Description of the Condition
Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are the most serious acute metabolic complications of diabetes. Recent data indicate there are more than 144,000 hospital admissions per year for DKA in the United States and the number of cases show an upward trend, with a 30% increase in the annual number of cases between 1995 and 2009.
Treatment of DKA utilizes a large number of resources with an annual medical expense of $2.4 billion. The rate of hospital admissions for HHS is lower than for DKA, accounting for less than 1% of all diabetes-related admissions.
Although DKA and HHS are often discussed as separate entities, they represent points along a spectrum of hyperglycemic emergencies due to poorly controlled diabetes. Both DKA and HHS are characterized by insulinopenia and severe hyperglycemia. Clinically, they differ only by the degree of dehydration and the severity of metabolic acidosis.
DKA has long been considered a key clinical feature of type 1 diabetes (T1D), but in contrast to popular belief, DKA is more common in patients with type 2 diabetes (T2D). T2D now accounts for up to one half of all newly diagnosed diabetes in children ages 10-21 years. In the U.S., the SEARCH for Diabetes in Youth Study found that 29.4% of participants under 20 years of age with T1D presented with DKA, compared with 9.7% of youth with T2D. In community-based studies more than 40% of patients with DKA are older than 40 and more than 20% are older than 55.
Patients with T2D may develop DKA under stressful conditions such as trauma, surgery or infections. In addition, in recent years an increasing number of unprovoked ketoacidosis cases without precipitating cause have been reported in children, adolescents and adult subjects with T2D. HHS occurs most commonly in older patients with T2D, but it also occurs in children and young adults. As many as 20% of patients with HHS are under the age of 30.
In children and adult subjects with DKA, the overall mortality is less than 1%, but a mortality rate higher than 5% is reported in the elderly and in patients with concomitant life-threatening illnesses. Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis, but relates to the underlying precipitating illness. Mortality in patients with HHS is higher than in DKA and is between 5% and 16% of patients.
The prognosis of both conditions is substantially worsened at the extremes of age in the presence of coma, hypotension and severe comorbidities. In adult patients with diabetes, mortality increases substantially with age, with mortality rates for those over 65-75 years reaching 20-40%. In the older age groups, the major cause of death relates to the underlying medical illness (i.e., trauma, infection) that precipitated the ketoacidosis, but in the younger patient, mortality is more likely to be due to the metabolic disarray.
Pathogenesis of DKA AND HHS
The mechanisms that trigger DKA and HHS are multifactorial and include a combination of reduced secretion and action of insulin and raised levels of counterregulatory hormones (glucagon, catecholamines, cortisol and growth hormone). The association of insulin deficiency and increased counterregulatory hormones leads to altered glucose production and disposal, and to increased lipolysis and production of ketone bodies. Hyperglycemia results from increased hepatic and renal glucose production and impaired glucose utilization in peripheral tissues. This process is depicted in Figure 1. Increased gluconeogenesis results from the high availability of noncarbohydrate substrates (alanine, lactate and glycerol in the liver and glutamine in the kidney) and from the increased activity of gluconeogenic enzymes (phosphoenol pyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase and pyruvate carboxylase).
From a quantitative standpoint, increased hepatic glucose production represents the major pathogenic disturbance responsible for hyperglycemia in patients with DKA. In addition, both hyperglycemia and high ketone levels cause osmotic diuresis that lead to hypovolemia and decreased glomerular filtration rate; the latter further aggravates hyperglycemia.
Insulinopenia and increased counterregulatory hormones lead to increased lipolysis and and increased ketone production in DKA. Insulin deficiency causes the activation of hormone sensitive lipase in adipose tissue. The increased activity of tissue lipase causes breakdown of triglyceride into glycerol and free fatty acids. While glycerol becomes an important substrate for gluconeogenesis in the liver, the massive release of free fatty acids assumes pathophysiologic predominance, as they are the hepatic precursors of the ketoacids (Figure 2).
