Hyperglycemia in DKA is the result of reduced glucose uptake and utilization from the liver, muscle, and fat tissue and increased gluconeogenesis as well as glycogenolysis.
The lack of insulin results in an increase in gluconeogenesis, primarily in the liver but also in the kidney, and increased glycogenolysis in liver and muscle.8,9 In addition, the inhibitory effect of insulin on glucagon secretion is abolished and plasma glucagon levels increase. The increase of glucagon aggravates hyperglycemia by enhancing gluconeogenesis and glycogenolysis. In parallel, the increased concentrations of the other counter-regulatory hormones enhance further gluconeogenesis. In addition to increased gluconeogenesis, in DKA there is excess production of substances which are used as a substrate for endogenous glucose production. Thus, the amino acids glutamine and alanine increase because of enhanced proteolysis and reduced protein synthesis.8,9
Hyperglycemia-induced osmotic diuresis leads to dehydration, hyperosmolality, electrolyte loss (Na+, K +, Mg 2 +, PO 4 3+, Cl−, and Ca+), and eventually decline in glomerular filtration rate. With decline in renal function, glucosuria diminishes and hyperglycemia worsens. Dehydration results in augmentation of plasma osmolality, which results in water movement out of the cells to the extracellular space. Osmotic diuresis caused by hyperglycemia results in loss of sodium in urine; in addition, the excess of glucagon aggravates hyponatremia because it inhibits reabsorption of sodium in the kidneys. With impaired insulin action and hyperosmolality, utilization of potassium by skeletal muscles is markedly decreased leading to intracellular potassium deficiency. Potassium is also lost due to osmotic diuresis. In addition, metabolic acidosis leads to extracellular movement of potassium in exchange for H+, which may be lost in vomit or urine. Moreover, potassium transport is reinforced by protein catabolism due to insulin depletion. Therefore, patients with DKA may present initially with low, normal, or even high serum potassium levels. Nevertheless, a normal serum potassium level in DKA indicates a large body potassium deficit and institution of insulin therapy will lead to future hypokalemia.8,9
The grade of hyperglycemia in DKA varies but rarely exceeds 800 mg/dl (44.4 mmol/L). On the contrary, in HHS, hyperglycemia is usually greater and plasma glucose may exceed 1000 mg/dl (55 mmol/L).8
Ketonemia and metabolic acidosis
In DKA, insulin deficiency and increased levels of catabolic hormones (particularly catecholamines) promote breakdown of adipose tissue triglycerides (lipolysis). Concurrently, re-esterification of free fatty acids (FFAs) to triglycerides in adipose tissue is impaired by insulin deficiency. This combination results in the release into the circulation of large quantities of FFAs, which via the portal vein reach the liver. There, in the absence of insulin, FFAs are not converted to triglycerides as normally happens, and they are used, after they have entered the mitochondria, for the production of ketones (or ketone bodies), a procedure facilitated by the elevated glucagon levels.10 Thus, liver is the site for ketone formation.
The first ketone body produced is acetoacetic acid, which then is reduced to either beta-hydroxy-butyrate (beta-OHB) or acetone.6,9 beta-hydroxy-butyrate is the most abundant ketone (75%) to accumulate in blood in DKA. With the exception of acetone, ketone bodies are strong organic acids that dissociate fully at physiological pH, generating equimolar amounts of H+and ketoanions. The rapid increase in plasma H+ concentration outstrips the buffering capacity of the body fluids and tissues and metabolic acidosis develops. 6,9
Elimination of ketone bodies (ketolysis) from the body occurs in the mitochondria of organs that can use ketone bodies as an alternative energy source. Skeletal muscle is the main tissue that contributes to ketolysis. Some ketone bodies are eliminated in urine. The anionic charge of ketones leads to excretion of positively charged ions like sodium, potassium, calcium, and magnesium in urine, compounding the loss of water and electrolytes caused by glucosuria. Acetone is excreted via the lungs and produces the characteristic smell of the breath (like nail-varnish remover) in patients with DKA. 10
The cardinal manifestations of DKA are increasing polydipsia and polyuria, generalized weakness, and altered mental status. In the case of newly-diagnosed Type 1 diabetes, variable but rapid weight loss occurs. Symptoms usually develop over several days to weeks.1,6,9,10
Deep and rapid respiration (Kussmaul respiration) is the result of metabolic acidosis. Signs of dehydration and hypovolemia such as hypotension, orthostatic hypotension, tachycardia, poor skin turgor, and dry mucous membranes are often found. Decreased skin turgor suggests 5% dehydration. An orthostatic change in pulse alone suggests a 10% loss of extravascular fluid volume, whereas an orthostatic change in pulse and blood pressure (increase of 15 beats/min and decrease of 10 mmHg) suggests a 15–20% fluid deficit. Supine hypotension indicates either severe dehydration (fluid loss > 20%) or underlying sepsis.6,10
Nausea, vomiting, and abdominal pain may be present in DKA. Generalized abdominal pain is more common in young patients with severe acidosis and can mimic a surgical emergency (pseudoperitonitis). Abdominal pain has been associated with acidosis and resolves with treatment. A succussion splash may be evident on examination due to gastric stasis. 6,10
Some impairment in mental status is common in DKA, although coma occurs in only 10% of patients. Cerebral edema must always be considered in patients whose consciousness level declines during treatment, although subclinical cerebral edema may be present in DKA before initiation of treatment.8,10
Acidosis induces peripheral vasodilation, which in combination with hypotension may lead to hypothermia and mask infection. In such cases the rectal temperature should be taken. Obtaining a history and performing an examination to diagnose precipitating causes are important.
