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Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults 
Author 
Abbas E Kitabchi, PhD, MD, FACP, MACE 
Section  Editor 
David M Nathan, MD 
Deputy  Editor 
Jean E Mulder, MD 
Disclosures 
All topics are updated as new evidence becomes available and our peer review process is complete. 
Literature review current through: Mar 2014. | This topic last updated: dic 20, 2013. 
INTRODUCTION — Diabetic  ketoacidosis  (DKA)  and  hyperosmolar  hyperglycemic  state  (HHS,  also  known  as 
nonketotic hyperglycemia) are two of the most serious acute complications of diabetes. They are part of the spectrum 
of hyperglycemia and each represents an extreme in the spectrum. 
The clinical features and diagnosis of DKA and  HHS  will be reviewed here. The epidemiology, pathogenesis,  and 
treatment of these disorders are discussed separately. (See "Epidemiology and pathogenesis of diabetic ketoacidosis 
and  hyperosmolar  hyperglycemic state" and "Treatment of  diabetic  ketoacidosis and hyperosmolar hyperglycemic 
state in adults".) 
DEFINITIONS — DKA and HHS differ clinically according to the presence of ketoacidosis and usually the degree of 
hyperglycemia [1-4]. The definitions proposed by the American Diabetes Association for DKA and HHS are shown in a 
table, along  with criteria for classification of DKA as mild, moderate, or severe, based on the patient's arterial pH, 
serum bicarbonate, and mental status (table 1). 
●In HHS, there  is little or  no ketoacid  accumulation, the  serum  glucose concentration frequently exceeds 
1000 mg/dL (56 mmol/L), the plasma osmolality may reach 380 mosmol/kg, and neurologic abnormalities are 
frequently present  (including  coma in  25 to  50 percent of  cases) [2,3,5]. Most  patients with HHS  have an 
admission pH >7.30, a serum bicarbonate  >20 meq/L, a serum glucose >600 mg/dL (33.3 mmol/L), and test 
negative for ketones in serum and urine, although mild ketonemia may be present. 
●DKA  is  characterized  by  the  triad  of  hyperglycemia,  anion  gap  metabolic  acidosis,  and  ketonemia.  Metabolic 
acidosis  is  often  the  major  finding.  The  serum  glucose  concentration  is  usually  greater  than 
500 mg/dL (27.8 mmol/L) and less than 800 mg/dL (44.4 mmol/L) [2,6]. However, serum glucose concentrations 
may exceed  900 mg/dL (50 mmol/L) in patients with DKA  who are comatose [7]. In certain instances, such as 
DKA  in the  setting of  starvation  or pregnancy, or  treatment  with insulin  prior  to arrival  in the  emergency 
department,  the  glucose  may  be  only  mildly  elevated.  Factors  that  contribute  to  the  lesser  degree  of 
hyperglycemia in DKA, compared with HHS, are discussed below. (See 'Serum glucose' below.) 
Significant overlap between DKA and HHS has been reported in more than one-third of patients [8-11]. The typical 
total body deficits of water and electrolytes in DKA and HHS are compared in a table (table 2). 
PRECIPITATING FACTORS — A precipitating event can usually be identified in patients with DKA or HHS (table 3) 
[1,2,5,8,9,11]. The most common events are infection (often pneumonia or urinary tract infection) and discontinuation 
of or inadequate insulin therapy [12]. Compromised water intake due to underlying medical conditions, particularly in 
elderly patients, can promote the development of severe dehydration and HHS [8,13,14]. 
Other conditions and factors associated with DKA and HHS include: 
●Acute major illnesses such as myocardial infarction, cerebrovascular accident, or pancreatitis. 
●New onset type 1 diabetes, in which DKA is a common presentation. 
●Drugs  that  affect  carbohydrate  metabolism,  including  glucocorticoids,  higher  dose  thiazide  diuretics, 
sympathomimetic agents (eg, dobutamine andterbutaline) [15], and second-generation antipsychotic agents [16]. 
●Cocaine use, which has been associated with recurrent DKA [17,18]. 
●Psychological problems associated with eating disorders and purposeful insulin omission, particularly in young 
patients with type 1 diabetes [19]. Factors that may lead to insulin omission in younger patients include fear of 
weight gain, fear of hypoglycemia, rebellion from authority, and the stress of chronic disease. 
●Poor compliance with the insulin regimen. Compliance issues, with substance abuse as a contributory factor, is 
the main cause of decompensated diabetes in urban African Americans [20]. 
●Malfunction  of  continuous  subcutaneous  insulin  infusion  devices  (CSII)  was  reported  in  the  early  1980s  [21]. 
However, the lack of more recent reports suggests that this risk may no longer be of concern [22]. 
CLINICAL PRESENTATION — DKA usually evolves rapidly, over a 24-hour period. In contrast, symptoms of HHS 
develop more insidiously with polyuria, polydipsia, and weight loss, often persisting for several days before hospital 
admission. 
The earliest symptoms of marked hyperglycemia are polyuria, polydipsia, and weight loss. As the degree or duration 
of hyperglycemia progresses, neurologic symptoms, including lethargy, focal signs, and obtundation, which can 
progress  to  coma  in  later  stages,  can  be  seen.  Neurological  symptoms  are  most  common  in  HHS,  while 
hyperventilation and abdominal pain are primarily limited to patients with DKA. 

Initial evaluation — Both DKA and HHS are medical emergencies that require prompt recognition and management. 