In the liver, free fatty acids are oxidized to ketone bodies, a process predominantly stimulated by glucagon. Increased concentration of glucagon lowers the hepatic levels of malonyl coenzyme A (CoA) by blocking the conversion of pyruvate to acetyl CoA through inhibition of acetyl CoA carboxylase, the first rate-limiting enzyme in the novo fatty acid synthesis. Malonyl CoA inhibits carnitine palmitoyl-transferase I (CPT I), the rate-limiting enzyme for transesterification of fatty acyl CoA to fatty acyl carnitine, allowing oxidation of fatty acid to ketone bodies. CPT I is required for movement of free fatty acid into the mitochondria, where fatty acid oxidation takes place. The increased fatty acyl CoA and CPT-I activity in DKA lead to increased ketogenesis in DKA. Increased production ketone bodies (acetoacetate [AcAc], and β- hydroxybutyrate [BOHB]) lead to ketonemia and metabolic acidosis.
HHS is characterized by a relative deficiency of insulin concentration to maintain normoglycemia, but adequate levels to prevent lipolysis and ketogenesis. Patients with HHS have been shown to have higher insulin concentration (demonstrated by basal and stimulated C-peptide levels) than those with DKA.
To date; however, very few studies have been performed comparing differences in counterregulatory response in DKA versus HHS. Furthermore, patients with HHS have reduced concentration of FFA, cortisol, growth hormone and glucagon compared to patients with DKA.
The excessive levels of circulating nutrients, including glucose and fatty acids, are associated with a pro-inflammatory and oxidative state. Previous studies have reported significant elevation of IL-6, IL-1B and IL-8, and TNF-α and increased counterregulatory hormones in patients with uncontrolled diabetes and ketoacidosis. Of interest, similar high levels of these markers occurred in patients with DKA and HHS, indicating that hyperglycemia, independent of the presence of ketoacidosis, induces changes in proinflammatory cytokines. These elevations of circulating proinflammatory cytokines are reduced to normal levels promptly in response to insulin therapy and normalization of blood glucose concentration. The increased cytokine release during DKA and HHS results in capillary perturbation and may explain why hyperglycemia is associated with poor outcomes in patients with acute myocardial infarction, stroke and cardiac surgery.
Precipitating Factor of DKA AND HHS
DKA is the initial manifestation of diabetes in 20% of adult patients and in 30-40% of children with T1D. In known diabetic patients, precipitating factors for DKA include infections, intercurrent illnesses, psychological stress and poor compliance with therapy. Infection is the most common precipitating factor for DKA, occurring in 30-50% of cases (Table I). Urinary tract infection and pneumonia account for the majority of infections. Other acute conditions that may precipitate DKA include cerebrovascular accident, alcohol abuse, pancreatitis, pulmonary embolism, myocardial infarction and trauma. Drugs that affect carbohydrate metabolism, such as corticosteroid, thiazides, sympathomimetic agents and pentamidine, may also precipitate the development of DKA, as well as the use of the atypical antipsychotic agents. More recently, the use of sodium- glucose co-transporter 2 inhibitors have been associated with several cases of DKA. Although in the FDA communication, the majority of the cases reported were of hyperglycemic DKA, euglycmeic DKA (glucose <300 mg/dl) has been reported as well in both type 1 (off-label use) and type 2 patients with diabetes mellitus. As up to 10% of DKA can be euglycemic, it is important to think of this diagnosis in the right clinical setting.
The importance of nonadherence to treatment and psychological factors in the incidence of DKA has been emphasized in young patients and in inner city populations. In adult patients with T1D, poor adherence to insulin therapy is reported as the major precipitating cause of DKA in inner-city populations. A recent study determined clinical, socioeconomic and psychological factors are associated with recurrence of DKA in inner-city minority patients. Discontinuation of insulin therapy accounted for more than two-thirds of all DKA admissions.
Several behavioral, socioeconomic, and psychosocial factors contributed to poor treatment adherence. Among patients with poor compliance with insulin therapy, one-third of patients “just stopped” (gave no clear reason for stopping insulin), one-third reported financial troubles, and most of the rest reported being away from supply or did not know how to handle insulin on sick days. Other studies have reported that psychological risk factors, including eating disorders, in up to 20% of recurrent episodes of ketoacidosis in young women.