The tests that should be included in the initial laboratory investigation when diabetic ketoacidosis is suspected are shown in Box 1.2 .6 As shown in Table 1.1 , arterial pH is low depending on the severity of acidosis. In severe DKA pH values in the range of 6.7–6.8 have been observed.
DKA is a high anion gap metabolic acidosis. The anion gap is calculated using the formula: (Na+) −[(Cl−) + (HCO3 −)]
The normal value of the gap is 12 (+3) mEq/L. The anion gap should be corrected by the degree of hypoalbuminemia (add 2.5 mEq/L to the calculated anion gap for every 1.0 g/dl [10 g/L] decrease in serum albumin levels less than 4.5 g/dl [45 g/L]). The severity of acidosis depends on the rate of formation of ketone bodies, the duration for which they have been produced (patients who immediately attend medical treatment have more benign acidosis), and their excretion rate in urine (patients with near normal renal function have the ability to increase H+excretion, thereby reducing the severity of acidosis). An anion gap greater than 12 mEq/L suggests anion gap acidosis, while a plasma bicarbonate level greater than 18 mEq/L rules out metabolic acidosis. Arterial PO2 concentration is increased and PCO2 is diminished in patients with normal respiratory function as a result of compensatory hyperventilation.6,8,10
Detection of ketone bodies in either serum or urine is usually performed via specific dipsticks that rely on the nitroprusside reaction, which colors the stick purple-violet. It should be noted that these sticks are essentially specific for acetoacetate; they do not react with beta-OHB and react only weakly with acetone. During treatment of DKA, 3-OHB is converted to acetoacetate; therefore, nitroprusside-based tests may give the mistaken impression that DKA is either worsening or not resolving. In addition, the test can give false negative results in patients being treated with agents containing sulfhydryl groups (for example captopril) and false positive results if the dipsticks have been exposed to air for a long time. 6,8,10
In recent years most biochemical laboratories have measured serum beta-OHB directly by spectrophotometry, thus ruling out false results obtained by blood or urine strips. Moreover, some newer glucose meters can measure beta-OHB in capillary blood using an electrochemical method with specific strips. The normal level of beta-OHB in serum or in capillary blood is less than 0.5 mmol/L; in DKA values more than 1.0 mmol/L are usually found. Determination of serum or capillary beta-OHB levels has a higher sensitivity and specificity than determination of urine ketone bodies for the diagnosis of DKA.16 As mentioned above, beta-OHB is an early and abundant ketoacid indicative of ketosis. Acetoacetate (determined by the nitroprusside method) may be negative in the blood in early DKA.
DKA is characterized by a significant loss of water and electrolytes. This is a result of osmotic diuresis due to glycosuria as well as ketonuria. Despite the contribution of ketonuria, the degree of dehydration in DKA is usually lower than in HHS because the latter arises more gradually and insidiously. Other factors also may contribute to dehydration, such as nausea, vomiting, use of diuretics, and fever. 6,8,10
Phosphorus levels in plasma are usually normal or increased. However, as in the case with potassium, the total body phosphorus deficit is large as a result of shift from the intracellular to the extracellular compartment and loss in urine.10
Most patients with DKA have leukocytosis with a left shift. This is due to dehydration and stress response to ketonemia and hyper-glycemia and does not necessarily suggest infection. However, a white cell count greater than 25,000/μl warrants a comprehensive search for infection. Increased hematocrit levels are found in most cases of DKA as a result of dehydration.8
Effective serum osmolality can be measured directly in the laboratory or derived from the following formula:
2 ×[measured Na+ (mEq/L)]+ glucose (mg/dl)/18 = mOsm/kg
2 ×[measured Na+ (mEq/L or mmol/L)]+ glucose(mmol/L) = mOsm/kg
The normal range is 285–295 mOsm/kg. The level of consciousness correlates more closely with serum osmolality than with pH. Values more than 340 mOsm/kg suggest great fluid loss and are associated with altered consciousness level (stupor or coma). However, such high levels are not usual in DKA and are more often seen in HHS. On the other hand, serum osmolality levels less than 320 mOsm/kg warrant further evaluation for coma from causes other than DKA.9,14
Serum amylase and lipase levels may be increased in 16% and 25% of cases, respectively, in DKA in the absence of acute pancreatitis. 17,18 The cause of this elevation is not known. Although serum lipase measurement is more specific for the diagnosis of pancreatitis, this is not true in DKA, and elevations of either amylase or lipase to more than three times normal do not confirm the diagnosis of pancreatitis in this situation. However, it should be noted that coexisting acute pancreatitis may be present in 10–15% of patients with DKA. Serum creatinine may be falsely elevated because of acetoacetate interference with the colorimetric creatinine assay. 10
Determination of HbA1c is indicative of the degree of diabetes control in the previous 2–3 months.
