Diabetic Ketoacidosis

Chapter 9

Diabetic Ketoacidosis Diabetic ketoacidosis (DKA) is an acute, severe, and potentially life-threatening phenomenon that is caused by severe hyperglycemia, in which the blood glucose levels exceed 250 mg/dL. There is excess production of ketoacids due to a lack of insulin. Insulin deficiency can be absolute or relative. The majority of patients who develop ketoacidosis are type 1 diabetics with poor control of their conditions. Approximately 20% of cases occur in patients presenting for the first time, recently having been diagnosed with the disease. However, varying amounts of ketoacidosis are being seen in type 2 diabetics. Adequate patient education about diabetes is an important way to prevent DKA from developing. When the body attempts to compensate for starvation, ketoacidosis develops. When fasting, the body normally performs transitions from glycolysis, the breakdown of glycogen, to lipolysis, the breakdown of fat, for energy. The adipocytes release free fatty acids, which are transported to the liver, bound to albumin. In the liver, they are broken down into acetate. This is transformed into the ketoacids called acetoacetate and beta-hydroxybutyrate. These ketoacids are moved from the liver to the peripheral tissues for oxidation—primarily, these peripheral tissues are the brain and muscles. Triggers for DKA include pneumonia, urinary tract infections, and other acute infections; myocardial infarction, stroke, pancreatitis, and trauma. Medications may also be causative, including corticosteroids, thiazide diuretics, and sympathomimetics. As hyperglycemia manifests, these processes are altered, and ketoacidosis develops. Large amounts of circulating glucose cannot be used for energy because of a lack of insulin. The ketogenic pathways are highly activated, and ketones exceed the ability to be used peripherally. The ketone bodies are acidic. High concentrations of them lower blood pH, causing ketoacidosis. In ketosis, a comparatively small amount of acetone is produced, making the breath have a “fruity” smell. High blood glucose level causes significant osmotic diuresis and dehydration. There are deficits of the key electrolytes, such as sodium, potassium, chloride, phosphate, magnesium, and calcium. Between 1% and 10% of patients with DKA will die from the condition. Variations are based on presentation of the patient at a specific stage of its development, and how the case is managed. The actual causes of death include acute myocardial infarction, septic shock, stroke, cerebral edema, and profound acidosis of the arterial blood. Treatment involves suppressing ketosis via administration of insulin, fluid resuscitation, restoration of electrolyte balances in the blood, and treating any co-existing conditions.

EPIDEMIOLOGY According to Diapedia, The Living Textbook of Diabetes, annual incidence of DKA varies between populations. Risk factors are onset of diabetes at less than 5 years of age, possibly because of poor symptom recognition, socioeconomic disadvantages, a lower body mass index, and a preceding infection. Today, ketoacidosis is more often seen in patients with established diabetes, usually related to other existing illnesses or poor compliance. Poor education is also linked. Type 2 diabetics may also develop ketoacidosis, especially in African-Americans or Hispanic-Americans.

ETHNIC DISPARITIES Statistics on DKA management show that the condition affects males and females in equal amounts. Previously, women were hospitalized for DKA more often, but this is now changing. Very young and very old patients are most likely to experience DKA. Minority racial groups are affected more often than majority groups. According to the Center for Disease Control and Prevention in 2015, DKA affected about 30 million people in the United States. After a slight decline during the years 2000 9, hospitalizations for DKA increased during 2009 14, in all age groups. They were highest in people over the age of 45. At the same time, in-hospital death rates due to DKA consistently decreased from 2000 to 2014. Epidemiology of Diabetes. DOI: https://doi.org/10.1016/B978-0-12-816864-6.00009-2 © 2019 Elsevier Inc. All rights reserved.

147

148

Epidemiology of Diabetes

As published in Metabolism—Clinical and Experimental, a 3-year study of DKA patients in New York revealed that 97% were African- or Hispanic-American. Most of the participants in the study had type 1 diabetes. However, a larger group of African-Americans had type 2 diabetes along with ketoacidosis than seen in other groups. The DKA was more severe in type 1 diabetics over all groups. In African-Americans, more than 50% of newly diagnosed cases of DKA have metabolic characteristics that are more closely aligned with type 2 diabetes. This data is based on a study published in Endocrine Practice. This subtype of diabetes is called ketosis-prone diabetes, and occurs in an estimated 33% of African-Americans with type 2 diabetes. The condition is also more prevalent in men from various ethnic groups than in women.