HHS is the initial manifestation of diabetes in 7-17% of patients. Infection is the major precipitating factor, occurring in 30-60% of HHS patients, with urinary tract infections and pneumonia being the most common infections. Other common precipitating causes of HHS include cerebrovascular events, myocardial infarction, peritoneal dialysis, various endocrinopathies, acute pulmonary embolus and pancreatitis. Drugs that can precipitate HHS include beta-adrenergic blockers including propranolol, diuretics, glucocorticoids, diazoxide and b-blockers. HHS commonly occurs in older adults with T2D in nursing homes who may not be aware of the need for hydration. Such patients typically harbor severe infection with insidious development of T2D.
Diagnosis of DKA and HHS
Symptoms and Signs
The clinical presentation of DKA usually develops rapidly, over a time span of less than 24 hours. Polyuria, polydipsia and weight loss may be present for several days prior to the development of ketoacidosis, while vomiting and abdominal pain are frequently the presenting symptoms. Abdominal pain, sometimes mimicking an acute abdomen, is reported in 40-75% of DKA cases.
In our institution, we have observed that the presence of abdominal pain is associated with a more severe metabolic acidosis and with a history of alcohol or cocaine abuse, but not with the severity of hyperglycemia or dehydration. In a group of 200 consecutive patients with DKA, abdominal pain was present in 86% of patients with serum bicarbonate below 5 mmol/L, in 66% of patients with levels above 5 and below 10 mmol/L, in 36% of patients with levels above 10 and below 15 mmol/L, and in 13% of patients with bicarbonate levels 15-18 mmol/L. Although a potential acute abdominal problem prompting surgical intervention should not be overlooked, in the majority of patients the abdominal pain spontaneously resolves after correction of metabolic disturbance.
Physical examination reveals signs of dehydration, including loss of skin turgor, dry mucous membranes, tachycardia and hypotension. Mental status can vary from full alertness to profound lethargy; however, fewer than 20% of patients are hospitalized with loss of consciousness. Most patients are normothermic or even hypothermic at presentation. Acetone on breath and labored Kussmaul respiration may also be present on admission, particularly in patients with severe metabolic acidosis.
The typical patient with HHS has undiagnosed diabetes, is between 55 and 70 years of age and frequently is a nursing home resident. Most patients who develop HHS do so over days to weeks during which they experience polyuria, dehydration and progressive decline in the level of consciousness. Physical examination reveals signs of volume depletion. Fever due to underlying infection is common, and signs of acidosis (Kussmaul respiration, acetone breath) are usually absent. Gastrointestinal manifestations (abdominal pain, vomiting) frequently reported in patients with DKA are not part of HHS; thus the presence of abdominal pain in patients without significant metabolic acidosis needs to be investigated.
In some patients, focal neurologic signs (hemiparesis, hemianopsia) and seizures (partial motor seizures more common than generalized) may be the dominant clinical features, resulting in a common misdiagnosis of stroke. Despite the focal nature of neurological findings, the neurologic manifestations often reverse completely after correction of the metabolic disorder. The degree of mental obtundation has been shown to correlate with serum osmolarity in DKA. Thus, the majority of patients with an effective osmolarity greater than 330 mOsm/kg are severely obtunded or are comatose, but mental obtundation rarely exists in patients with osmolarity below 320 mOsm/kg.
Key Laboratory and Imaging Tests
Although the diagnosis of DKA and HHS can be suspected on clinical grounds, the confirmation in based on laboratory tests. The syndrome of DKA consists of the triad of hyperglycemia, hyperketonemia and metabolic acidosis. As indicated in Table II, DKA can be classified as mild, moderate, or severe, depending on the extent of metabolic acidosis and level of sensorium.
The diagnostic criteria for HHS include a plasma glucose concentration greater than 600 mg/dL, a serum osmolality greater than 320 mOsm/kg of water and the absence of significant metabolic acidosis (Table III). Although by definition, patients with HHS have a serum pH greater than 7.3, a serum bicarbonate greater than 18 mEq/L and negative ketone bodies in urine and plasma, mild ketonemia may be present. Approximately 20-50% of patients with HHS have an increased anion gap metabolic acidosis as the result of concomitant ketoacidosis and/or to an increase in serum lactate levels.
