the reported DKA cases were euglycemic.12 The risk is higher in patients with significant insulin insufficiency or DM1 (up to 9%), and, therefore, the FDA does not recommend SGLT-2 inhibitors for DM1.12
Hypoglycemia, on the other hand, is much more common, with data from the 2018 National Diabetes Statistics Reports indicating 242,000 ED visits for hypoglycemia,1 and other sources indicating that it is one of the most common acute metabolic events leading to hospitalization in the diabetic population.13
Etiology
DKA and HHS
It was long believed that DKA was an emergency complication limited to those with DM1, and HHS was unique to patients with DM2. However, while these are the associations that are commonly recognized in clinical practice, now it is well documented that there is more overlap between these two entities than previously thought.14 For instance, DKA often can be the first presentation of previously undiagnosed DM1 or DM2. Most commonly, DKA is the result of a complete or absolute deficiency of insulin, a characteristic usually found with DM1, but studies have shown that it is important to keep in mind that patients presenting with DKA may ultimately be diagnosed with DM2.15,16 Per some reports, it is possible that this number of eventual DM2 diagnoses could even be as high as one-third of all cases.17
While DKA can be the initial indication of underlying diabetes, it more commonly presents in those with a known diagnosis.18 Similarly, while the classic presentation of HHS involves an older patient with a known diagnosis of DM2, there are a growing number of cases of HHS in people with type 1 diabetes and as the initial representation of both classes of diabetes mellitus.19 Additionally, it is possible to see characteristics of both disease processes present at one time, although this article will largely continue to refer to them as separate entities.20 Nonetheless, while it is being found that presentations and associations with underlying disease may be more heterogeneous than previously thought, precipitating factors for these two diabetic emergencies share many similarities, and it is important to remember to investigate and treat the underlying trigger.
For both HHS and DKA, the most prevailing inciting circumstances in adults are infection and omission of either insulin dosing or antidiabetic medications.19-22 However, although these are the most common, an initial broad approach must be used, since the potential inciting causes are numerous, and most of the associated morbidity and mortality come from them rather than from the pathophysiology of the diabetic emergency itself. Other precipitating causes that should be considered in DKA and HHS if associated signs and/or symptoms are present are listed in Table 1.14,16,19-21,22-25
Table 1. Potential Precipitants of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Syndrome | |
|
Diabetic Ketoacidosis |
Hyperosmolar Hyperglycemic Syndrome |
|
|
EDKA
As noted earlier, the three most common precipitating events for EDKA are pregnancy, the use of SGLT-2 inhibitors, and a fasting state where insulin is being used. Other possible inciting factors that should be considered include chronic alcohol use, substance use (primarily cocaine), liver disease, infections, recent bariatric surgery, and cerebral or myocardial infarction.20,26
Hypoglycemia
As with hyperglycemic emergencies, hypoglycemia usually occurs in the setting of an underlying trigger. It can be spontaneous, although this is a rarer occurrence. Rather, it usually is seen in patients with underlying diabetes mellitus and frequently is a complication of treatment. (See Table 2.)
The risk of hypoglycemia increases with age, since autonomic failure begins to occur, renal clearance of insulin declines, oral intake decreases, and increased polypharmacy makes patients more susceptible.16,27,28 Other possible etiologies of hypoglycemia include means by which sensitivity to insulin is increased, such as in exercise, fasting, and weight loss.
Table 2. Medications that Can Increase the Risk of Hypoglycemia16,28-30 |
|
Hypoglycemia also can be induced in situations where gluconeogenesis and glycogenolysis are impeded, such as in hepatic failure, kidney injury, and with alcohol consumption. Additionally, although it may be largely out of the scope of the ED management, it is important to keep in mind that hypoglycemia may be the presenting feature in metabolism dysregulation, particularly in the setting of endocrine disorders (e.g., Addison’s disease, panhypopituitarism, growth hormone deficiency, or hypothyroidism).16,28,29
Pathophysiology
Diabetes
Simply put, diabetes results from excessive glucose in the blood because of a lack of insulin or inability to use insulin properly, ultimately leading to widespread pathology if excessive levels are not treated. Insulin is the main anabolic hormone of the body and is released from beta cells in the islet of Langerhans of the pancreas in response to an increase in blood glucose. It promotes uptake of glucose from the blood into the liver, fat, and muscle, where it can be used immediately for energy or converted into glycogen and triglycerides for energy stores. Opposing insulin is glucagon, the main catabolic hormone of the body that is released from the alpha cells of the pancreas. When the serum blood glucose is low, glucagon is released, triggering gluconeogenesis and glycogenolysis in the liver and lipolysis in adipose to increase glucose and fatty acids to be used as energy. The counterbalancing interaction of insulin and glucagon regulate each other to restore and maintain normoglycemia.31
In DM1, there is autoimmune destruction of the insulin-producing pancreatic beta cells, so no insulin is made. This occurs in genetically susceptible individuals and likely is triggered by a variety of factors, such as viral infections or changes in the gut microbiome. There is no identified association between diet or obesity in DM1. After the inciting event, it can take months to years to manifest hyperglycemia because of the large number of beta cells that need to be destroyed to affect glucose metabolism.
