Data adapted from ref. DKA is the most common cause of death in children and adolescents with type 1 diabetes and accounts for half of all deaths in diabetic patients younger than 24 years of age 5 , 6. Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis but relates to the underlying precipitating illness 4 , 9. The prognosis of both conditions is substantially worsened at the extremes of age in the presence of coma, hypotension, and severe comorbidities 1 , 4 , 8 , 12 , In DKA, reduced effective insulin concentrations and increased concentrations of counterregulatory hormones catecholamines, cortisol, glucagon, and growth hormone lead to hyperglycemia and ketosis. Hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues 12 —
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Timely diagnosis, comprehensive clinical and biochemical evaluation, and effective management is key to the successful resolution of DKA and HHS. Critical components of the hyperglycemic crises management include coordinating fluid resuscitation, insulin therapy, and electrolyte replacement along with the continuous patient monitoring using available laboratory tools to predict the resolution of the hyperglycemic crisis. Understanding and prompt awareness of potential of special situations such as DKA or HHS presentation in comatose state, possibility of mixed acid-base disorders obscuring the diagnosis of DKA, and risk of brain edema during the therapy are important to reduce the risks of complications without affecting recovery from hyperglycemic crisis.
Identification of factors that precipitated DKA or HHS during the index hospitalization should help prevent subsequent episode of hyperglycemic crisis.
DKA and HHS remain important causes of morbidity and mortality among diabetic patients despite well-developed diagnostic criteria and treatment protocols 1. The annual incidence of DKA from population-based studies is estimated to range from 4 to 8 episodes per 1, patient admissions with diabetes 2.
The incidence of DKA in the US continues to increase and it accounted for about , hospitalizations in Figure 1a and, most recently, in for , hospitalizations 3 , 4. In , there were reported , emergency department visits with a diagnosis of hyperglycemic crisis 7. Decompensated diabetes imposes a heavy burden in terms of economics and patient outcomes. DKA is responsible for more than , hospital days per year at an estimated annual direct medical expense and indirect cost of 2.
The mortality rate for DKA and hyperglycemic crises has been falling over the years Figure 1b 3. In , among adults aged 20 years or older, hyperglycemic crisis caused 2, deaths 9. Severe dehydration, older age, and the presence of comorbid conditions in patients with HHS account for the higher mortality in these patients View in own window Figure 1a.
Incidence of DKA Figure 1b. Age-Adjusted DKA hospitalization rate per 1, persons with diabetes and in-hospital case-fatality rate, United States, — 4.
Figure 2. The triad of DKA hyperglycemia, acidemia, and ketonemia and other conditions with which the individual components are associated. From Kitabchi and Wall Clinically, they differ by the severity of dehydration, ketosis and metabolic acidosis It also occurs in type 2 diabetes under conditions of extreme stress, such as serious infection, trauma, cardiovascular or other emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder called ketosis-prone type 2 diabetes PATHOGENESIS The underlying defects in DKA and HHS are 1 reduced net effective action of circulating insulin as a result of decreased insulin secretion DKA or ineffective action of insulin in HHS , 2 elevated levels of counter regulatory hormones: glucagon 16 , 17 , catecholamines 16 , 18 , cortisol 16 , and growth hormone 19 , 20 , resulting in increased hepatic glucose production and impaired glucose utilization in peripheral tissues, and 3 dehydration and electrolyte abnormalities, mainly due to osmotic diuresis caused by glycosuria 21 Figure 3.
Diabetic ketoacidosis is also characterized by increased gluconeogenesis, lipolysis, ketogenesis, and decreased glycolysis In general, the body is shifted into a major catabolic state with breakdown of glycogen stores, hydrolysis of triglycerides from adipose tissues, and mobilization of amino acids from muscle The released triglycerides and amino acids from the peripheral tissues become substrates for the production of glucose and ketone bodies by the liver Hyperglycemia and ketone bodies production play central roles in developing this metabolic decompensation Hyperglycemia The hyperglycemia in DKA is the result of three events: a increased gluconeogenesis; b increased glycogenolysis, and c decreased glucose utilization by liver, muscle and fat.