The assessment of augmented ketonemia, the key diagnostic feature of ketoacidosis, is usually performed by the nitroprusside reaction. However, clinicians should be aware that the nitroprusside reaction provides a semiquantitative estimation of acetoacetate and acetone levels, but does not recognize the presence of b-hydroxybutyrate, which is the main ketoacid in DKA. Therefore, this test may underestimate the level of ketosis. Direct measurement of b-hydroxybutyrate is now available by finger stick method, which is a more accurate indicator of ketoacidosis and response to medical treatment.
The admission serum sodium is usually low because of the osmotic flux of water from the intracellular to the extracellular space in the presence of hyperglycemia. To assess the severity of sodium and water deficit, serum sodium may be corrected by adding 1.6 mg/dL to the measured serum sodium for each 100 mg/dL of glucose above 100 mg/dL. An increase in serum sodium concentration in the presence of hyperglycemia indicates a rather profound degree of water loss.
The admission serum potassium concentration is usually elevated in patients with DKA. The mean serum potassium in patients with DKA and HHS was 5.6 mEq/l and 5.7 mEq/L, respectively. These high levels occur because of a shift of potassium from the intracellular to the extracellular space due to acidemia, insulin deficiency and hypertonicity. Similarly, the admission serum phosphate level may be normal or elevated because of metabolic acidosis. Dehydration also can lead to increases in total serum protein, albumin and creatine phosphokinase concentration in patients with acute diabetic decompensation.
Patients with DKA frequently present with leukocytosis in the absence of infection. However, a leukocyte count greater than 25,000 mm3 or the presence of greater than 10% neutrophil bands is seldom seen in the absence of bacterial infection. Because most patients with DKA present with abdominal pain, nausea, or vomiting, the differential diagnosis of acute pancreatitis should be considered. Hyperamylasemia has been reported in 21-79% of patients with DKA. There is little correlation between the presence, degree or isoenzyme type of hyperamylasemia and the presence of symptoms or abnormalities noted by pancreatic imaging studies.
Unfortunately, increased serum amylase, which may be released from extrapancreatic tissues, is not definitive for the diagnosis of pancreatitis in DKA. Nonspecific serum lipase elevation has also been reported in about one-third of patients with DKA in the absence of clinical and radiological evidence of acute pancreatitis.
Patients with chronic ethanol abuse with a recent binge culminating in nausea, vomiting and acute starvation may present with alcoholic ketoacidosis. The key diagnostic feature that differentiates diabetic and alcohol-induced ketoacidosis is the concentration of blood glucose. While DKA is characterized by severe hyperglycemia, the presence of ketoacidosis without hyperglycemia in an alcoholic patient is virtually diagnostic of alcoholic ketoacidosis.
In addition, some patients with decreased food intake (lower than 500 calories/day) for several days may present with starvation ketosis. However, a healthy subject is able to adapt to prolonged fasting by increasing ketone clearance by peripheral tissue (brain and muscle), and by enhancing the kidney’s ability to excrete ammonia to compensate for the increased acid production. Therefore, a patient with starvation ketosis rarely presents with a serum bicarbonate concentration less than 18 mEq/L.
Management and Treatment of the Disease
Table IV shows the recommended algorithm suggested by the recent position statement from the American Diabetes Association for treatment of DKA and HHS. The goals of DKA therapy are (a) to improve circulatory volume and ultimately tissue perfusion; (b) to correct hyperglycemia by gradually decreasing serum glucose and plasma osmolarity; (c) to correct electrolyte imbalance and reduce serum and urine ketone bodies to normal; and (d) to identify and treat precipitating events.
Frequent monitoring of vital signs, volume and rate of fluid administration, insulin dosage, urine output, and to assess response to medical treatment and document resolution of hyperglycemia and/or metabolic acidosis are essential for the successful management of DKA and HHS. Serial laboratory measurements include glucose and electrolyte, and in patients with DKA, venous pH, bicarbonate, and anion gap values until resolution of hyperglycemia and metabolic acidosis.