DM1 typically is diagnosed in childhood, with two age peaks, 4 to 7 years and 10 to 14 years of age. The presence of autoantibodies in DM1 — termed DM1A — along with the progressive destruction of beta cells allows three stages to be defined for DM1A: stage 1, in which autoantibodies present but the patient is normoglycemic; stage 2, autoantibodies present and the patient is dysglycemia, but without symptoms; and stage 3, autoantibodies, dysglycemia, and symptoms are present. There is a much smaller subgroup of DM1 — DM1B — that presents the same as DM1A, but upon testing, no autoantibodies are found.32
In contrast, DM2 results from insulin resistance and impaired insulin secretion. Normally, the liver responds to insulin by decreasing glucose release and instead using it to build glycogen stores. However, when it is resistant to insulin, it inappropriately releases glucose into the blood, contributing to hyperglycemia. Although the mechanism is not understood, obesity, particularly central adipose, and lack of exercise are heavily linked to the development of DM2. The impaired insulin secretion likely is twofold from genetic influences as well glucotoxicity where hyperglycemia has a toxic effect on pancreatic beta cells, resulting in a destructive cycle.33 While DM2 is classically called adult-onset diabetes, this has proven to be a misnomer, as the incidence and prevalence among children and young adults is climbing because of rising obesity at an earlier age.
According to the American Diabetes Association (ADA), to be diagnosed with diabetes, one of the following criteria must be met:34
• HbA1C ≥ 6.5%;
• Eight-plus-hour fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L);
• Two-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test;
• In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L); the most common way DM is identified in the ED.
DKA
The defining features of DKA include hyperglycemia (> 250 mg/dL), acidosis (pH < 7.3), and ketonemia/ketonuria. The serum bicarbonate levels typically are low (< 18 mEq/L), and the anion gap is elevated. These metabolic changes ultimately occur because of insulin deficiency and/or resistance, which allows for excess counterregulatory hormone activity, including glucagon, catecholamines, and cortisol. (See Figure 1.) Despite elevated serum glucose, without the negative feedback signal of insulin, the body believes it is in a state of hypoglycemia.
Figure 1. Pathophysiology of Diabetic Ketoacidosis |
|
AGMA: anion gap metabolic acidosis; RAAS: renin-angiotensin-aldosterone system; AKI: acute kidney injury; GFR: glomerular filtration rate |
The liver performs glycogenolysis and gluconeogenesis to increase serum glucose, contributing to hyperglycemia. This excess blood glucose increases the osmolality of the blood and, to autoregulate, fluid shifts from in cells to the vasculature. Ultimately, the kidneys see this excess fluid and glucose and attempt to compensate via the process of osmotic diuresis, leading to dehydration.21 Over time, though, the dehydration impairs the kidney by affecting the glomerular filtration rate (GFR) and can lead to acute kidney injury (AKI). There is a resulting hypovolemic hyponatremia because of the dilutional effect of fluid shifts on sodium in the vasculature; traditionally, for every 100 mg/dL increase in glucose above normal (100 mg/dL), there is an estimated 1.6 mEq/L decrease in serum sodium.35 However, this may be an underrepresentation of the degree of dilutional hyponatremia, as Hillier showed, especially when there is significant hyperglycemia > 400 mg/dL, and a larger correction factor of 2.4 mEq/L for every 100 mg/dL above normal may be more accurate.36
The absence of insulin results in glucagon-induced lipolysis of triglycerides to produce free fatty acids. These undergo beta oxidation and ketogenesis to become the ketone bodies acetoacetic acid and beta hydroxybutyric acid, which serve as an energy source in starved states.21 However, as their names suggest, they have a low pH and cause the elevated anion gap metabolic acidosis. To maintain physiologic pH, the body uses the bicarbonate buffering system (CO2 + H2O H2CO3 HCO3- + H+), accounting for the low bicarbonate levels seen. However, in DKA, this mechanism cannot fully compensate, and often patients are noted to be hyperventilating to blow off CO2, ultimately countering the metabolic acidosis with a respiratory alkalosis.