Insulinopenia and elevated cortisol levels also lead to a shift from protein synthesis to proteolysis with resultant increase in production of amino acids alanine and glutamine , which further serve as substrates for gluconeogenesis 5 , Furthermore, muscle glycogen is catabolized to lactic acid via glycogenolysis. The lactic acid is transported to the liver in the Cori cycle where it serves as a carbon skeleton for gluconeogenesis Increased levels of glucagon, catecholamines and cortisol with concurrent insulinopenia stimulate gluconeogenic enzymes, especially phosphoenol pyruvate carboxykinase PEPCK 19 , Decreased glucose utilization is further exaggerated by increased levels of circulating catecholamines and FFA Ketogenesis Excess catecholamines coupled with insulinopenia promote triglyceride breakdown lipolysis to free fatty acids FFA and glycerol.
The latter provides a carbon skeleton for gluconeogenesis, while the former serves as a substrate for the formation of ketone bodies 28 , The key regulatory site for fatty acid oxidation is known to be carnitine palmitoyltransferase 1 CPT1 which is inhibited by malonyl CoA in the normal non-fasted state but the increased ratio of glucagon and other counter regulatory hormones to insulin disinhibit fatty acid oxidation and incoming fatty acids from fat tissue can be converted to ketone bodies 30 , Ketonemia is further is maintained by the reduced liver clearance of ketone bodies in DKA.
Extracellular and intracellular buffers neutralize hydrogen ions produced during hydrolysis of ketoacids. When overwhelming ketoacid production exceeds buffering capacity, a high anion gap metabolic acidosis develops. Studies in diabetic and pancreatectomized patients have demonstrated the cardinal role of hyperglucagonemia and insulinopenia in the genesis of DKA In the absence of stressful situations, such as intravascular volume depletion or intercurrent illness, ketosis is usually mild 10 , Elevated levels of pro-inflammatory cytokines and lipid peroxidation markers, as well as procoagulant factors such as plasminogen activator inhibitor-1 PAI-1 and C-reactive protein CRP have been demonstrated in DKA.
The levels of these factors return to normal after insulin therapy and correction of hyperglycemia This inflammatory and procoagulant state may explain the well-known association between hyperglycemic crisis and thrombotic state 36 , In addition, in HHS there is a smaller increase in counter regulatory hormones 13 , Figure 3.
FFA, free fatty acid. Adapted from Kitabchi et al. Other provoking factors include myocardial infarction, cerebrovascular accidents, pulmonary embolism, pancreatitis, alcohol and illicit drug use Table 1. Drugs such as corticosteroids, thiazide diuretics, sympathomimetic agents e.
Most recently, two new classes of medications have emerged as triggers for DKA. Sodium-glucose cotransporter 2 SGLT-2 inhibitors canagliflozin, dapagliflozin, and empagliflozin that are used for diabetes treatment have been implicated in the development of DKA in patients with both type 1 and type 2 diabetes On the other hand, anti-cancer medications that belong to classes of immune checkpoint inhibitors such as Ipilimumab, Nivolumab, Pembrolizumab can cause DKA as the initial presentation of type 1 diabetes 42 , Cocaine use also is associated with recurrent DKA 45 , Mechanical problems with continuous subcutaneous insulin infusion CSII devices can precipitate DKA 47 ; however, with an improvement in technology and better education of patients, the incidence of DKA have been declining in insulin pump users There are also case reports of patients with DKA as the primary manifestation of acromegaly These ketosis-prone type 2 diabetic patients develop sudden-onset impairment in insulin secretion and action, resulting in profound insulinopenia A genetic disease, glucosephosphate dehydrogenase deficiency, has been also linked with ketosis-prone diabetes On the other hand, development of HHS is insidious and may occur over days to weeks The common clinical presentation of DKA and HHS is due to hyperglycemia and include polyuria, polyphagia, polydipsia, weight loss, weakness, and physical signs of intravascular volume depletion, such as dry buccal mucosa, sunken eye balls, poor skin turgor, tachycardia, hypotension and shock in severe cases.
Kussmaul respiration, acetone breath, nausea, vomiting and abdominal pain may also occur primarily in DKA and are due to ketosis and acidosis. Therefore, in the presence of acidosis, DKA as an etiology of abdominal pain should be considered. Patients usually have normal body temperature or mild hypothermia regardless of presence of infection Therefore, a careful search for a source of infection should be performed even in the absence of fever.