There are no guidelines determining the safety and cost effectiveness of treating adult patients with DKA in an ICU or in non-ICU settings. Several observational and prospective studies have indicated no clear benefits resulting from treating DKA patients in the ICU compared to step-down units or general medicine wards. The mortality rate, length of hospital stay and time to resolve ketoacidosis are similar between patients treated in ICU and non-ICU settings. In addition, ICU admission has been shown to be associated with more testing and significantly higher hospitalization cost in patients with DKA. Thus, the majority of patients with mild to moderate DKA can be safely managed in the emergency department or in step-down units, and only patients with severe DKA or those with a critical illness as precipitating cause (i.e. myocardial infarction, gastrointestinal bleeding, sepsis) should be treated in the ICU. In addition, trained nursing personnel are critical for the management of DKA in non-ICU settings.
Patients with DKA and HHS are invariably volume depleted with an estimated water deficit of approximately 100 ml/kg of body weight. Therefore, aggressive fluid therapy is needed for expansion of intravascular volume and restoration of renal perfusion. In addition, hydration alone may also reduce the level of counter-regulatory hormones and hyperglycemia. Isotonic saline (0.9% NaCl) infused at a rate of 500-1000 mL/h during the first 2 hours is usually adequate, but in patients with hypovolemic shock, a third or fourth liter of isotonic saline may be needed to restore normal blood pressure and tissue perfusion.
After intravascular volume depletion has been corrected, the rate of normal saline infusion should be reduced to 250 mL/h or changed to 0.45% saline (250-500 mL/h) depending upon the serum sodium concentration and state of hydration. The choice and rate of subsequent fluid will be based on the patient’s sodium concentration and hydration status. The water deficit can be estimated, based on corrected serum sodium concentration, using the following equation: water deficit = (0.6)(body weight in kilograms) x (1- [corrected sodium / 140]). The goal is to replace half the estimated water deficit over a period of 24 hours. Iatrogenic fluid overload can be avoided by frequent patient monitoring.
During treatment of DKA, hyperglycemia is corrected faster than ketoacidosis. The mean duration of treatment until blood glucose reaches less than 250 mg/dl and ketoacidosis is corrected is 6 and 12 h, respectively. Once the plasma glucose is approximately 250 mg/dL, 5-10% dextrose should be added to replacement fluids to allow continued insulin administration until ketonemia is controlled, while at the same time avoiding hypoglycemia. An additional important aspect of fluid management is to replace the volume of urinary losses, especially in those subjects with excessive polyuria. Failure to adjust fluid replacement for urinary losses may delay correction of water deficit.
The cornerstone of DKA and HHS therapy is insulin in physiologic doses. Insulin increases peripheral glucose utilization and decreases hepatic glucose production, thereby lowering blood glucose concentration. In addition, insulin therapy inhibits the release of free fatty acid from adipose tissue and decreases ketogenesis, both of which lead to the reversal of ketogenesis. In critically ill and mentally obtunded patients, regular insulin given intravenously by continuous infusion is the treatment of choice. Many treatment algorithms have recommended the use of an intravenous bolus of regular insulin followed by continuous infusion of regular insulin at a dose of 0.1 U/kg/h, followed by a continuous infusion of regular insulin at a dose of 0.1 unit/kg per hour (5-10 unit/h).
A randomized prospective study has recently demonstrated that in the treatment of DKA, an initial bolus of insulin is not necessary if the hourly insulin infusion rate is 0.14 U/kg body weight (e.g., 10 U/h in a 70-kg patient). This will result in a fairly predictable decrease in plasma glucose concentration at a rate of 65-125 mg/h. The optimal rate of glucose decrement should be between 50 and 150 mg/h. If glucose levels do not decrease by 50-75 mg/dL during the first hour of insulin therapy, the insulin infusion should be increased every hour until a steady decline in glucose levels is achieved.
When plasma glucose reaches 200 mg/dL, the insulin rate should be decreased to 0.02-0.05 U/kg/h and an infusion of 5% dextrose may be started. In DKA, the rate of insulin should be adjusted to maintain blood glucose between 150 and 200 mg/dL until DKA is resolved. Similarly, in patients with HHS, treatment should be adjusted to maintain a plasma glucose concentration of approximately 200 mg/dL until mental obtundation and hyperosmolar state are corrected.
A patient with uncomplicated DKA can be treated with subcutaneous rapid-acting insulin analogs. Recent studies have shown that, for mild to moderate cases of DKA, the use of subcutaneous lispro or insulin aspart given every 1-2 hours is as effective as the use of regular insulin given intravenously in the ICU.