Although many electrolytes are affected in DKA, potassium is one of the most significant, since it has important effects on many organs, including cardiovascular functioning. Dehydration triggers the renin-angiotensin-aldosterone system (RAAS), which stimulates sodium and chloride resorption in the tubules of the kidneys to retain water in exchange for potassium that is lost. As the metabolic acidosis worsens, hydrogen ions are shifted intracellularly in exchange for potassium ions intravascularly, yet these are lost via osmotic diuresis. In addition, there often is gastrointestinal loss of potassium in the form of vomiting and decreased oral intake. Although serum values may be normal or even hyperkalemic, the total body potassium is reduced because of these factors, with total body deficits commonly 300 mEq to 600 mEq.21
HHS
A significantly elevated serum glucose > 600 mg/dL, profound dehydration, and hyperosmolality > 320 mOsm/kg without significant ketosis, acidosis, or bicarbonate derangement is the metabolic picture of HHS. Although the hyperglycemia and dehydration may be very similar to DKA, the disease process differs. This is because in HHS the insulin deficiency is less severe, but insulin resistance persists and may be acutely worse. In addition, one of the main contributing factors to the disease pathophysiology is that the patient cannot hydrate adequately. HHS occurs more in the elderly population, who may have an impaired thirst mechanism or debility that inhibits easy access to water. This propagates a worsening cycle of hyperosmolality, osmotic diuresis, and dehydration, ultimately leading to the average 9 L water deficit in these patients.
The presence of some insulin is sufficient enough in HHS to prevent lipolysis, so ketones are minimally, if not at all, produced.6,19 Therefore, as opposed to DKA, there is little effect on serum acid-base status. Unfortunately, the concentration of insulin required to suppress lipolysis is only one-tenth that required to promote glucose utilization, so while ketone formation is blocked, there is not enough insulin to promote glucose utilization or prevent gluconeogenesis and glycogenolysis in the liver.6
The hyperglycemia in HHS is more extreme than in DKA for two reasons: ketoacidosis in DKA causes earlier symptoms than the hyperosmolality of HHS, so DKA patients present sooner, and patients with DKA tend to be younger with a better renal function and more capacity to excrete glucose to at least initially slow the rise of hyperglycemia.6 The extreme hyperglycemia and glucosuria in HHS leads to an osmotic diuresis of largely electrolyte-free urine, causing a greater degree of dehydration and increased effective plasma osmolality compared with DKA.19 This is exacerbated by patients failing to compensate for the water loss, leading to a worsening cycle of hyperglycemia, hyperosmolality (mainly sodium), and hypovolemia. (See Figure 2.)
Figure 2. Pathophysiology of Hyperosmolar Hyperglycemic Syndrome |
Similar to DKA, serum potassium levels in HHS may be normal to high initially, but total body stores are low. The potassium deficit in HHS usually is greater than in DKA because of hyperosmolality; with water moving out of the cell, potassium is both dragged out of the cell and also passively moves out as the intracellular concentration rises with the loss of water. In addition, insulin normally promotes potassium uptake by cells, but with the insulin deficiency and resistance, it cannot aid in this process. Osmotic diuresis, as in DKA, continually flushes extracellular potassium out of the body.
EDKA
As the name suggests, EDKA is characterized by euglycemia — a relatively normal blood glucose (< 250 mg/dL) — but with the rest of the findings of DKA, including metabolic acidosis with pH < 7.3, low serum bicarbonate < 18 mEq/L, and the presence of ketones.11 A carbohydrate deficit, rather than the insulin deficiency or resistance, is the main factor contributing to this pathophysiology.11 Ultimately, in EDKA, a fasting state causes decreased serum insulin and depletes the liver’s glycogen stores so glycogenolysis and gluconeogenesis cannot compensate, and the hyperglycemia of DKA is not seen. However, because of the lack of carbohydrates and, therefore, energy, counterregulatory hormones still are released, and glucagon triggers ketogenesis, producing the other findings typical of DKA.11,12 (See Figure 3.) Just as in DKA, dehydration occurs from decreased oral intake, vomiting, and osmotic diuresis, and only increases the counterregulatory hormones worsening the lipolysis and ketogenesis.