PATHOPHYSIOLOGY DKA results from relative or absolute insulin deficiency that causes the body to metabolize triglycerides and muscle instead of glucose, for energy. There is a rapid breakdown of energy stores from muscle and fat deposits. Serum glycerol and free fatty acids increase due to uncontrolled lipolysis. Alanine also increases, due to muscle catabolism. Gluconeogenesis in the liver utilizes glycerol and alanine. The process is stimulated by excessive glucagon, which accompanies insulin deficiency. Increased amounts of amino acids move to the liver, to be converted to glucose, as fatty acids also move to this organ for conversion to ketones. The mitochondrial conversion of free fatty acids into ketones is stimulated by glucagon. Ketogenesis is normally blocked by insulin, via inhibition of transporting free fatty acid derivatives into the mitochondrial matrix. However, ketogenesis proceeds when insulin is absent. In DKA, increased hydrogen ion concentrations in the extracellular fluid cause hydrogen ions to shift into cells, in exchange for potassium ions, while diuresis is ongoing. Normal potassium ion levels are maintained in the plasma as they are lost in the urine. This causes a deficit in the amount of total body potassium. Total body potassium ions are depleted, which is seen when insulin treatment and rehydration therapy is started. In insulin deficiency and ketosis, glucagon levels, and the levels of insulin-counterregulatory hormones increase. These include catecholamines, cortisol and other glucocorticosteroids, epinephrine, glucagon, and growth hormone. They antagonize insulin via increased glucose production and decreased use of glucose by various body tissues. Significant insulin deficiency causes decreased glucose uptake, increased fat mobilization with fatty acid release, and faster gluconeogenesis and ketogenesis. Increased levels of glucagon aid in activation of gluconeogenic and ketogenic pathways in the liver. The liver’s overproduction of beta-hydroxybutyrate and acetoacetic acids increases concentrations of ketones. Commonly, ketones are used as an energy source in the tissues to regenerate bicarbonate, which balances losses of bicarbonate that occur when ketones are formed. Hyperketonemia may occur by impaired use of ketones in the peripheral tissues. This allows free circulation of strong organic acids. Bicarbonate buffering does not happen, and a metabolic acidosis develops. The pathophysiology of DKA and hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) is shown in Fig. 9.1. This figure details how relative insulin insufficiency and various precipitating factors act in the body, influencing the development of DKA and HHNKS. FIGURE 9.1 Pathophysiology of DKA and HHNKS in Diabetes Mellitus.

Diabetic Ketoacidosis Chapter | 9

149

CLINICAL MANIFESTATIONS The clinical manifestations of DKA are varied. It usually develops over 24 hours. DKA may be the initial presentation that leads to diagnosis of type 1 diabetes mellitus. However, more often, it occurs in patients who have established diabetes. Nausea and vomiting are very common. There may be severe abdominal pain that resembles acute pancreatitis. Hypotension can occur, due to blood volume depletion, combined with peripheral vasodilation. The osmotic diuresis related to hyperglycemia causes polyuria and dehydration. In severe decompensation, lethargy and somnolence often occur. The patient may be hypotensive and tachycardic due to dehydration and acidosis. There are usually sodium, magnesium, and phosphorus deficits. The most important electrolyte disturbance is a deficiency of total body potassium. The serum potassium concentration may be normal or elevated, due to volume contraction and potassium shifting in and out of the cells and blood, due to metabolic acidosis. Total potassium deficiency can reach 3 5 mEq/kg. Symptoms of DKA include Kussmaul respirations, in which there is hyperventilation that attempts to compensate for the acidosis. Additional symptoms include central nervous system depression, postural dizziness, anorexia, ketonuria, abdominal pain, nausea, polyuria, and thirst. Patients with DKA may have stupor, and obvious profound dehydration. There may be focal neurologic deficits, such as Babinski reflexes, asymmetric reflexes, cranial nerve findings, and aphasia. Patients have a “fruity” breath odor because of exhaled acetone. Fever is not actually a sign of DKA itself, but if present, indicates an underlying infection. Untreated DKA will lead to coma and death. Acute cerebral edema occurs in just 1% of patients, mostly in children, and less often in adolescents and younger adults. This is often accompanied by headache and varying levels of consciousness. However, respiratory arrest is the first manifestation in some patients. It is most common in children under 5 years of age, when DKA is the first manifestation of diabetes. Children with the highest blood urea nitrogen and lowest partial pressure of carbon dioxide seem to be at highest risk. Additional risk factors include delay in correcting hyponatremia and the use of bicarbonate during treatment.