- Ioannidis I. Diabetic coma. In: Katsilambros N, Diakoumopoulou E, Ioannidis I, Liatis S, Makrilakis K, Tentolouris N, Tsapogas P (ed), Diabetic ketoacidosis in adults 31 Diabetes in Clinical Practice, Questions and Answers from Case Studies, West Sussex, England: John Wiley & Sons Ltd, 2006: 81 – 91.
- Umpierrez GE, Smiley D , Kitabchi AE . Narrative review: ketosis – prone type 2 diabetes mellitus . Ann Intern Med 2006 ; 144 : 350 – 7.
- Faich GA , Fishbein HA , Ellis SE . The epidemiology of diabetic acidosis: a population – based study Am J Epidemiol 1983 ; 117 : 551 – 8.
- Katsilambros N. Epidemiology of acute manifestations and complications . In: Williams R , Papoz L , Fuller J (ed), Diabetes in Europe, A Monograph on Diabetes Epidemiology in Europe produced as part of the ‘ Eurodiab ‘ Concerted Action Programme of the European Community , London, UK : John Libbey & Company Ltd , 1994 : 39 – 209.
- Ellemann K , Soerensen JN , Pedersen L , Edsberg B , Andersen O . Epidemiology and treatment of diabetic ketoacidosis in a community population . Diabetes Care 1984 ; 7 : 528 – 32.
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- Kitabchi AE , Umpierrez GE , Murphy MB , Barrett EJ , Kreisberg RA , Malone JI , Wall BM . Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001: 24 : 131 – 53.
- Kitabchi AE , Umpierrez GE , Miles JM , et al. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association . Diabetes Care 2009; 32: 1335 –43.
- Krentz AJ , Nattrass M . Acute metabolic complications of diabetes: diabetic ketoacidosis, hyperosmolar non – ketotic hyperglycemia and lacticacidosis . In: Pickup JC , Williams G (ed), Textbook of Diabetes Mellitus , 3 rd edn , Oxford, UK : Blackwell Publishing , 2003 : 32 . 1 – 24.
- Maldonado M , Hampe CS , Gaur LK , et al. Ketosis – prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta – cell functional classifi cation, prospective analysis, and clinical outcomes . J Clin Endocrinol Metab 2003 ; 88 : 5090 – 8.
- Balasubramanyam A , Nalini R , Hampe CS , Maldonado M . Syndromes of ketosis – prone diabetes mellitus . Endocr Rev 2008 ; 29 : 292 – 302.
- Umpierrez , GE . Ketosis – prone type 2 diabetes: time to revise the classify cation of diabetes . Diabetes Care 2006 ; 29 : 2755 – 7.
- Newton CA , Raskin P . Diabetic ketoacidosis in Type 1 and Type 2 diabetes mellitus . Arch Intern Med 2004 ; 164 : 1925 – 31.
- Pinero – Pilona A , Raskin P . Idiopathic Type 1 diabetes . J Diabetes Complications 2001 ; 15 : 328 – 35 .
- Voulgari C , Tentolouris N . The performance of a glucose – ketone meter in the diagnosis of diabetic ketoacidosis in patients with Type 2 diabetes in the emergency room . Diabetes Technol Ther 2010 ; 12 : 529 – 35.
- Yadav D , Nair S , Norkus EP , Pitchumoni CS . Nonspecifi c hyperamylasemia and hyperlipasemia in diabetic ketoacidosis: incidence and correlation with biochemical abnormalities . Am J Gastroenterol 2000 ; 95 : 3123 – 8.
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- Fowler M . Hyperglycemic crisis in adults : Pathophysiology, presentation, pitfalls, and prevention . Clinical Diabetes 2009 ; 27 : 19 – 23.
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- Sacks HS , Shahshahani M , Kitabchi AE , Fisher JN , Young RT . Similar responsiveness of diabetic ketoacidosis to low – dose insulin by intramuscular injection and albumin – free infusion . Ann Intern Med 1979 ; 90 : 36 – 42.
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Nikolaos Katsilambros, MD, PhD, FACP
SCOPE Founding Fellow
Professor of Internal Medicine
Athens University Medical School
Evgenideion Hospital and Research Laboratory ‘Christeas Hall’
Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital
Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.
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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.
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