Figure 3. Pathophysiology of Euglycemic Diabetic Ketoacidosis |
|
AGMA: anion gap metabolic acidosis |
As previously mentioned, EDKA has three main precipitating causes. SGLT-2 inhibitors are a class of medication to treat diabetes by preventing reabsorption of glucose in the proximal convoluted tubule of the kidney, producing glucosuria to decrease glucose levels in the body. However, this creates a state of carbohydrate deficit and volume depletion, the two components that promote glucagon release leading to an increase in the glucagon/insulin ratio and ketogenesis with euglycemia.11,12
Normal physiologic changes in pregnancy include mechanisms that enhance nutrient storage in the mother and shunt glucose to the fetus and placenta, producing a state of carbohydrate deficit and insulin resistance in the mother.11,12 In addition, because of the increased levels of progesterone, there is a natural respiratory alkalosis in pregnancy, and the body compensates with bicarbonate loss in the urine. Therefore, the stage is set for any trigger, commonly pregnancy-associated vomiting, to cause EKDA, since there is already a carbohydrate deficit, increased counterregulatory hormones, and a diminished ability to buffer acidosis, and ketogenesis and metabolic acidosis occur faster during pregnancy than when not pregnant and at lower blood sugar levels.12
Partially treated DKA will cause EDKA as well. In states of fasting or illness, there is a carbohydrate deficit, but if someone taking insulin does not adjust for this, it will keep serum glucose low and glycogen stores depleted and will prevent gluconeogenesis, but lipolysis and ketogenesis will continue for needed energy.12
Hypoglycemia
Simply put, hypoglycemia is low blood sugar. The brain’s main source of energy is glucose, so if serum levels are low, the brain cannot function normally. Usually, the body has several mechanisms to prevent hypoglycemia, and it is a rare occurrence in healthy individuals.
The American Diabetes Association (ADA) defines hypoglycemia as any low level of serum glucose (with or without symptoms) that exposes the patient to harm.34 It often is defined as serum glucose < 70 mg/dL, which is the lower limit of the physiologic fasting nondiabetic range. However, more recently, ≤ 54 mg/dL was deemed clinically important biochemical hypoglycemia, since it is does not occur in nondiabetics under physiologic conditions and has identifiable immediate and long-term harm.37
As previously described, insulin is anabolic and functions when glucose is plentiful in the blood. When blood sugar levels start to decline, normally the body decreases insulin production, which triggers the liver to perform glycogenolysis and gluconeogenesis. As the glucose levels continue to drop below normal levels, glucagon is released, which further stimulates the liver’s actions as well as lipolysis as an alternative source of fuel. If these systems fail to normalize glucose levels, the adrenal glands release epinephrine, which has some stimulatory effect on glycogenolysis and gluconeogenesis but also acts on other organs to decrease their use of glucose, thereby prioritizing the supply for the brain. With prolonged hypoglycemia, cortisol and growth hormone also are released but are much less effective than epinephrine.
In people with diabetes, these processes do not function optimally, making them prone to hypoglycemic episodes. In both DM1 and DM2, over time, there is a progressive loss of the pancreatic beta cells that release insulin, which prevents paracrine crosstalk to the glucagon-secreting alpha cells, leading to impaired release during hypoglycemia.38 The sympathetic defense also is impaired over time in what has been described as hypoglycemic-associated autonomic failure; episodes of hypoglycemia reset the threshold for epinephrine release to a lower glucose level.38 The most common cause of hypoglycemia in patients with diabetes is the medications used to treat diabetes. Usually this is associated with mismanagement of medication, such as continuing to take exogenous insulin during fasting states, skipped meals, increased activity, and illness.
Clinical Features
Diabetes
The classic symptoms of diabetes mainly are due to ongoing hyperglycemia. Once the serum glucose exceeds the renal threshold for glucose reabsorption, glucose spills into the urine. Increased blood glucose and glucosuria cause osmotic diuresis, leading to the polyuria and nocturia as well as dry skin. This ultimately leads to dehydration, hypovolemia, and reflexive polydipsia. Despite having increased hunger drive and ample amounts of glucose, people with diabetes cannot use it properly for energy, and the body turns to using other sources of fuel, including stored glucose, fat, and muscle, contributing to unintentional weight loss and fatigue.