An initial history and rapid but careful physical examination should focus on: 
●Airway, breathing, and circulation (ABC) status 
●Mental status 
●Possible precipitating events (eg, source of infection, myocardial infarction) 
●Volume status 
Neurologic  symptoms  and  plasma  osmolality — Neurologic  deterioration  primarily  occurs  in  patients  with 
an effective plasma  osmolality  above  320  to  330 mosmol/kg [5,6,10,11].  Mental  obtundation  and  coma  are  more 
frequent in HHS than DKA because of the usually greater degree of hyperosmolality in HHS (table 1) [23]. In addition, 
some patients with HHS have focal neurologic signs  (hemiparesis  or hemianopsia) and/or seizures [23-27]. Mental 
obtundation may occur in patients with DKA, who have lesser degrees of hyperosmolality, when severe acidosis is 
also present [28]. 
In the calculation  of  effective plasma  osmolality, the urea concentration is  not  taken into account  because  urea is 
freely permeable and its accumulation does not induce major changes in intracellular (including brain) volume or the 
osmotic gradient across the cell membrane [29]. 
The effective plasma osmolality (Posm, in mosmol/kg) can be estimated from the following equation: 
 Effective Posm =  [2  x  Na (meq/L)] +  [glucose (mg/dL) ÷  18] 
Where  Na  is  the  serum  sodium  concentration,  the  multiple  2  accounts  for  the  osmotic  contribution  of  the  anions 
accompanying  sodium  (primarily  chloride  and  bicarbonate),  and  18  is  a  conversion  factors  from  units 
of mg/dL into mmol/L. Where standard units are used, the following equation applies: 
 Effective Posm =  [2  x  Na (mmol/L)] +  glucose (mmol/L) 
Importance of osmotic diuresis — The rise in plasma osmolality in DKA and HHS is only in part due to the rise in 
serum glucose. The increase in plasma osmolality pulls water out of the cells, which reduces the plasma osmolality 
toward normal and lowers the serum sodium. The marked hyperosmolality seen in HHS is primarily due to the glucose 
osmotic diuresis that causes water loss in excess of sodium and potassium [2]. 
These principles and the importance of effective plasma osmolality in the development of neurologic symptoms are 
illustrated  by  observations  in  diabetic  patients  with  end-stage  renal  disease.  These  patients  can  develop  severe 
hyperglycemia, with serum glucose concentrations that can exceed 1000 to 1500mg/dL (56 to 83 mmol/L). However, 
because there is little or no osmotic diuresis, the rise in plasma osmolality is limited, hyponatremia is present, and 
there are few or no neurologic symptoms [30,31]. 
The  presence  of  stupor  or  coma  in  diabetic  patients  with  an  effective  plasma  osmolality  lower  than 
320 mosmol/kg demands immediate consideration of other causes of the mental status change. 
Abdominal pain  in  DKA — Patients  with DKA may present  with nausea,  vomiting, and  abdominal pain;  although 
more common in children, these symptoms can be seen in adults [32]. Abdominal pain is unusual in HHS. In a review 
of 189 consecutive episodes of DKA and 11 episodes of HHS, abdominal pain was reported in 46 percent of patients 
with DKA compared with none of the patients with HHS [33]. The presence of abdominal pain was associated with the 
severity of the metabolic acidosis (occurring in 86 and 13 percent of those  with a serum bicarbonate ≤5 and 
≥15 meq/L, respectively) but did not correlate with the severity of hyperglycemia or dehydration. 
Possible causes of abdominal pain include delayed gastric emptying and ileus induced by the metabolic acidosis and 
associated electrolyte abnormalities [11]. Other causes for abdominal pain should be sought when it occurs in the 
absence of severe metabolic acidosis and when it persists after the resolution of ketoacidosis. 
Physical examination — Signs of volume depletion are common in both DKA and HHS, including decreased skin 
turgor, dry axillae  and  oral  mucosa, low jugular  venous  pressure  and, if severe, hypotension. Neurologic  findings, 
noted  above,  also  may  be  seen,  particularly  in  patients  with  HHS.  (See 'Neurologic  symptoms  and  plasma 
osmolality' above and "Etiology, clinical manifestations, and diagnosis of volume depletion in adults".) 
Patients with DKA may have a fruity odor (due to exhaled acetone and similar to the odor of nail polish remover), and 
deep respirations reflecting the compensatory hyperventilation (called Kussmaul respirations). 
Fever is rare even in the presence of infection, because of peripheral vasoconstriction due to hypovolemia. 
LABORATORY FINDINGS — Hyperglycemia and hyperosmolality are the two primary laboratory findings in patients 
with DKA or HHS; patients with DKA also have a high anion gap metabolic acidosis. Most patients also have acute 
elevations in the blood urea nitrogen (BUN) and  serum creatinine  concentration, which reflect the reduction in 
glomerular filtration rate induced by hypovolemia. 
A  variety  of  additional  laboratory  tests  may  be  affected.  The  impact  of  hyperglycemia,  insulin  deficiency,  osmotic 
diuresis, and fluid intake in individual patients leads to variability in laboratory findings, depending upon the relative 
importance of these factors. 

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Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults Author Abbas E Kitabchi, PhD, MD, FACP, MACE Section Editor David M Nathan, MD Deputy Editor Jean E Mulder, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2014. | This topic last updated: dic 20, 2013. INTRODUCTION — Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also known as nonketotic hyperglycemia) are two of the most serious acute complications of diabetes. They are part of the spectrum of hyperglycemia and each represents an extreme in the spectrum. The clinical features and diagnosis of DKA and HHS will be reviewed here. The epidemiology, pathogenesis, and treatment of these disorders are discussed separately. (See "Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state" and "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults".) DEFINITIONS — DKA and HHS differ clinically according to the presence of ketoacidosis and usually the degree of hyperglycemia [1-4]. The definitions proposed by the American Diabetes Association for DKA and HHS are shown in a table, along with criteria for classification of DKA as mild, moderate, or severe, based on the patient's arterial pH, serum bicarbonate, and mental status (table 1). ●In HHS, there is little or no ketoaci ...
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