DIAGNOSIS Diagnosis of DKA is based on symptoms of abdominal pain, vomiting, acetone odor on the breath, dehydration, and sense-related changes. There are five criteria according to the American Diabetes Association: G G G G G

Serum glucose levels over 250 mg/dL Serum bicarbonate levels under 18 mg/dL Serum pH below 7.30 Presence of an anion gap Presence of urine and serum ketones

Diagnosis is based on measurement of blood urea nitrogen, serum creatinine levels, serum electrolytes, glucose, ketones, and osmolarity. The urine is tested for ketones. For those who are extremely ill and patients with positive ketones, the arterial blood gases are measured. The arterial pH ranges between 6.8 and 7.3, based on the severity of the acidosis. When urine glucose and ketones are strongly positive, a presumptive diagnosis can be made. The degree of ketosis can be underestimated by urine test strips and certain serum ketone assays. This is because they detect acetoacetic acid, and not beta-hydroxybutyric acid, which is usually the primary ketoacid. Cultures, imaging, and other studies should be performed to determine any underlying illnesses. Adults should have an ECG to screen for acute myocardial infarction, and to assess serum potassium abnormalities. Additional abnormalities may include elevated serum creatinine, hyponatremia, and elevated serum osmolarity. Dilutional hyponatremia may be caused by hyperglycemia. Therefore measure serum sodium is balanced by adding 1.6 mEq/L for every 100 mg/dL elevation of the serum glucose above 100 mg/dL. Serum potassium drops as acidosis is corrected. Initial potassium levels of less than 4.5 mEq/L indicate significant potassium depletion, requiring immediate supplementation. There are often elevations of serum amylase and lipase, even when pancreatitis is not present. The differential diagnoses of DKA include alcoholic ketoacidosis, starvation ketosis, and other types of increased anion gap acidosis.

PROGNOSIS DKA is fatal in 1% 10% of patients. Prognosis is worsened if the patient is admitted while in shock or coma. Primary causes of death are circulatory collapse, hypokalemia, and infection. In children with cerebral edema, 57% recover totally, 21% survive but have neurologic sequelae, and 21% die from the condition.