DKA
As a result of the multifactorial pathophysiology of DKA, the presenting chief concerns and clinical features often can be complicated and vary based on the severity of illness. In general, DKA is thought to precipitate in an acute fashion, usually developing over hours and at most a few days. The general appearance of patients can range from relatively well-appearing and only demonstrating mild symptoms of volume loss to obtunded with impending respiratory failure. Because of the hyperglycemia and osmotic diuresis, polyuria and compensatory polydipsia may be the only symptoms present until metabolic derangements develop.
Generalized abdominal pain is one of the most common chief complaints, and it tends to correlate with the severity of acidosis.16,21,39 Other common early and often vague chief complaints to the ED include nausea, vomiting, loss of appetite, general weakness, and fatigue.16,20 Significant unintentional weight loss usually only occurs in the setting of a new diagnosis where patients have had a prolonged state of hyperglycemia.39 Osmotic diuresis and vomiting lead to volume depletion, which can present with subjective symptoms, such as lightheadedness and dry mouth, but can produce physical signs such as tachycardia, orthostatic hypotension, poor skin turgor, and dry mucous membranes.16
As ketoacidosis further develops, patients begin to exhibit tachypnea and hyperpnea to reduce pCO2, producing respiratory alkalosis to compensate for the worsening metabolic acidosis.40 Eventually, as acidosis progresses, patients will begin to experience Kussmaul respirations: rapid, deep, and labored respirations at a constant pace.40 Classically, a fruity breath odor can be detected because of the increase in acetone production.16,21,41
It also is important to keep in mind the electrolyte abnormalities previously discussed and potential signs that could be due to their imbalance. It also is possible for patients to present with neurological symptoms, ranging from mild altered mental status to coma, which are thought to be the result of various aspects of the DKA syndrome, including hyperosmolarity, low volume status, and acidosis.16,21,39,42 And as discussed previously, DKA generally is precipitated by another event or disease that needs to be addressed in management. As such, it is vital to obtain a history encompassing medication administration, glucose monitoring, and insulin pump function, if the patient has one. It also is necessary to obtain a review of systems to assess any underlying infection, ischemia, substance use, concurrent endocrine pathology, hemorrhage, possible pregnancy, or coagulopathy.16,21,23
HHS
In contrast to DKA, HHS tends to evolve over a longer period of time, with symptoms progressing over days to weeks.16,19,20,43 Presenting chief complaints often are general and nonspecific, such as generalized weakness, fatigue, vomiting, muscle cramps, and anorexia.16,20 Because there is a significant hyperglycemic load present, patients often will have osmotic diuresis that presents in the form of polyuria and polydipsia and often leads to profound dehydration.20
It also is common for patients to present with neurologic abnormalities, including but not limited to lethargy, confusion, delirium, visual changes, and sensory deficits.19,20 Altered mental status correlates to the magnitude of dehydration and hyperosmolality, with it usually seen in patients with a serum osmolality > 330 mOsm/kg.6,14,19 Some studies have suggested that up to 15% of patients may present with focal or generalized seizures that often are resistant to anticonvulsant agents.16,20 Evaluation of the patient commonly shows signs of significant dehydration, including dry mucous membranes, poor skin turgor, sunken eyes, tachycardia, hypotension, and hypothermia.16,19,20
Additionally, because HHS commonly is precipitated by another pathology or event, it is important to obtain as much information as possible regarding potential causes. This may be difficult at times if patients are presenting with altered mental status, but the provider should attempt to include a detailed review of medications and symptoms of infection, particularly pneumonia and urinary tract infections, since they are the most common. It also is essential to complete a review of systems to assess for any symptoms of hemorrhage, ischemia, infarction, ingestion, inflammation, or trauma.16,19,44 For instance, in contrast to DKA, because significant ketosis is not usually present in HHS, abdominal pain is not typically a presenting symptom. If abdominal pain is present, further workup is necessary because it likely is related to a precipitating cause rather than due to the pathophysiology HHS itself.19,23
EDKA
Similar to DKA, EDKA presents with many of the same vague symptoms, including nausea, vomiting, anorexia, and generalized fatigue. With progression of the disease state, patients also begin to exhibit Kussmaul breathing. However, unlike DKA, polyuria and polydipsia are not as pronounced without a significant glucose load to cause these osmotic symptoms. Similarly, while often present, dehydration is not as marked in EDKA.20,26,45