After an initial subcutaneous dose of 0.2-0.3 U/kg of lispro or aspart, these analogs can be given in doses of 8-10 Units every 2 hours on general medical wards, as long as adequate personnel are available for frequent measuring of blood glucose by finger-stick testing every 2 hours and frequent monitoring of electrolytes and venous pH (every 4-6 hours) with adequate administration of hydrating fluid.
In the above-mentioned studies, the incidence of hypoglycemia was the same as with the intravenous insulin protocol in the ICU. The use of rapid-acting insulin analogs is not recommended for patients with severe DKA or HHS. This is because no prospective randomized studies have compared the infusion of rapid- acting insulin analogs with the infusion of intravenous regular insulin in the ICU.
During therapy, capillary blood glucose should be determined every 1-2 hours at the bedside using a glucose oxidase reagent strip and blood should be drawn every 2-4 hours for determination of serum electrolytes, glucose, blood urea nitrogen, creatinine, magnesium, phosphorus, and venous pH. During the follow-up period, pH determination in DKA should be performed by venous rather than arterial puncture because arterial blood gases are seldom needed in such patients.
Patients with DKA and HHS have total-body total body potassium deficit of approximately 3-5 mEq/kg of body weight. Despite this deficit, most patients with DKA have a serum potassium level at or above the upper limits of normal. These high levels occur because of a shift of potassium from the intracellular to the extracellular space due to acidemia, insulin deficiency and hypertonicity.
Both insulin therapy and correction of acidosis decrease serum potassium levels by stimulating cellular potassium uptake in peripheral tissues. Therefore, it is important that potassium be carefully monitored during therapy. Intravenous potassium should be initiated as soon as the serum potassium concentration is below 5.0 mEq/L. The treatment goal is to maintain serum potassium levels within the normal range of 4-5 mEq/L. In some hyperglycemic patients admitted with severe potassium deficiency, insulin administration may precipitate profound hypokalemia, which can induce life-threatening arrhythmias and respiratory muscle weakness. Thus, if the initial serum potassium is lower than 3.3 mEq/L, potassium replacement should begin immediately by an infusion of potassium chloride at a rate of 20 mEq per hour and insulin therapy should be delayed until serum potassium is (3(3(mEq/L or more.
Severe metabolic acidosis can lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications; however, several studies have reported that bicarbonate therapy for DKA offers no advantage in improving cardiac and neurologic functions or in the rate of recovery of hyperglycemia and ketoacidosis.
Nine small studies have evaluated the effect of alkalinization in a total of 434 patients with DKA, 217 treated with bicarbonate, and 178 patients without alkali therapy. Moreover, several deleterious effects of bicarbonate therapy have been reported, such as increased risk of hypokalemia, decreased tissue oxygen uptake, and cerebral edema. Despite the lack of evidence in support of the use of bicarbonate therapy in patients with DKA, clinical guidelines recommend that in patients with severe metabolic acidosis (pH less than 6.9), 50-100 mmol of sodium bicarbonate should be given as isotonic solution (in 200 ml of water) every 2 hours until pH rises to approximately 6.9-7.0.
In patients with arterial pH of 7.0 or higher, no bicarbonate therapy is necessary. There is no indication for bicarbonate treatment in patients with HHS as such patients do not have significant metabolic acidosis. DKA in children is not usually treated with bicarbonate even when pH is low, as its use may increase the risk of brain edema.
Total body phosphate deficiency is universally present in patients with DKA, but its clinical relevance and benefits of replacement therapy remain uncertain. Severe hypophosphatemia may lead to rhabdomyolysis, hemolytic uremia, muscle weakness and paralysis; however, several studies have failed to show any beneficial effect of phosphate replacement on clinical outcome. Furthermore, aggressive phosphate therapy is potentially hazardous, as indicated in case reports of children with DKA who developed hypocalcemia, tetany and seizures secondary to intravenous phosphate administration.
Theoretic advantages of phosphate therapy include prevention of respiratory depression and generation of erythrocyte 2,3-diphosphoglycerate. Because of these potential benefits, careful phosphate replacement may be indicated in patients with cardiac dysfunction, anemia, respiratory depression, and in those with serum phosphate concentration lower than 1.0-1.5 mg/dL. In such patients, because of the risk of hypocalcemia, serum calcium and phosphate levels must be monitored during phosphate infusion.