The relationship of depressed consciousness and severity of hyperosmolality or DKA causes has been controversial 63 , Some studies suggested that pH is the cause of mental status changes 65 ; while, others concluded that osmolality 66 is responsible for the comatose state. More recently, it has been proposed that consciousness level in adolescents with DKA was related to the severity of acidosis pH and not to a blood glucose levels Our study showed that glucose, bicarbonate, BUN and osmolality, and not pH were significantly different between non-comatose and comatose patients.
Furthermore, in 3 separate studies in which cases of DKA were evaluated, serum osmolality was also the most important determinant of mental status changes Identifying this class of patients, who are at a higher risk for poorer prognosis, may be helpful in triaging them, thus further improving the outcome Disease severity scores are not, but precipitating cause is, predictive of prolonged hospital stays in patients with DKA Table 2.
In patients with HHS, neurological symptoms include clouding of sensorium which can progress to mental obtundation and coma Occasionally, patients with HHS may present with focal neurological deficit and seizures 72 , An electrocardiogram, blood, urine or sputum cultures and chest X-ray should also be performed, if indicated.
HbA1c may be useful in differentiating chronic hyperglycemia of uncontrolled diabetes from acute metabolic decompensation in a previously well-controlled diabetic patient It also provides a simple method for calculating anion gap and serum osmolality.
Table 3. However, some of them may have ketonemia. Several studies on serum osmolarity and mental alteration have established a positive linear relationship between osmolarity, pH and mental obtundation Therefore, the occurrence of coma in the absence of definitive elevation of serum osmolality requires immediate consideration of other causes of mental status change.
In patients with chronic kidney disease stage , the diagnosis of DKA could be challenging due to the presence of concomitant underlying chronic metabolic acidosis or mixed acid-base disorders. Therefore, DKA must be excluded if high anion gap metabolic acidosis is present in a diabetic patient treated with SGLT-2 inhibitors irrespective if hyperglycemia is present or not.
The major cause of water deficit in DKA and HHS is glucose-mediated osmotic diuresis, which leads to loss of water in excess of electrolytes Despite the excessive water loss, the admission serum sodium tends to be low. Because serum glucose in the presence of insulinopenia of DKA and HHS cannot penetrate to cells, in hyperglycemic crises, glucose becomes osmotically effective and causes water shifts from intracellular space to the extra cellular space resulting in dilution of sodium concentration — dilutional or hyperosmolar hyponatremia.
It is, however, accepted now that true or corrected serum sodium concentration in patients experiencing hyperglycemic crisis should be calculated by adding 2. If the corrected sodium level remains low, hypertriglyceridemia secondary to uncontrolled diabetes should be also suspected. In this condition the plasma becomes milky and lipemia retinalis may be visible in physical examination Osmotic diuresis and ketonuria also promote a total body sodium deficit via urinary losses, although concurrent conditions, such as diarrhea and vomiting, can further contribute to sodium losses.
Total body sodium loss can result in contraction of extracellular fluid volume and signs of intravascular volume depletion. Serum potassium may be elevated on arrival due to insulin deficiency, volume depletion and a shift of potassium from intracellular to extra cellular compartments in response to acidosis However, total body potassium deficit is usually present from urinary potassium losses due to osmotic diuresis and ketone excretion.
More frequently, the initial serum potassium level is normal or low which is a danger sign. Initiation of insulin therapy, which leads to the transfer of potassium into cells, may cause fatal hypokalemia if potassium is not replaced early. Phosphate depletion in DKA is universal but on admission, like the potassium, it may be low, normal or high Table 4.
The exact etiology of this non-specific leukocytosis is not known. The origin of amylase in DKA is usually non-pancreatic tissue such as the parotid gland Pitfalls of Laboratory Tests and Diagnostic Considerations for Interpreting Acid Base Status in DKA False positive values for lipase may be seen if plasma glycerol levels are very high due to rapid breakdown of adipose tissue triglycerides glycerol is the product measured in most assays for plasma lipase.
Hyperglycemic Crises in Adult Patients With Diabetes