It is important to note that the diagnosis of EDKA often is delayed because of the normal or near-normal levels of glucose and, subsequently, often results in a delay in management. Therefore, this diagnosis relies heavily on good history-taking skills to assess risk factors and maintaining a high suspicion for the pathology. Important topics to address during evaluation to uncover potential precipitating causes of EDKA include medication history (e.g., SGLT-2 inhibitors), fasting, alcohol intake, extensive exercise, pregnancy, history of liver disease, history of renal disease, recent surgery (e.g., bariatric surgery), history of gastroparesis, and any symptoms that could suggest an infection.12,26,45 Furthermore, it is imperative to ask patients with insulin-dependent diabetes if they administered insulin for their symptoms prior to arrival to the ED, since this could reflect a true DKA diagnosis in which treatment was self-initiated by the patient.26
Hypoglycemia
In evaluating for hypoglycemia, the presenting signs and symptoms usually are divided into neuroglycopenic or autonomic in nature. Neuroglycopenic signs and symptoms include confusion, lightheadedness, lethargy, agitation, seizures, combativeness, stroke-mimicking symptoms such as focal neurological deficits, and even coma. In response to hypoglycemia, autonomic symptoms include both adrenergic and cholinergic pathway activation. Adrenergic symptoms include palpitations, tremors, anxiety, irritability, nausea, and vomiting. Because of cholinergic activation, symptoms also may include diaphoresis, paresthesias, and hunger.16,29
Overall, in evaluation of the patient, obtaining a history directly from the patient may be difficult at times with neurologic symptoms being prevalent. However, when possible, information should be obtained regarding risk factors for hypoglycemia, including medication history, medical history (e.g., diabetes, renal disease), symptoms of serious infection, symptoms associated with hormone deficiencies (e.g., adrenal insufficiency), or drug and alcohol use.16,46,47
It also is important to note hypoglycemia unawareness is a common phenomenon experienced by patients with both type 1 and 2 diabetes and could worsen with increased time after diagnosis. With repeated episodes of hypoglycemia, patients’ autonomic response becomes muted to the metabolic abnormality, and the common symptoms will not develop. As such, patients often will miss the initial warning signs that would give them time to attempt to correct their blood glucose before it decreases to severe ranges.27,28,46,48
Whipple’s triad is a set of three conditions that must be met to define a hypoglycemic crisis: signs and symptoms of hypoglycemia are present, the measured glucose is ≤ 70 mg/dL, and the signs and symptoms of hypoglycemia resolve after blood glucose rises and returns to normal. Several categories of hypoglycemia can be defined:37
• Severe: event requiring another person to actively administer carbohydrates, glucagon, or other resuscitation efforts. Plasma glucose may not be measured during event, but neurological recovery attributable to restoration of plasma glucose is sufficient to conclude hypoglycemia as the cause;
• Documented symptomatic: typical symptoms of hypoglycemia accompany a measured glucose < 70 mg/dL;
• Asymptomatic: an event without the typical symptoms of hypoglycemia but with a measured glucose < 70 mg/dL;
• Probable symptomatic: an event with typical symptoms of hypoglycemia but glucose not measured but presumably low glucose was the cause;
• Pseudohypoglycemia: an event with typical symptoms of hypoglycemia but measured glucose ≥ 70 mg/dL.
References
- Centers for Disease Control and Prevention. National Diabetes Statistics Report. Last reviewed Jan. 18, 2022. https://www.cdc.gov/diabetes/data/statistics-report/index.html
- International Diabetes Federation. Diabetes around the world in 2021. IDF Diabetes Atlas. Last updated 2021. https://diabetesatlas.org
- Centers for Disease Control and Prevention. New research uncovers concerning increases in youth living with diabetes in the U.S. Aug. 24, 2021. https://www.cdc.gov/media/releases/2021/p0824-youth-diabetes.html
- Andes LJ, Cheng YJ, Rolka BD, et al. Prevalence of prediabetes among adolescents and young adults in the United States, 2005-2016. JAMA Pediatr 2020;174:e194498.
- McCoy RG, Galindo RJ, Swarn KS, et al. Sociodemographic, clinical, and treatment-related factors associated with hyperglycemic crises among adults with type 1 or type 2 diabetes in the US from 2014 to 2020. JAMA Netw Open 2021;4:e2123471.
- Wolf RA, Haw JS, Paul S, et al. Hospital admissions for hyperglycemic emergencies in young adults at an inner-city hospital. Diabetes Res Clin Pract 2019;157:107869.
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This two-part series of Emergency Medicine Reports will discuss the latest concepts in diabetic emergencies. Part I will cover epidemiology, pathophysiology, and clinical features.
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