Patients with DKA and HHS frequently have large magnesium deficits, but there are no data to determine whether replacement of magnesium is beneficial. Replacement of magnesium should be considered in the occasional patient who experiences severe hypomagnesemia and hypocalcemia during therapy. The recommended dose is 25-50 mg/kg per dose for 3-4 doses given every 4-6 hours, with a maximum infusion rate of 150 mg/min and 2 g/h.
Immediate Follow-up Care After Hyperglycemic Crisis
Intravenous insulin therapy should continue until the hyperglycemic crisis has resolved. Criteria for resolution of DKA include the following:
Blood glucose lower than 200 mg/dL
Serum bicarbonate level equal to orgreater than 18 mEq/L
Venous pH greater than 7.3
Calculated anion gap equal to or lower than 14 mEq/L
The resolution of HHS is indicated when total serum osmolarity is less than 320 mOsm/kg and blood glucose is 250 mg/dL or less, with a gradual recovery to mental alertness.
It is important to recognize that the half-life of intravenous regular insulin is very short (5-7 minutes); therefore, if low-dose insulin infusion is interrupted suddenly, the insulin concentration in blood could reach undetectable levels, with relapse of the hyperglycemia and ketoacidosis. Therefore, we recommend that intravenous infusion of insulin be continued for 2-4 hours after subcutaneous insulin is started. Recent reports have suggested that the administration of subcutaneous basal insulin early in the course of treatment may facilitate treatment and prevent rebound hyperglycemia after discontinuation of IV insulin therapy.
The best time to transition from subcutaneous insulin is once the patient is alert and able to take food by mouth. Patients known to be diabetics and treated with insulin can resume their previous regimen (if it had been controlling their diabetes). Insulin-naïve adult patients can be started on 0.5-0.7 U/kg/d, in divided doses, to achieve adequate glycemic control.
The American Diabetes Association (ADA) position statement recommends a transition to a split-mixed insulin regimen with neutral protamine Hagedorn (NPH) and regular insulin twice daily or to a multi-dose regimen of short- or rapid-acting and intermediate- or long-acting insulins. Several studies have reported hospital rates of hypoglycemic events up to 30% with the use of NPH and regular insulin after discontinuation of IV insulin.
The inadequate duration of action of NPH insulin and an undesirable peak activity at 4-6 hours after injection, as well as the high day-to-day variability in absorption, partially explain the high rate of hypoglycemic events. A recent randomized study compared the safety and efficacy of insulin analogs and human insulins during the transition from intravenous to SC insulin in patients with DKA. During the transition to SC insulin, there were no differences in mean daily glucose levels, but 41% of patients treated with NPH and regular insulin had higher rate of hypoglycemia compared to 15% of patients treated with glargine once daily and glulisine before meals. Thus, a basal bolus regimen with insulin analogs is safer and should be preferred over NPH and regular insulin following the resolution of DKA.
Complications of Therapy
The two most common acute complications associated with the treatment of DKA in adult subjects are hypoglycemia and hypokalemia. Hypoglycemia is reported in 10-25% of patients during insulin therapy. Hypoglycemic events most commonly occur after several hours of insulin infusion (between 8 and 16 hours) or during the transition phase. The failure to reduce the insulin infusion rate or to use dextrose-containing solutions when glucose levels reach 250 mg/dL are the two most common causes of hypoglycemia during insulin therapy.
Frequent blood glucose monitoring (every 1-2 hours) is mandatory to recognize hypoglycemia because many patients with DKA who develop hypoglycemia during treatment do not experience adrenergic manifestations of sweating, nervousness, fatigue, hunger and tachycardia. Both insulin therapy and correction of acidosis decrease serum potassium levels by stimulating cellular potassium uptake in peripheral tissues and may lead to hypokalemia. Aggressive potassium replacement early in the management has been shown to minimize the risk of hypokalemia.
To prevent hypokalemia, initiate replacement with intravenous potassium as soon as the serum potassium concentration is below 5.5 mEq/L. In addition, in patients who present with normal or reduced serum potassium, aggressive IV potassium replacement should begin immediately and insulin therapy should be held until serum potassium is 3.3 mEq/ L or greater.