150

Epidemiology of Diabetes

TREATMENT Treatment of DKA involves administration of insulin to lower glucose levels, and fluids to replace lost fluid volume. As fluid volume is replaced, electrolyte deficits will appear. These are treated as needed with intravenous (IV) sodium, potassium, and phosphorus. There must be close monitoring of fluids and electrolytes. After insulin administration, beta-hydroxybutyrate concentrations quickly decrease. Concentrations of acetoacetate show a slight increase, which is followed by a decrease in levels. Persistent ketonuria may be present for several days following treatment. Continuous monitoring is vital to ensure an uncomplicated recovery. It is important to understand DKA predisposing factors and strategies that help avoid development of the condition. Treatment of ketoacidosis is handled in intensive care settings, because hourly assessments are required along with quick adjustments in treatment. Intravascular volume is quickly restored, raising blood pressure (BP) and ensuring glomerular perfusion. Then, any remaining total body water deficits are corrected slowly, usually over 24 hours. Adult patients usually require at least 3 L of saline over the first 5 hours. Once BP is stable and urine flow is normalized, the normal saline is replaced by 0.45% saline. When plasma glucose falls below 250 mg/dL, the IV fluid is changed to 5% dextrose in 0.45% saline. For children, fluid deficits are estimated at 60 100 mL per kilogram of body weight. Maintenance fluids are provided for ongoing losses. Initial fluid therapy is 0.9% saline at 20 mL/kg over 1 2 hours. This is followed by 0.45% saline when the BP is stabilized and urine output adequate. Remaining fluid deficits should be replaced over 36 hours, usually at about 2 4 mL/kg/h based on the amount of dehydration. Hyperglycemia is treated with regular insulin 0.15 unit/kg IV bolus at first. This is followed by continuous IV infusion of 0.1 unit/kg/h in 0.9% saline solution. Insulin must be withheld until the serum potassium is 3.3 mEq/L or higher. Inconsistent effects may occur because of insulin adsorption onto IV tubing. This can be minimized by pre-flushing the tubing with insulin solution. If plasma glucose does not reduce by 50 75 mg/dL within the first hour, doses of insulin must be doubled. Children should be administered continuous IV insulin at 0.1 unit/kg/h or more, with or without a bolus. Ketones usually clear within hours once insulin is administered sufficiently. This clearance can be slower than desired due to conversion of beta-hydroxybutyrate to acetoacetate, while acidosis is resolving. Usually, serum pH and bicarbonate levels also quickly improve. However, restoration of a normal serum bicarbonate level can take 24 hours to occur. Rapid correction of pH via bicarbonate administration may be considered if the pH stays at less than 7.0 after approximately 1 hour of initial fluid resuscitation. However, bicarbonate is related to the development of acute cerebral edema, mostly in children, and should not be routinely used. If it is, only slight pH elevation should be attempted, with a target pH of about 7.1. Doses of 50 100 mEq are given over 30 60 minutes, followed by repeated measurement of arterial pH and serum potassium. In adults, when plasma glucose becomes 250 300 mg/dL (or 13.88 16.65 mmol/L), 5% dextrose is added to the IV fluids, to reduce risks of hypoglycemia. Dosages of insulin can then be reduced at a minimum of 1 2 units/ h. However, continuous IV infusion of regular insulin must be maintained until the anion gap has narrowed, and both blood and urine are repeatedly negative for ketones. Insulin replacement can then be switched to regular insulin at 5 10 units subcutaneously, every 4 6 hours. Once the patient is stable and can eat, a usual split-mixed or basal-bolus insulin regimen is started. The IV insulin is continued for 1 4 hours following the initial dose of subcutaneous insulin. Children should receive 0.05 units/kg/h insulin infusion, until subcutaneous insulin is started and the pH is .7.3. Prevention of hypokalemia requires replacement of 20 30 mEq of potassium in each liter of IV fluid. This keeps the serum potassium between 4 and 5 mEq/L. If serum potassium is less than 3.3 mEq/L, insulin is withheld. Potassium is administered at 40 mEq/h until the serum potassium is more than 3.3 mEq/L. If the serum potassium is more than 5 mEq/L, potassium supplementation can be withheld. Initial serum potassium measurements that are normal or elevated can reveal shifts from intracellular stores that are responses to acidemia. They may not show the true potassium deficits that nearly every DKA patient has. Insulin replacement quickly moves potassium into the cells. Therefore levels are checked every hour or every other hour in the initial treatment stages. Hypophosphatemia often develops, but phosphate repletion is not of clear benefit in most patients. If rhabdomyolysis, hemolysis, or neurologic deterioration occurs, there can be an infusion, over 6 12 hours, of potassium phosphate, at 1 2 mmol/kg. If potassium phosphate is administered, serum calcium levels usually decrease, and must be monitored. Treatment of any suspected cerebral edema includes corticosteroids, hyperventilation, and mannitol. However, these treatments are often not effective following onset of respiratory arrest.