Relapse of DKA may occur after sudden interruption of IV insulin therapy or in patients without concomitant use of SC insulin administration or lack of frequent monitoring. To prevent recurrence of ketoacidosis during the transition period to SC insulin, it is important to allow an overlap of 1-2 hours between discontinuation of IV insulin and the administration of SC regular insulin.
Other complications of diabetes include hyperchloremic acidosis with an excessive use of NaCl or KCl, resulting in a nonanionic gap metabolic acidosis. This acidosis has no adverse clinical effects and is gradually corrected over the subsequent 24-48 hours by enhanced renal acid excretion. The development of hyperchloremia can be prevented with reduction of the chloride load by judicious use of hydration solutions.
Cerebral edema is a rare complication in adult patients with DKA. Symptoms and signs of cerebral edema are variable and include onset of headache, gradual deterioration in level of consciousness, seizures, sphincter incontinence, pupillary changes, papilledema, bradycardia, elevation in blood pressure and respiratory arrest. Cerebral edema typically occurs 4-12 hours after treatment is activated, but it can be present before treatment has begun or may develop any time during treatment for DKA.
Although, no single factor has been identified that can be used to predict the development of cerebral edema, a number of mechanisms have been proposed, including the role of cerebral ischemia and hypoxia, the generation of various inflammatory mediators, increased cerebral blood flow, disruption of cell membrane ion transport, and rapid shift in extracellular and intracellular fluids resulting in changes in osmolality.
Rhabdomyolysis may occur in patients with DKA and more commonly with HHS, resulting in acute kidney failure, severe hyperkalemia, hypocalcemia and muscle swelling causing compartment syndrome. The classic symptom triad of rhabdomyolysis includes myalgia, weakness and dark urine, and monitoring creatine kinase concentrations every 2-3 hours is recommended for early detection.
The most common precipitating causes of DKA include infection, intercurrent illness, psychological stress, and noncompliance with therapy. With improved outpatient treatment programs and better adherence to self-care, approximately 50-75% of DKA admissions may be preventable with management. Outpatient management is more cost effective and can minimize missed days of school and work for patients with diabetes and their family members.
The frequency of hospitalizations for DKA has been reduced following diabetes education programs, improved follow-up care, and access to medical advice. Many patients with recurrent DKA are unaware of sick-day management or the consequences of skipping or discontinuing insulin therapy. It has been shown that quarterly visits to the endocrine clinic will reduce the number of emergency department admissions for DKA.
An important feature of patient education is how to deal with illness. This includes (a) communicating the importance of insulin therapy during illness and emphasizing that insulin should never be discontinued; (b) early contact with healthcare providers; (c) initiation of early management of fevers and infections; and (d) adequate fluid intake. In addition, diabetes education and sick-day management should be reviewed periodically in patients with diabetes and should include specific information on when to contact the health-care provider, blood glucose and A1C goals, use of supplemental short- or rapid-acting insulin during illness, and, most important, the importance of never discontinuing insulin and of seeking immediate medical attention in the case of severe hyperglycemia.
A recent study in adolescents reported that an intensive home-based multidisciplinary intervention resulted in a significant decrease in DKA admissions over 2 years. In that study, a multidisciplinary diabetes team met with study patients frequently and addressed barriers to communication, access to care and medical adherence on the family, school, and health-care levels. Despite the expense of providing such an intensive intervention, the multidisciplinary intervention incurred less cost to the health-care system because of the decreased number of DKA admissions. In addition, patients with type 1 diabetes should be instructed on the use of home blood ketone monitoring during illness and persistent hyperglycemia, which may allow for early recognition of impending ketoacidosis, and in turn may help to guide insulin therapy at home and, possibly, may prevent hospitalization for DKA.
Finally, the alarming rise in insulin discontinuation because of economic reasons as the precipitating cause for DKA in urban patients illustrates the need for health-care legislation to ensure reimbursement for medications to treat diabetes. Novel approaches to patient education incorporating a variety of health-care beliefs and socioeconomic issues are critical to an effective prevention program.
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- Description of the Condition
- Key Laboratory and Imaging Tests
- Management and Treatment of the Disease