Diabetic Ketoacidosis Chapter | 9

151

FURTHER READING [1] 12 Diabetic ketoacidosis (DKA) symptoms and warning signs. ,https://www.medicinenet.com/diabetic_ketoacidosis_symptoms/views.htm.. [2] Acetoacetate—an overview. ,https://www.sciencedirect.com/topics/chemistry/acetoacetate.. [3] Admissions for diabetic ketoacidosis in ethnic minority groups in a city hospital. ,https://www.sciencedirect.com/science/article/pii/ s002604950600343x.. [4] Applied Research Press. Reducing episodes of diabetic ketoacidosis within a youth population: a group study with patients and families. CreateSpace Independent Publishing Platform; 2015. [5] Calculating the anion gap in diabetic ketoacidosis. ,https://www.consultant360.com/content/calculating-anion-gap-diabetic-ketoacidosis.. [6] Dennis M, Bowen WT, Cho L. Mechanisms of clinical signs. Churchill Livingstone; 2012. [7] Diabetes complications. ,https://www.healthguideinfo.com/diabetes-complications/p113772/.. [8] Diabetic ketoacidosis. ,https://www.healthline.com/health/type-2-diabetes/ketoacidosis.. [9] Diabetic ketoacidosis (DKA). ,https://www.webmd.com/diabetes/ketoacidosis.. [10] Diabetic ketoacidosis in African Americans. ,https://www.endocrineweb.com/professional/diabetes-complications/diabetic-ketoacidosis-lookstype-2-diabetes-african-americans.. [11] Diabetic ketoacidosis: practice essentials. ,https://emedicine.medscape.com/article/118361-overview.. [12] DKA and hyperglycemic hyperosmolar state. ,https://www.diapedia.org/acute-and-chronic-complications-of-diabetes/71040851425/diabeticketoacidosis-and-hyperglycaemic-hyperosmolar-state.. [13] DKA (ketoacidosis) & ketones. ,http://www.diabetes.org/living-with-diabetes/complications/ketoacidosis-dka.html.. [14] Duck SC, Hageman JR. Pediatric diabetic ketoacidosis: risk factors and pathophysiology, management strategies and outcomes (pediatrics-laboratory and clinical research). Nova Science Publications Inc.; 2016. [15] Elevated beta hydroxybutyrate levels. ,www.medicalhealthtests.com/articles/294/general-articles/elevated-beta-hydroxybutyrate.html.. [16] Haddad SF. X-plain diabetic ketoacidosis-DKA. Patient Education Institute; 2016. [17] Harris RE. Epidemiology of chronic disease: global perspectives. Jones & Bartlett Learning; 2012. [18] HHNKS. ,http://diabetes.org/living-with-diabetes/complications/hyperosmolar-hyperglycemic.html.. [19] Icon Group International. Acetoacetate: Webster’s timeline history, 1949 2007. ICON Group International, Inc.; 2009. [20] Icon Group International. Ketoacidosis: Webster’s timeline history, 1967 2007. ICON Group International, Inc.; 2010. [21] Icon Health Publications. Ketoacidosis—a medical dictionary, bibliography, and annotated research guide to internet references. ICON Health Publications; 2004. [22] Katsilambros N, Kanaka-Gantenbein C, Liatis S, et al. Diabetic emergencies: diagnosis and clinical management. 2nd ed. Wiley-Blackwell; 2011. [23] Ketosis vs. ketoacidosis: what’s the difference? ,https://www.healthline.com/health/ketosis-vs-ketoacidosis.. [24] Kumari O, Gupta D, Kumar V. Kinetic study of keto acids and alcohols. Lambert; 2017. [25] Loriaux L. Endocrine emergencies: recognition and treatment (contemporary endocrinology). Humana Press; 2014. [26] Porter RS. The Merck manual. 19th ed. Merck; 2011. [27] RN Review. Diabetic ketoacidosis (DKA)—a high yield review for nursing students. Amazon Digital Services LLC; 2014. [28] Shea SS, Hoyt KS, Kathleen J, et al. Pediatric emergent/urgent and ambulatory care: the pocket NP. Springer Publishing Company; 2016. [29] Syndromes of ketosis-prone diabetes mellitus. ,https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2528854.. [30] Trends in diabetic ketoacidosis hospitalizations and in-hospital mortality. ,https://www.cdc.gov/mmwr/volumes/67/wr/mm6712a3.htm.. [31] USMLE Review. Diabetic ketoacidosis—a high yield review for medical students. Amazon Digital Services LLC; 2014. [32] What is diabetic ketoacidosis? ,https://www.emedicinehealth.com/diabetic_ketoacidosis/article_em.htm..